Reaction 04 08 2019 192415 PDF

SciFinder® Page 1
1. Single Step
Step Stages Notes Yield

1 Reactants: 1, Reagents: 1, Solvents: 1,
1.1 R:LiCl, S:Me2CO, overnight, rt → 65°C Steps: 1, Stages: 1
Transformation:
1. Formation of Alkyl Halides from
Sulfuric/ Sulfonic Acid Esters
Source
A halogen-containing optical active 2-
carbonyl-1,3-oxazine compound, its
preparation method and application
Shi, Yian; Liu, Weigang; Pan,
Hongjie; Tian, Hua
Assignee Institute of Chemistry,
Chinese Academy of Sciences, Peop.
Rep. China
2015
Patent Information
Nov 04, 2015
CN 105017172
A
Number of Steps
1
CASREACT ®: Copyright © 2019 American Chemical Society. All Rights Reserved. CASREACT contains reactions
from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations
database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006
John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced
under license. All Rights Reserved.
2. Single Step

SciFinder® Page 2
1.1 R:NaH, S:THF, S:DMF, 0°C; 20 min, rt 80%
Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C Transformations:
1.3 R:NH4Cl, S:H2O, rt 1. Alkylation at a Carbon Bearing an
Active Hydrogen
2. C-Alkylation of Ketones,
Aldehydes, Nitriles, and Carboxylic
Esters
Experimental Procedure
Malonate 11. To a solution of sodium hydride in a mixture of THF and DMF (1/1, 76 mL) at 0C,
dimethyl-malonate was added dropwise. The resulting mixture was stirred at room temperature 20
min then the mesylate 10 (2.49 g, 7.63 mmol) and potassium iodide (2.53 g, 15.27 mmol) were added.
The solution was stirred at 80 0C for 3 h. The mixture was quenched at room temperature with sat
NH4Cl (70 mL) and extracted with a mixture of Et2O and hexane (1/1, 3 × 70 mL). The organic layer
was dried over MgSO4 , the solvent was removed, and the residue was chromatographed on silica gel
with 20% Et2O in hexane yielded 11 (2.56 g, 80%). 1H NMR (300 MHz, CDCl3, δ ppm): 5.50-5.25 (2H,
m, CH=CH); 4.65 (1H, ABX, JBX=6Hz, JAX=6.5Hz, CHOTIPS); 3.75 (6H, s, CH3O); 3.50 (1H, ABX,
JAB=11Hz, JBX=6Hz, CHHCl); 3.40 (1H, t, J=7Hz, CHCO2Me); 3.35 (1H, ABX, JAB=11Hz, JAX=6.5Hz,
CHHCl); 2.15-2.05 (2H, m, CH2-CH=CH); 2.00-1.95 (2H, m, CH2CH); 1.10-0.85 (21H, m, TIPS). 13C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
17.84, 12.18. IR (film, ν cm-1): 2946, 2807, 1755, 1738, 1469, 1434, 1249. MS (M - C3H7)+ : 377. (M -
CH2Cl)+ : 371. HRMS calcd: 377.1551 (M - C3H7)+; found: 377.1556.
Reaction Protocol
Step 1
Procedure 1. Add dimethyl-malonate dropwise to a solution of sodium hydride in a mixture of THF and DMF (1/1,
76 mL) at 0 °C.
2. Stir the resulting mixture at room temperature for 20 minutes.
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Comparative Effects of Conjugated
and Deconjugated Isomeric Enones
on the Transannular Diels-Alder
Reaction
Caussanel, Franck; Deslongchamps,
Pierre; Dory, Yves L.
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Company/Organization
Laboratoire de Synthese Organique
and Laboratoire de Synthese
Supramoleculaire, Departement de
Chimie, Institut de Pharmacologie
Universite de Sherbrooke
Sherbrooke, Can. J1H 5N4
SciFinder® Page 3
Number of Steps
1
3. 9 Steps (Converging)
Sequence 1 | Sequence 2
3 Steps

1.1 R:1H-Imidazole, S:CH2Cl2, 0°C; 1 h, rt 93%
Steps: 1, Stages: 2
1.2 R:H2O
Ether 15. To the compound 14 (2.29 g, 6.17 mmol) in CH2Cl2 (40 mL), imidazole (1.05 g, 15.43 mmol)
and t-butyldimethylsilyl chloride (1.12 g, 7.4 mmol) were added at 0°C. After stirring for 1 h at room
temperature, water was added (40 mL), and the solution was extracted with CH2Cl2 (3 × 40 mL). The
organic layer was dried over MgSO4, the solvent was removed and the residue was chromatographed
on silica gel with 10% Et2O in hexane yielding 15 as an oil (2.65 g, 93%). 1H NMR (300 MHz, CDCl3,
δ ppm): 6.17 (1H, ABX, JAB=19Hz, JAX=1.5Hz, CH=CHSn); 6.05 (1H, ABX, JAB=19Hz, JBX=4Hz,
CH=CHSn); 4.20 (2H, ABX, JBX=4Hz, JAX1.5Hz, CH2 OTBDMS); 1.60-1.43 (6H, m, CH2Sn); 1.40-
1.25 (6H, m, CH2 CH2Sn); 1.00-0.75 (24H, m, CH3CH2CH2 CH2Sn, C(CH3)3); 0.05 (6H, s, CH3Si).
13C NMR (75 MHz, CDCl , δ ppm): 147.25, 126.77, 66.69, 28.94, 27.21, 25.92, 13.67, 9.36,-5.17. IR
3
(film, ν cm-1): 2928, 2855, 1463, 1361, 1253, 1093. MS (M - C4H9)+ : 405. HRMS calcd: 405.1636 (M -
C4H9)+; found: 405.1639.
Reaction Protocol
Sequence 1
Step 1
Procedure 1. Add an imidazole (1.05 g, 15.43 mmol) and t-butyldimethylsilyl chloride (1.12 g, 7.4 mmol) to the
stannane derivative (2.29 g) in CH2Cl2 (40 mL) at 0 °C.
2. Stir the reaction mixture for 1 hour at room temperature.
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[Reactant]

2 2.1 C:PdCl2(CH3CN)2, S:DMF, 3 h, rt Reactants: 2, Reagents: 1, Catalysts: 1, 80%
Solvents: 2, Steps: 1, Stages: 2
2.2 R:NH4Cl, S:H2O
General/Typical Procedure: To a solution of the alcohol 12 (0.82 g, 4.39 mmol) in N,N-
dimethylformamide (45 mL), the compound 15 (2.79 g, 5.75 mmol) was added and the mixture was
degassed. Bis-acetonitrile palladium-chloride (57 mg, 0.22 mmol) was added and the mixture was
degassed again. The solution was stirred for 3 h at room temperature, quenched with saturated NH4Cl
(50 mL) and extracted with a mixture of Et2O and hexane (1/1, 3 × 50 mL). The organic layer was
dried over MgSO4, the solvent was removed and the residue was chromatographed on silica gel with
20% Et2O in hexane. Diene 18. an oil (0.8 g, 80%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.55 (1H, dd,
J=15Hz, 11Hz, CH=CHCH=CH); 6.10 (1H, t, J=11Hz, CH=CHCH=CH); 5.80 (1H, dt, J=15Hz, 5Hz,
CH=CHCH=CH); 5.58 (1H, m, CH=CHCH=CH); 4.30 (2H, td, J=6Hz, 1Hz, CH2OH); 4.25 (2H, dd,
J=4.5Hz, 1.5Hz, CH2OTBDMS); 1.30-0.90 (9H, m, (CH3)3C); 0.05 (6H, s, CH3Si). 13C NMR (75 MHz,
CDCl3, δ ppm): 134.63, 129.85, 129.25, 124.08, 63.28, 58.61, 25.89, 18.37,-5.27. IR (film, ν cm-1):
3345, 2929, 2857, 1656, 1613, 1471. MS (M - C4H9)+ : 171; (M - H2O)+ : 210. HRMS calcd: 171.0841
(M - C4H9)+; found: 171.0846; calcd: 210.1440 (M - H2O)+; found: 210.1447.
Reaction Protocol
Sequence 1
Step 2
Procedure 1. Add the stannane derivative (2.79 g) to a solution of the alcohol derivative (4.39 mmol) in N,N-
dimethylformamide (45 mL).
2. Degas the mixture.
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3.1 R:MeSO2Cl, R:LiCl, R:s-Collidine, S:DMF, 3 h, 80%
Steps: 1, Stages: 2
0°C
3.2 R:H2O
General/Typical Procedure: To a solution of alcohol 18 (0.50 g, 2.2 mmol) in N,N-dimethylformamide
(20 mL) at 0°C were added 2,4,6-collidine (1.16 mL, 8.78 mmol) methanesulfonyle chloride (0.68 mL,
8.78 mmol) and dry lithium chloride (372 mg, 8.78 mmol). The solution was stirred at 0°C for 3 h and
water (20 mL) was added. The mixture was extracted with hexane and ether (1/1, 3 × 30 mL). The
organic layer was dried over MgSO4, the solvent was removed, and the residue was
chromatographed on silica gel with 20% Et2O in hexanes. Diene 19. as an oil (0.43 g, 80%). 1H NMR
(300 MHz, CDCl3, δ ppm): 6.55 (1H, dd, J=15Hz, 11Hz, CH=CHCH=CH); 6.10 (1H, t, J=11Hz,
CH=CHCH=CH); 5.90 (1H, dt, J=15Hz, 4.5Hz, CH=CHCH=CH); 5.60 (1H, dt, J=11Hz, 8Hz,
CH=CHCH=CH); 4.30 (2H, dd, J=4.5Hz, 1Hz, CH2 OTBDMS); 4.21 (2H, d, J=8Hz, CH2Cl); 1.30-0.90
(9H, m, (CH3)3C); 0.05 (6H, s, CH3Si). 13C NMR (75 MHz, CDCl3, δ ppm): 136.47, 132.27, 124.96,
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
C4H9)+ : 189; (M - Cl)+ : 211. HRMS calcd: 189.0502 (M - C4H)+; found: 189.0502.
Reaction Protocol
Sequence 1
Step 3
Procedure 1. Add 2,4,6-collidine (1.16 mL, 8.78 mmol), methanesulfonyle chloride (0.68 mL, 8.78 mmol) and dry
lithium chloride (372 mg, 8.78 mmol) to a solution of the alcohol derivative (2.2 mmol) in N,N-
dimethylformamide (20 mL) at 0 °C.
2. Stir the solution at 0 °C for 3 hours.
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6 Steps

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Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
1.3 R:NH4Cl, S:H2O, rt
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
SciFinder® Page 7
General/Typical Procedure: To a solution of sodium hydride (215 mg, 5.38 mmol) in N,N-
dimethylformamide and tetrahydrofuran (1/1, 40 mL) at 0°C, the compound 11 (2.16 g, 5.13 mmol)
was added dropwise via a cannula. The mixture was stirred at room temperature during 20 min,
cooled at 0°C and the diene 17 (1.22 g, 5.65 mmol) in tetrahydrofuran (5 mL) was added dropwise via
a cannula. The solution was stirred at room temperature for 17 h and quenched with sat. NH4Cl (40
mL). The mixture was extracted with hexane and ether (1/1, 3 × 30 mL). The organic layer was dried
over MgSO4, the solvent was removed, and the residue was chromatographed on silica gel with
toluene. Triene 21. as an oil (2.2 g, 96%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.50 (1H, dd, J=15Hz,
11Hz, CH=CHCH=CH); 6.10 (1H, t, J=11Hz, CH=CHCH=CH); 5.80 (1H, dt, J=15Hz, 5Hz,
CH=CHCH=CH); 5.50-5.30 (2H, m, CH=CHCH=CH, CH=CH); 5.20 (1H, dt, J=8Hz, 7.5Hz, CH=CH);
4.60 (1H, ABX, JAX=6.5Hz, JBX=6Hz, CHOTIPS); 4.20 (2H, d, J=5Hz, CH2OTBDMS); 3.70 (3H, s,
CH3O); 3.68 (3H, s, CH3O); 3.45 (1H, ABX, JAB=11Hz, JBX=6Hz, CHHCl); 3.35(1H, ABX, JAB=11Hz,
JAX=6.5Hz, CHHCl); 2.80 (2H, d, J=8Hz, CCH2 CH=CH); 2.00-1.90 (4H, m, CH2CH2); 1.10-0.90 (21H,
m, TIPS); 0.9 (9H, s, (CH3)3C); 0.05 (6H, s, CH3Si). 13C NMR (75 MHz, CDCl3, δ ppm): 171.35,
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
- C3H7)+ : 587. HRMS calcd: 587.2991 (M - C3H7)+; found: 587.2980.
Reaction Protocol
Sequence 2
Step 2
Procedure 1. Add dienophile precursor (2.16 g) dropwise to a solution of sodium hydride (215 mg, 5.38 mmol) in
N,N-dimethylformamide and tetrahydrofuran (1/1, 40 mL) via a cannula at 0 °C.
2. Stir the mixture at room temperature for 20 minutes.
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3 3.1 C:p-MeC6H4SO3H, S:MeOH, 2 h, rt Reactants: 1, Reagents: 1, Catalysts: 1, 95%
3.2 R:NaHCO3, S:H2O
SciFinder® Page 8
General/Typical Procedure: To a solution of THP ether 20 (2.68 g, 4.46 mmol) in methanol (50 mL),
para-toluene-sulfonic acid (42 mg, 0.23 mmol) was added. The mixture was stirred for 2 h at room
temperature, and quenched with NaHCO3 sat (30 mL). The methanol was removed in vacuo and
extracted with ether (3 × 45 mL). The organic layer was dried over MgSO4, the solvent was removed,
and the residue was chromatographed on silica gel with 20% Et2O in hexanes. Alcohol 27. as an oil
(1.71 g, 95%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.50 (1H, dd, J=15Hz, 11Hz, CH=CHCH=CH); 6.10
(1H, t, J=11Hz, CH=CHCH=CH); 5.85 (1H, dt, J=15Hz, 6Hz, CH=CHCH=CH); 5.45-5.20 (3H, m,
CH=CHCH=CH, CH=CH); 4.60 (1H, ABX, JAX=6.5Hz, JBX=6Hz , CHOTIPS); 4.20 (2H, td, J=5Hz,
1Hz, CH2OH); 3.70 (6H, s, CH3O); 3.50 (1H, ABX, JAB=11Hz, JBX=6Hz, CHHCl); 3.35 (1H, ABX,
JAB=11Hz, JAX=6.5Hz, CHHCl); 2.80 (2H, d, J=7Hz, CCH2CH=CH); 2.00-1.85 (4H, m, CH2 CH2);
1.10-0.90 (21H, m, TIPS). 13C NMR (75 MHz, CDCl3, δ ppm): 171.38, 133.91, 131.52, 131.35,
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
cm-1): 3444, 2950, 2867, 1738, 1667, 1455. MS (M - C3H7)+ : 473. HRMS calcd: 473.2126 (M -
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
Procedure 1. Add para-toluene-sulfonic acid (42 mg, 0.23 mmol) to a solution of the THP ether derivative (2.68 g)
in methanol (50 mL).
2. Stir the mixture for 2 hours at room temperature.
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4.1 R:Cl3CC(=O)CCl3, R:PPh3, S:THF, 5 min, - 98%
Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
SciFinder® Page 9
General/Typical Procedure: To a solution of alcohol 22 (1.73 g, 3.34 mmol) in tetrahydrofuran (59 mL)
at -20°C were added triphenylphosphine (1.75 g, 6.64 mmol) and hexachloroacetone (0.76 mL, 5
mmol). After 5 min, the solution was quenched with sat. NH4Cl (50 mL) and extracted with ether (3 ×
40 mL). The organic layer was dried over MgSO4, the solvent was removed and the residue was
chromatographed on silica gel with 20% Et2O in hexane. Chloride 28. as an oil (1.68 g, 98%). 1H
NMR (300 MHz, CDCl3, δ ppm): 6.55 (1H, dd, J=15Hz, 11Hz, CH=CHCH=CH); 6.10 (1H, t, J=11Hz,
CH=CHCH=CH); 5.85 (1H, dt, J=15Hz, 7Hz, CH=CHCH=CH); 5.50-5.30 (3H, m, CH=CHCH=CH,
CH=CH); 4.60 (1H, ABX, JAX=6.5Hz, JBX=6Hz, CHOTIPS); 4.10 (2H, d, J=7Hz, CH=CHCH2Cl); 3.70
(6H, s, CH3O); 3.50 (1H, ABX, JAB=11Hz, JBX=6Hz, CHHCl); 3.35 (1H, ABX, JAB=11Hz, JAX=6.5Hz,
CHHCl); 2.80 (2H, d, J=8Hz, CCH2CHCH); 2.00-1.80 (4H, m, CH2 CH2); 1.10-0.90 (21H, m, TIPS).
13C NMR (75 MHz, CDCl , δ ppm): 171.23, 131.57, 130.64, 130.50, 129.90, 128.64, 126.44, 69.09,
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
1654, 1458, 1201. MS (M - C3H7)+ : 491. HRMS calcd: 491.1787 (M - C3H7)+; found: 491.1778.
Reaction Protocol
Sequence 2
Step 4
Procedure 1. Add triphenylphosphine (1.75 g, 6.64 mmol) and hexachloroacetone (0.76 mL, 5 mmol) to a
solution of the alcohol derivative (1.73 g) in tetrahydrofuran (59 mL) at -20 °C.
2. After 5 minutes, quench the solution with saturated NH4Cl (50 mL).
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Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
SciFinder® Page 10
General/Typical Procedure: To a solution of NaH (267 mg, 6.67mmol) in N,N-dimethylformamide and
tetrahydrofuran (1/1, 65 mL) at 0°C was added dropwise the dimethylmalonate (0.76 mL, 6.68 mmol).
The mixture was stirred at room temperature during 20 min and a solution of the allyl chloride 23 (1.78
g, 3.34 mmol) and potassium iodide (1.1 g, 6.67 mmol) in tetrahydrofuran (5 mL) was added dropwise
at 0°C. The mixture was stirred at room temperature for 2h, quenched with sat. NH4Cl (50 mL) and
extracted with ether and hexane (1/1, 3 × 50 mL). The organic layer was dried over MgSO4, the
solvent was removed, and the residue was chromatographed on silica gel with 20% Et2O in hexane.
Substituted malonate 29. as an oil (1.41 g, 71%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.35 (1H, dd,
CH=CHCH=CH); 5.50-5.30 (2H, m, CH=CH); 5.20 (1H, br q, J=7.5Hz, CH=CH-CH=CH); 4.60 (1H,
ABX, JAX=6.5Hz, JBX=6Hz, CHOTIPS); 3.75 (6H, s, CH3O); 3.70 (6H, s, CH3O); 3.50 (1H, ABX,
JAB=11Hz, JBX=6Hz, CHHCl); 3.45 (1H, t, J=7.5Hz, CH(CO2CH3)2); 3.35 (1H, ABX, JAB=11Hz,
JAX=6.5Hz, CHHCl); 2.80 (2H, d, J=8Hz, CCH2CH=CH); 2.70 (2H, t, J=7.5Hz, CH2CH(CO2Me)2);
2.00-1.90 (4H, m, CH2CH2); 1.05 (21H, m, TIPS). 13C NMR (75 MHz, CDCl3, δ ppm): 171.34, 169.10,
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
587. HRMS calcd: 587.2443 (M - C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
Procedure 1. Add dimethylmalonate (0.76 mL, 6.68 mmol) dropwise to a solution of NaH (267 mg, 6.67 mmol) in
N,N-dimethylformamide and tetrahydrofuran (1/1, 65 mL) at 0 °C.
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
SciFinder® Page 11
General/Typical Procedure: To a solution of silyl ether 24 (0.69 g, 1.1 mmol) in tetrahydrofuran (12
mL) at -20°C was added 1 M tetra-n-butylammonium fluoride (2.75 mL, 2.75 mmol). The solution was
stirred at -20°C during 2 h. The solution was quenched with sat. NH4Cl (20 mL) and extracted with
ether (3 × 20 mL). The organic layer was dried over MgSO4, the solvent was removed and the residue
was chromatographed on silica gel with 40% Et2O in hexane. Chlorohydrine 30. as an oil (0.44 g,
84%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.35 (1H, dd, J=15Hz, 11Hz, CH=CHCH=CH); 6.05 (1H, t,
J=11Hz, CH=CHCH=CH); 5.65 (1H, dt, J=15Hz, 7Hz, CH=CHCH=CH); 5.50 (1H, m, CH=CHCH=CH);
5.45 (1H, dd, J=11Hz, 8Hz, CH=CH); 5.15 (1H, dt, J=11Hz, 7.5Hz, CH=CH); 4.55 (1H, m, CHOH);
3.70 (6H, s, OCH3); 3.68 (6H, s, OCH3); 3.50 (2H, m, CH2Cl); 3.45 (1H, t, J=7.5Hz, CH(CO2Me)2);
2.80 (2H, d, J=7.5Hz, CCH2CH=CH); 2.70 (2H, t, J=7Hz, CH2 CH(CO2Me)2); 2.11-1.90 (4H, m, CH2
CH2). 13C NMR (75 MHz, CDCl3, δ ppm): 171.40, 169.13, 133.07, 131.57, 130.93, 129.02, 127.65,
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
3011, 2954, 2846, 1733, 1435. MS (M - OCH3)+ : 443; (M - Cl)+ : 439. HRMS calcd: 443.1473 (M -
OCH3)+; found: 443.1465.
Reaction Protocol
Sequence 2
Step 6
Procedure 1. Add 1M tetra-n-butylammonium fluoride (2.75 mL, 2.75 mmol) to a solution of the silyl ether
derivative (1.1 mmol) in tetrahydrofuran (12 mL) at -20 °C.
2. Stir the solution at -20 °C for 2 hours.
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Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
9
SciFinder® Page 12
3 Steps

1 1.1 C:p-MeC6H4SO3H, S:CH2Cl2, overnight, rt first stage in the dark, Reactants: 2, 95%
Reagents: 1, Catalysts: 1, Solvents: 2,
1.2 R:NaHCO3, S:H2O Steps: 1, Stages: 2
Ether 13. To a solution of the iodoalcohol 12 (1.32 g, 7.16 mmol) in CH2Cl2 (50 mL), were added p-
toluenesulfonic acid (181 mg, 0.72 mmol) and 3,4-dihydro-2H-pyran (1 mL, 10.97 mmol) at room
temperature. The solution was stirred overnight in the dark. The mixture was quenched with saturated
aqueous NaHCO3 (50 mL) and extracted with Et2O (3 × 50 mL). The organic layer was dried over
MgSO4, the solvent was removed, and the residue was chromatographed on silica gel with 20% Et2O
in hexanes to give 13 (1.82 g, 95%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.48 (1H, ddd, J=8Hz, 6Hz,
5Hz, CH=CHI); 6.40 (1H, dt, J=8Hz, 1.5Hz, CH=CHI); 4.65 (1H, m, OCHO); 4.28 (1H, complex
system AB appearing as a ddd, JAB=13.5Hz, J=5Hz, J=1.5Hz, CHHOTHP); 4.12 (1H, complex system
AB appearing as a ddd, JAB=13.5Hz, J=6Hz, J=1.5Hz, CHHOTHP); 3.90-3.85 (1H, m, CHHO THP);
3.55-3.50 (1H, m, CHHO THP); 1.85-1.5 (6H, m, CH2 THP). 13C NMR (75 MHz, CDCl3, δ ppm):
138.29, 98.42, 82.79, 69.99, 62.2, 30.49, 25.36, 19.34. IR (film, ν cm-1): 2945, 2865, 1612, 1447. MS
(M - OTHP)+ : 167 HRMS calcd: 166.9358 (M - OTHP)+; found: 166.9363.
Reaction Protocol
Sequence 1
Step 1
Procedure 1. Add p-toluenesulfonic acid (181 mg, 0.72 mmol) and 3,4-dihydro-2H-pyran (1 mL, 10.97 mmol) to a
solution of the iodoalcohol derivative (1.32 g) in CH2Cl2 (50 mL) at room temperature.
2. Stir the solution overnight in the dark.
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SciFinder® Page 13
[Reactant]

2 2.1 C:PdCl2(CH3CN)2, S:THF, S:DMF, 3 h, rt Reactants: 2, Reagents: 1, Catalysts: 1, 85%
2.2 R:NH4Cl, S:H2O
20% Et2O in hexane. Compound no 16: yield: 85%.
Reaction Protocol
Sequence 1
Step 2
2. Degas the reaction mixture.
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Steps: 1, Stages: 2
0°C
3.2 R:H2O
chromatographed on silica gel with 20% Et2O in hexanes. Compound no 17: yield: 80%.
SciFinder® Page 14
Reaction Protocol
Sequence 1
Step 3
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6 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
SciFinder® Page 15
Sequence 2
Step 1
76 mL) at 0 °C.
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Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
toluene. triene 20. as an oil (2.68 g, 87%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.40 (1H, dd, J=15Hz,
11Hz, CH=CHCH=CH); 6.05 (1H, t, J=11Hz, CH=CHCH=CH); 5.60-5.40 (4H, m, CH=CHCH=CH,
CHCH); 4.65-4.60 (2H, m, CHOTIPS, OCHO); 4.30 (1H, complex AB, JAB=13Hz, J=6.5Hz,
CHHOTHP); 4.20 (1H, complex AB, JAB=13Hz, J=7Hz, CHHOTHP); 3.90-3.80 (1H, m, CHHO THP);
3.75 (6H, s, CH3O); 3.55-3.50 (2H, m, CHHCl, CHHO THP); 3.35 (1H, ABX, JAB=11Hz, JAX=6.5Hz,
CHHCl); 2.70 (2H, d, J=7.5Hz, CCH2 CH=CHCH=CH); 2.00-1.45 (10H, m, CH2); 1.10-0.90 (21H, m,
TIPS). 13C NMR (75 MHz, CDCl3, δ ppm): 171.22, 131.45, 130.82, 130.60, 129.13, 126.61, 97.72,
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
12.22. IR (film, ν cm-1): 2947, 2867, 1732, 1655, 1454, 1441. MS (M - C3H7)+ : 557. HRMS calcd:
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
SciFinder® Page 16
Sequence 2
Step 2
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3.2 R:NaHCO3, S:H2O
(1.72 g, 75%). 1H NMR (300 MHz, CDCl3, δ ppm): 6.35 (1H, dd, J=14.5Hz, 11Hz, CH=CHCH=CH);
6.00 (1H, t, J=11Hz, CH=CHCH=CH); 5.60-5.30 (4H, m, CH=CHCH=CH, CH=CH); 4.60 (1H, ABX,
JAX=6.5Hz, JBX=6Hz, CHOTIPS); 4.30 (2H, dd, J=7Hz, 1Hz, CH2OH); 3.70 (6H, s, CH3O); 3.50 (1H,
ABX, JAB=11Hz, JBX=6Hz, CHHCl); 3.35 (1H, ABX, JAB=11Hz, JAX=6.5Hz, CHHCl); 2.70 (2H, d,
J=7.5Hz, CCH2CH=CH); 2.00-1.85 (4H, m, CH2 CH2); 1.10-0.90 (21H, m, TIPS). 13C NMR (75 MHz,
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
(M - C3H7)+ : 473. HRMS calcd: 473.2126 (M - C3H7)+; found: 473.2119.
Reaction Protocol
SciFinder® Page 17
Sequence 2
Step 3
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Experimental
Data
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
CH=CHCH=CH); 5.65 (1H, dt, J=15Hz, 7.5Hz, CH=CHCH=CH); 5.55 (1H, dt, J=10.5Hz, 8Hz,
CH=CHCH=CH); 5.50-5.30 (2H, m, CH=CH); 4.60 (1H, ABX, JAX=6.5Hz, JBX=6Hz, CHOTIPS); 4.15
(2H, d, J=8Hz, CH2Cl); 3.70 (6H, s, CH3O); 3.50 (1H, ABX, JAB=11Hz, JBX=6Hz, CHCHHCl); 3.35
(1H, ABX, JAB=11Hz, JAX=6.5Hz, CHCHHCl); 2.75 (2H, d, J=7.5Hz, CCH2CH=CH); 2.00-1.85 (4H, m,
CH2CH2); 1.10-0.90 (21H, m, TIPS). 13C NMR (75 MHz, CDCl3, δ ppm): 171.20, 132.29, 131.57,
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
IR (film, ν cm-1): 2949, 2867, 1785, 1731, 1651, 1453, 1201. MS (M - C3H7)+ : 491. HRMS calcd:
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
SciFinder® Page 18
Sequence 2
Step 4
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Data
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[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
J=15Hz, 11Hz, CH=CHCH=CH); 6.00 (1H, t, J=11Hz, CH=CHCH=CH); 5.65-5.25 (4H, m,
CH=CHCH=CH, CH=CH); 4.60 (1H, ABX, JAX= 6.5Hz, JBX=6Hz, CHOTIPS); 3.72 (12H, s, CH3O);
3.50 (1H, ABX, JAB=11Hz, JBX=6Hz, CHHCl); 3.40 (1H, t, J=7.5Hz, CH(CO2CH3)2); 3.35 (1H, ABX,
JAB=11Hz, JAX=6.5Hz, CHHCl); 2.70-2.60 (4H, m, CCH2 CH=CH); 2.00-1.80 (4H, m, CH2 CH2); 1.10-
0.90 (21H, m, TIPS. 13C NMR (75 MHz, CDCl3, δ ppm): 171.27, 169.13, 131.46, 130.80, 130.60,
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
12.23. IR (film, ν cm-1): 2951, 2867, 1731, 1435. MS (M - C3H7)+ : 587. HRMS calcd: 587.2443 (M -
C3H7)+; found: 587.2446.
Reaction Protocol
SciFinder® Page 19
Sequence 2
Step 5
2. Stir the reaction mixture at room temperature during 20 minutes.
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
J=11Hz, CH=CHCH=CH); 5.65-5.35 (3H, m, CH=CHCH=CH, CH=CH); 5.28 (1H, td, J=7.5Hz, 7Hz,
CH=CHCH=CH); 4.55 (1H, m, CHOH); 3.73 (12H, s, CH3O); 3.50 (2H, m, CH2Cl); 3.40 (1H, t,
J=7.5Hz, CH(CO2CH3)2); 2.80-2.70 (4H, m, CCH2 CH=CH); 2.20-1.90 (4H, m, CH2CH2). 13C NMR
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
1435. MS (M - OCH3)+ : 443; (M - Cl)+ : 439. HRMS calcd: 443.1473 (M - OCH3)+; found: 443.1465.
Reaction Protocol
SciFinder® Page 20
Sequence 2
Step 6
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Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
9
Single Step
SciFinder® Page 21

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Data
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7 Steps
SciFinder® Page 22

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
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Experimental
Data
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Steps: 1, Stages: 2
0°C
2.2 R:H2O
SciFinder® Page 23
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 2
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Data
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[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
SciFinder® Page 24
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 3
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Data
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4.2 R:NaHCO3, S:H2O
SciFinder® Page 25
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 4
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Data
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Steps: 1, Stages: 2
20°C
5.2 R:NH4Cl, S:H2O
SciFinder® Page 26
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 5
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Data
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[Reactant]

Steps: 1, Stages: 3
6.2 R:KI, S:THF, 0°C; 2 h, rt
6.3 R:NH4Cl, S:H2O
SciFinder® Page 27
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 6
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Data
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7.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
7.2 R:NH4Cl, S:H2O
SciFinder® Page 28
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Sequence 2
Step 7
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Experimental
Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
8
SciFinder® Page 29
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 1
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Data
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SciFinder® Page 30
6 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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Data
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SciFinder® Page 31
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
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3
SciFinder® Page 32

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
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Data
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
SciFinder® Page 33
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 4
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Data
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[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
SciFinder® Page 34
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 5
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Data
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
SciFinder® Page 35
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Sequence 2
Step 6
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Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
SciFinder® Page 36
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Data
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SciFinder® Page 37
7 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
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Steps: 1, Stages: 2
0°C
2.2 R:H2O
SciFinder® Page 38
Reaction Protocol
Sequence 2
Step 2
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[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
SciFinder® Page 39
Sequence 2
Step 3
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Data
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4.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
SciFinder® Page 40
Sequence 2
Step 4
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Data
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Steps: 1, Stages: 2
20°C
5.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
SciFinder® Page 41
Sequence 2
Step 5
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Experimental
Data
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[Reactant]

Steps: 1, Stages: 3
6.2 R:KI, S:THF, 0°C; 2 h, rt
6.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
SciFinder® Page 42
Sequence 2
Step 6
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Data
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7.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
7.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
Reaction Protocol
SciFinder® Page 43
Sequence 2
Step 7
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Experimental
Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
8
Single Step
SciFinder® Page 44

Steps: 1, Stages: 2
0°C
1.2 R:H2O
Reaction Protocol
Sequence 1
Step 1
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6 Steps

SciFinder® Page 45
Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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Experimental
Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
SciFinder® Page 46
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
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Data
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 47
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
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Data
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
SciFinder® Page 48
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
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Experimental
Data
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[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
SciFinder® Page 49
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
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Data
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
SciFinder® Page 50
Reaction Protocol
Sequence 2
Step 6
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Experimental
Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
9. 6 Steps
1
SciFinder® Page 51

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
SciFinder® Page 52
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Step 2
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 53
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Step 3
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Data
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
SciFinder® Page 54
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Step 4
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Data
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[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
SciFinder® Page 55
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Step 5
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
SciFinder® Page 56
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Step 6
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Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
SciFinder® Page 57
10. 6 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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2
SciFinder® Page 58
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Step 2
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 59
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Step 3
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
SciFinder® Page 60
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Step 4
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Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
SciFinder® Page 61
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Step 5
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
Reaction Protocol
SciFinder® Page 62
Step 6
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Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
11. 3 Steps
1
SciFinder® Page 63

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
SciFinder® Page 64
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Step 2
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 65
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Step 3
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
3
SciFinder® Page 66
12. 3 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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2
SciFinder® Page 67
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Step 2
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 68
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Step 3
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
3
SciFinder® Page 69
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
Reaction Protocol
Sequence 1
Step 1
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3 Steps
SciFinder® Page 70

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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[Reactant]

SciFinder® Page 71
Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
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Data
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 72
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
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Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
4
SciFinder® Page 73
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 1
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SciFinder® Page 74
3 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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Data
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SciFinder® Page 75
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
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3
SciFinder® Page 76

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
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Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
SciFinder® Page 77
Number of Steps
4
3 Steps

138.29, 98.42, 82.79, 69.99, 62.2, 30.49, 25.36, 19.34. IR (film, ν cm-1): 2945, 2865, 1612, 1447. MS
Reaction Protocol
SciFinder® Page 78
Sequence 1
Step 1
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2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 2
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SciFinder® Page 79

Steps: 1, Stages: 2
0°C
3.2 R:H2O
Reaction Protocol
Sequence 1
Step 3
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7 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C

SciFinder® Page 80
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
SciFinder® Page 81
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
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Data
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3.2 R:NaHCO3, S:H2O
SciFinder® Page 82
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
SciFinder® Page 83
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
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[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
SciFinder® Page 84
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
SciFinder® Page 85
Reaction Protocol
Sequence 2
Step 6
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7.1 R:i-Pr2NH, R:Martin's reagent, S:CH2Cl2, 20 85%
Steps: 1, Stages: 2
min, rt
7.2 R:Na2S2O3, S:H2O
General/Typical Procedure: To a solution of chlorohydrine 25 (124 mg, 0.26 mmol) in
dichloromethane (6 mL) was added diisopropylamine (37 µL, 0.26 mmol) and Dess-Martin reagent
(382 mg, 0.78 mmol). The mixture was stirred at room temperature during 20 min. The solution was
quenched with 10% NaS2O3 (10 mL), extracted with dichloromethane (3 × 15 mL). The organic layer
was dried over MgSO4, the solvent was removed, and the residue was chromatographed on Florisil
(treated with Et3N) with 40% Et2O in hexane. Chloroketone 26. as an oil (104 mg, 85%). 1H NMR (300
MHz, CD2Cl2, δ ppm): 6.40 (1H, ddd, J=15Hz, 11Hz, 1Hz, CH=C HCH=CH); 6.35-6.20 (2H, m,
CH=CH); 6.00 (1H, t, J=11Hz, CH=CHCH=CH); 5.55 (1H, dt, J=15Hz, 8Hz, CH=CH-CH=CH); 5.30
(1H, dt, J=11Hz, 8Hz, CH=CHCH=CH); 4.15 (2H, s, CH2Cl); 3.70 (6H, s, OCH3); 3.68 (6H, s, OCH3);
3.40 (1H, t, J=7.5Hz, CH(CO2CH3)2); 2.75-2.70 (4H, m, CH=CHCH=CHCH2); 2.60-2.55 (2H, m,
CH=CHCH2); 2.00-1.95 (2H, m, CH=CHCH2 CH2). 13C NMR (75 MHz, CD2Cl2, δ ppm): 191.63,
171.09, 169.08, 150.02, 130.59, 129.11, 128.75, 125.73, 123.17, 57.44, 52.32, 51.42, 49.29, 35.92,
31.36, 27.02, 24.43. IR (film, ν cm-1): 3008, 2956, 2848, 1730, 1695, 1621, 1435. MS (M)+ : 472; (M -
HCl)+ : 436. HRMS calcd: 472.1500 (M)+; found: 472.1507; calcd: 436.1733 (M - HCl)+; found:
436.1739.
Reaction Protocol
SciFinder® Page 86
Sequence 2
Step 7
Procedure 1. Add diisopropylamine (37 µL, 0.26 mmol) and Dess-Martin reagent (382 mg, 0.78 mmol) to a
solution of the chlorohydrine derivative (124 mg) in dichloromethane (6 mL).
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Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
10
Single Step
SciFinder® Page 87

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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9 Steps
SciFinder® Page 88

Steps: 1, Stages: 2
1.2 R:H2O
3
C4H9)+; found: 405.1639.
Reaction Protocol
Sequence 2
Step 1
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SciFinder® Page 89
2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 2
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Data
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Steps: 1, Stages: 2
0°C
3.2 R:H2O
SciFinder® Page 90
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 3
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Data
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[Reactant]

Steps: 1, Stages: 3
4.2 S:THF, 0°C; 17 h, rt
4.3 R:NH4Cl, S:H2O
SciFinder® Page 91
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 4
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5.2 R:NaHCO3, S:H2O
SciFinder® Page 92
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 5
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Steps: 1, Stages: 2
20°C
6.2 R:NH4Cl, S:H2O
SciFinder® Page 93
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 6
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Steps: 1, Stages: 3
7.2 R:KI, S:THF, 0°C; 2 h, rt
7.3 R:NH4Cl, S:H2O
SciFinder® Page 94
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 7
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8.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
8.2 R:NH4Cl, S:H2O
SciFinder® Page 95
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Sequence 2
Step 8
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Steps: 1, Stages: 2
min, rt
SciFinder® Page 96
CH=CHCH=CH, COCH=CH); 6.05 (1H, t, J=11Hz, CH=CHCH=CH); 5.65 (1H, dt, J=15Hz, 7.5Hz,
CH=CHCH=CH); 5.25 (1H, br q, J=9Hz, COCH=CH); 4.25 (2H, s, CH2Cl); 3.71 (6H, s, OCH3); 3.70
(6H, s, OCH3); 3.45 (1H, t, J=7.5Hz, CH(CO2CH3)2); 2.80 (2H, d, J=8Hz, CCH2CH=CH); 2.75 (2H, t,
J=7.5Hz, CH2 CH(CO2Me)2); 2.58 (2H, m, COCH=CHCH2); 2.00-1.95 (2H, m, COCH=CHCH2 CH2).
13C NMR (75 MHz, CD Cl , δ ppm): 191.58, 171.15, 169.07, 150.07, 131.53, 130.81, 127.75, 123.76,
2 2
123.16, 57.25, 52.32, 51.50, 49.36, 41.13, 31.95, 31.28, 30.55, 24.55. IR (film, ν cm-1): 3008, 2956,
2848, 1730, 1695, 1621, 1435. MS (M)+ : 472; (M - HCl)+ : 436. HRMS calcd: 472.1500 (M)+; found:
472.1507; calcd: 436.1733 (M - HCl)+; found: 436.1739.
Reaction Protocol
Sequence 2
Step 9
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Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
10
SciFinder® Page 97
2 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 1
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Data
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SciFinder® Page 98

Steps: 1, Stages: 2
0°C
2.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 2
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7 Steps
1
SciFinder® Page 99

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
SciFinder® Page 100
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow

6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Sequence 2
Step 6
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Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
min, rt
2 2
123.16, 57.25, 52.32, 51.50, 49.36, 41.13, 31.95, 31.28, 30.55, 24.55. IR (film, ν cm-1): 3008, 2956,
472.1507; calcd: 436.1733 (M - HCl)+; found: 436.1739.
Reaction Protocol
Sequence 2
Step 7
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
9
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
View with
MethodsNow
7 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
3

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow

6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
min, rt
2 2
123.16, 57.25, 52.32, 51.50, 49.36, 41.13, 31.95, 31.28, 30.55, 24.55. IR (film, ν cm-1): 3008, 2956,
472.1507; calcd: 436.1733 (M - HCl)+; found: 436.1739.
Reaction Protocol
Sequence 2
Step 7
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
8
2 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 1
View more...
View with
MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
Reaction Protocol
Sequence 1
Step 2
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7 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow

6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
min, rt
171.09, 169.08, 150.02, 130.59, 129.11, 128.75, 125.73, 123.17, 57.44, 52.32, 51.42, 49.29, 35.92,
31.36, 27.02, 24.43. IR (film, ν cm-1): 3008, 2956, 2848, 1730, 1695, 1621, 1435. MS (M)+ : 472; (M -
436.1739.
Reaction Protocol
Sequence 2
Step 7
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
9
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
Reaction Protocol
Sequence 1
Step 1
View more...
View with
MethodsNow
7 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow

6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
min, rt
171.09, 169.08, 150.02, 130.59, 129.11, 128.75, 125.73, 123.17, 57.44, 52.32, 51.42, 49.29, 35.92,
31.36, 27.02, 24.43. IR (film, ν cm-1): 3008, 2956, 2848, 1730, 1695, 1621, 1435. MS (M)+ : 472; (M -
436.1739.
Reaction Protocol
Sequence 2
Step 7
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
8
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
5 Steps

138.29, 98.42, 82.79, 69.99, 62.2, 30.49, 25.36, 19.34. IR (film, ν cm-1): 2945, 2865, 1612, 1447. MS
Reaction Protocol
Sequence 2
Step 1
View more...

Experimental
Data
View with
MethodsNow
[Reactant]
2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 2
View more...
View with
MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
Reaction Protocol
Sequence 2
Step 3
View more...
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
4.2 S:THF, 0°C; 17 h, rt
4.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow

5.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
5 Steps

Steps: 1, Stages: 2
1.2 R:H2O
3
C4H9)+; found: 405.1639.
Reaction Protocol
Sequence 2
Step 1
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
4.2 S:THF, 0°C; 17 h, rt
4.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow

5.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
2 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 1
View more...
View with
MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
Reaction Protocol
Sequence 1
Step 2
View more...
View with
MethodsNow
3 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
2 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 2
View more...

Experimental
Data
View with
MethodsNow
3 Steps
1

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
25. 7 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Step 2
View more...

Experimental
Data
View with
MethodsNow
3

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Step 5
View more...

Experimental
Data
View with
MethodsNow

6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 84%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
123.67, 67.55, 57.14, 52.53, 52.54, 51.5, 49.16, 32.15, 31.98, 30.94, 22.93. IR (film, ν cm-1): 3522,
OCH3)+; found: 443.1465.
Reaction Protocol
Step 6
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
min, rt
2 2
123.16, 57.25, 52.32, 51.50, 49.36, 41.13, 31.95, 31.28, 30.55, 24.55. IR (film, ν cm-1): 3008, 2956,
472.1507; calcd: 436.1733 (M - HCl)+; found: 436.1739.
Reaction Protocol
Step 7
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Experimental
Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
26. 7 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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Experimental
Data
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2
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Step 2
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Experimental
Data
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3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Step 3
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Experimental
Data
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Step 4
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Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Step 5
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Experimental
Data
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6.1 R:Bu4N+ •F-, S:THF, 2 h, -20°C 80%
Steps: 1, Stages: 2
6.2 R:NH4Cl, S:H2O
(75 MHz, CDCl3, δ ppm): 171.30, 169.22, 132.92, 130.71, 129.08, 128.99, 128.62, 125.59, 67.59,
57.32, 52.53, 51.47, 51.35, 49.02, 36.34, 32.22, 27.06, 22.82. IR (film, ν cm-1): 2951, 2867, 1731,
Reaction Protocol
Step 6
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Experimental
Data
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Steps: 1, Stages: 2
min, rt
171.09, 169.08, 150.02, 130.59, 129.11, 128.75, 125.73, 123.17, 57.44, 52.32, 51.42, 49.29, 35.92,
31.36, 27.02, 24.43. IR (film, ν cm-1): 3008, 2956, 2848, 1730, 1695, 1621, 1435. MS (M)+ : 472; (M -
436.1739.
Reaction Protocol
Step 7
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Experimental
Data
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MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
27. 4 Steps
1

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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Experimental
Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Step 2
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Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Step 3
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Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Step 4
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Experimental
Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
4
28. 4 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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Experimental
Data
View with
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2
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Step 2
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Experimental
Data
View with
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3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Step 3
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Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Step 4
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Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
4
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
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6 Steps

138.29, 98.42, 82.79, 69.99, 62.2, 30.49, 25.36, 19.34. IR (film, ν cm-1): 2945, 2865, 1612, 1447. MS
Reaction Protocol
Sequence 2
Step 1
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Experimental
Data
View with
MethodsNow
[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 2
View more...
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MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
Reaction Protocol
Sequence 2
Step 3
View more...
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
4.2 S:THF, 0°C; 17 h, rt
4.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 4
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Experimental
Data
View with
MethodsNow

5.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
6.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Experimental
Data
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5 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
View more...
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MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
Reaction Protocol
Sequence 2
Step 2
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View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 3
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Experimental
Data
View with
MethodsNow

4.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
5.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Experimental
Data
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6 Steps

Steps: 1, Stages: 2
1.2 R:H2O
3
C4H9)+; found: 405.1639.
Reaction Protocol
Sequence 2
Step 1
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Experimental
Data
View with
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[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
4.2 S:THF, 0°C; 17 h, rt
4.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 4
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Experimental
Data
View with
MethodsNow

5.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 5
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Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
6.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Experimental
Data
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5 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
View more...

Experimental
Data
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2

Steps: 1, Stages: 2
0°C
2.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 3
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Experimental
Data
View with
MethodsNow

4.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
5.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
View with
MethodsNow
4 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
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3

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
Reaction Protocol
Sequence 1
Step 1
View more...
View with
MethodsNow
4 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
35. 2 Steps

1 reactant also recovered, prophetic
1.1 R: reaction, Reactants: 1, Reagents: 2,
R:Bu4N+ •F-, S:t-BuOH, 36 h, reflux
[Reactant]
2.1 R:NaOH, S:MeOH, S:H2O, 18 h, rt Steps: 1, Stages: 2
2.2 R:HCl, S:H2O, acidify
Source
Preparation of spiroimidazolone
derivatives for activating intracellular
cAMP response
Esaki, Tohru; Nishimura, Yoshikazu;
Isshiki, Yoshiaki; Okamoto, Naoki;
Furuta, Yoshiyuki; Mizutani, Akemi;
Ohta, Masateru; Lai, Wayne Wen;
Kotake, Tomoya
Assignee Chugai Seiyaku Kabushiki
Kaisha, Japan
2010
Patent Information
Nov 04, 2010
WO 2010126030
A1
Number of Steps
2
36. Single Step

1.1 R:POCl3, S:CH2Cl2, 5 h, reflux; reflux → rt 94%
Steps: 1, Stages: 2
1.2 R:NaHCO3, S:H2O, pH 7 Transformation:
Source
Process for preparation of loxoprofen
sodium
Zhang, Xingxian; Hu, Kebin; Ni,
Jiankun; Zhou, Dunfeng; Chen,
Wenlong; Yang, Ping; Chen, Zhifeng
Assignee Zhejiang Apeloa Medical
Technology Co., Ltd., Peop. Rep.
China
2009
Patent Information
Apr 22, 2009
CN 101412670
A
Number of Steps
1
37. 2 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Step 2
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
2
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
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MethodsNow
2 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
3
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Experimental
Data
View with
MethodsNow
3 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
4
3 Steps

Steps: 1, Stages: 2
1.2 R:H2O
3
C4H9)+; found: 405.1639.
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 2
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 3
View more...

Experimental
Data
View with
MethodsNow
2 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
3 Steps

138.29, 98.42, 82.79, 69.99, 62.2, 30.49, 25.36, 19.34. IR (film, ν cm-1): 2945, 2865, 1612, 1447. MS
Reaction Protocol
Sequence 1
Step 1
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Experimental
Data
View with
MethodsNow
[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 2
View more...
View with
MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
Reaction Protocol
Sequence 1
Step 3
View more...
View with
MethodsNow
5 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C

NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
8
3 Steps

Steps: 1, Stages: 2
1.2 R:H2O
3
C4H9)+; found: 405.1639.
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 2
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
3.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 3
View more...

Experimental
Data
View with
MethodsNow
5 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
8
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
6 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

4.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
5.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
6.2 R:KI, S:THF, 0°C; 2 h, rt
6.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
122.92, 63.15, 39.51, 25.89, 18.35,-5.27. IR (film, ν cm-1): 2955, 2857, 1651, 1613, 1471. MS (M -
Reaction Protocol
Sequence 1
Step 1
View more...

Experimental
Data
View with
MethodsNow
5 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
3

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
6 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
View more...
View with
MethodsNow

Steps: 1, Stages: 2
0°C
2.2 R:H2O
Reaction Protocol
Sequence 2
Step 2
View more...
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

4.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
5

Steps: 1, Stages: 2
20°C
5.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
6.2 R:KI, S:THF, 0°C; 2 h, rt
6.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 6
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
7
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
Reaction Protocol
Sequence 1
Step 1
View more...
View with
MethodsNow
5 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Sequence 2
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Sequence 2
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
6
47. 5 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
134.45, 131.58, 131.49, 130.59, 124.25, 123.67, 69.08, 63.46, 57.33, 52.4, 52.34, 48.79, 32.25,
30.91, 25.86, 23.15, 17.90, 12.23,-5.28. IR (film, ν cm-1): 2949, 2865, 1738, 1654, 1463, 1254. MS (M
Reaction Protocol
Step 2
View more...

Experimental
Data
View with
MethodsNow
3

3.2 R:NaHCO3, S:H2O
130.60, 125.45, 124.54, 69.10, 63.19, 57.3, 52.5, 48.78, 32.18, 30.90, 23.14, 17.94, 12.24. IR (film, ν
C3H7)+; found: 473.2135.
Reaction Protocol
Step 3
View more...

Experimental
Data
View with
MethodsNow

Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
3
57.33, 52.53, 48.73, 44.89, 32.2, 30.94, 23.14, 17.92, 12.24. IR (film, ν cm-1): 2951, 2867, 1794,
Reaction Protocol
Step 4
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
131.53, 130.74, 130.58, 130.20, 127.76, 123.65, 69.09, 57.32, 52.54, 52.46, 51.58, 48.79, 32.22,
32.04, 30.95, 23.15, 17.9, 12.24. IR (film, ν cm-1): 2948, 2867, 1737, 1440, 1202. MS (M - C3H7)+ :
Reaction Protocol
Step 5
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
48. 5 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Step 2
View more...

Experimental
Data
View with
MethodsNow
3

3.2 R:NaHCO3, S:H2O
CDCl3, δ ppm): 171.28, 131.51, 130.60, 130.12, 129.43, 129.06, 128.81,69.12, 58.71, 52.46, 48.72,
36.43, 32.49, 23.13, 17.95, 17.90, 12.24. IR (film, ν cm-1): 3367, 2947, 2866, 1731, 1654, 1454. MS
Reaction Protocol
Step 3
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Experimental
Data
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Steps: 1, Stages: 2
20°C
4.2 R:NH4Cl, S:H2O
131.21, 130.54, 127.87, 125.02, 69.13, 52.52, 48.72, 39.31, 36.56, 32.60, 23.15, 17.95, 17.90, 12.25.
491.1787 (M - C3H7)+; found: 491.1792.
Reaction Protocol
Step 4
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Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
5.2 R:KI, S:THF, 0°C; 2 h, rt
5.3 R:NH4Cl, S:H2O
128.87, 128.73, 125.55, 69.09, 57.59, 52.49, 52.43, 51.45, 48.76, 36.49, 32.47, 27.09, 23.14, 17.99,
C3H7)+; found: 587.2446.
Reaction Protocol
Step 5
View more...

Experimental
Data
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Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
49. Single Step

1.1 R:LiCl, S:DMF 94%
Steps: 1, Stages: 1
Transformation:
Source
Lithium-halogen exchange-initiated
cyclization reactions. 3.
Intramolecular conjugate addition
reactions of unsaturated
acylphosphoranes
Cooke, Manning P., Jr.; Widener,
Rexford K.
Journal of Organic Chemistry
Volume 52
Issue 8
Pages 1381-96
Journal
1987
Dep. Chem.
Washington State Univ.
Pullman, USA 99164
Number of Steps
1
50. 2 Steps

1.1 R:LiCl, S:Me2CO, overnight, rt → 65°C Steps: 1, Stages: 1
[Reactant]

2 2.1 S:CH2Cl2, overnight, rt Reactants: 2, Solvents: 1, Steps: 1,
Stages: 1
Source
A halogen-containing optical active 2-
carbonyl-1,3-oxazine compound, its
preparation method and application
Shi, Yian; Liu, Weigang; Pan,
Hongjie; Tian, Hua
Assignee Institute of Chemistry,
Chinese Academy of Sciences, Peop.
Rep. China
2015
Patent Information
Nov 04, 2015
CN 105017172
A
Number of Steps
2
51. Single Step

1.1 R:CaCl2, S:Glycerol 54%
Steps: 1, Stages: 1
Transformation:
Source
3-(Hydroxymethyl)cyclohexene
halogenation
Volynskii, N. P.; Zegel'man, L. A.;
Gordadze, G. N.
Izvestiya Akademii Nauk SSSR,
Seriya Khimicheskaya
Issue 12
Pages 2805-9
Journal
1987
Inst. Neftekhim. Sint. im. Topchieva
Moscow, USSR
Number of Steps
1
52. Single Step

1 Reactants: 1, Reagents: 1, Steps: 1,
1.1 R:LiCl Stages: 1
Transformation:
Source
Models for the ion-pair cluster
mechanism in nucleophilic
substitution reactions
Ramos, Socorro; Rosen, William
Volume 46
Issue 17
Pages 3530-3
Journal
1981
Dep. Chem.
Univ. Rhode Island
Kingston, USA 02881
Number of Steps
1
53. Single Step

1 1.1 C:2797-28-6, S:Benzene reflux, Reactants: 2, Catalysts: 1, 97%
Transformation:
1. Friedel-Crafts Alkylation
Source
Lithium
tetrakis(pentafluorophenyl)borate-
catalyzed Friedel-Crafts benzylation
reactions
Mukaiyama, Teruaki; Nakano,
Masakazu; Kikuchi, Wataru; Matsuo,
Jun-Ichi
Chemistry Letters
Issue 9
Pages 1010-1011
Journal
2000
Department of Applied Chemistry,
Faculty of Science
Science University of Tokyo
Tokyo, Japan 162-8601
Number of Steps
1
54. 2 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Step 1
76 mL) at 0 °C.
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Experimental
Data
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[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Step 2
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
2
Single Step

Steps: 1, Stages: 2
0°C
1.2 R:H2O
Reaction Protocol
Sequence 1
Step 1
View more...
View with
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2 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
3
Single Step

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 1
Step 1
76 mL) at 0 °C.
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Experimental
Data
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3 Steps

1.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 2
Step 1
View more...
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Steps: 1, Stages: 2
0°C
2.2 R:H2O
Reaction Protocol
Sequence 2
Step 2
View more...
View with
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[Reactant]

Steps: 1, Stages: 3
3.2 S:THF, 0°C; 17 h, rt
3.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 3
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
4
3 Steps

138.29, 98.42, 82.79, 69.99, 62.2, 30.49, 25.36, 19.34. IR (film, ν cm-1): 2945, 2865, 1612, 1447. MS
Reaction Protocol
Sequence 1
Step 1
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Experimental
Data
View with
MethodsNow
[Reactant]

2.2 R:NH4Cl, S:H2O
Reaction Protocol
Sequence 1
Step 2
View more...
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Steps: 1, Stages: 2
0°C
3.2 R:H2O
Reaction Protocol
Sequence 1
Step 3
View more...
View with
MethodsNow
2 Steps

Steps: 1, Stages: 3
1.2 R:KI, 3 h, 80°C
NMR (75 MHz, CDCl3, δ ppm): 169.37, 131.96, 130.18, 68.95, 52.34, 50.83, 48.68, 28.38, 25.81,
Reaction Protocol
Sequence 2
Step 1
76 mL) at 0 °C.
View more...

Experimental
Data
View with
MethodsNow
[Reactant]

Steps: 1, Stages: 3
2.2 S:THF, 0°C; 17 h, rt
2.3 R:NH4Cl, S:H2O
69.09, 62.63, 62.10, 57.53, 53.41, 52.38, 48.72, 36.47, 32.45, 30.56, 25.41, 23.12, 19.39, 17.92,
557.2701 (M - C3H7)+; found: 557.2708.
Reaction Protocol
Sequence 2
Step 2
View more...

Experimental
Data
View with
MethodsNow
Source
Reaction
Organic Letters
Volume 5
Issue 25
Pages 4799-4802
Journal
2003
Number of Steps
5
58. 4 Steps

1 Reactants: 2, Reagents: 1, Catalysts: 2, 97%
1.1 R:Et3N, C:CuI, C:PdCl2(PPh3)2, S:THF, Solvents: 2, Steps: 1, Stages: 1
S:DMF, 12 h, 40°C

2.1 R:H2, C:Pd, S:EtOH, S:THF, 12 h, 20°C, 1 atm Solvents: 2, Steps: 1, Stages: 1

3.1 R:LiAlH4, S:THF, 0°C; 3 h, 0°C 100%
Steps: 1, Stages: 2
3.2 R:H2O, cooled

4.1 R:SOCl2, S:THF, 45 h, 20°C 81%
Steps: 1, Stages: 2
4.2 R:H2O, cooled
Source
Different Gelation and Self-Sorting
Properties of Two Isomeric
Polyamides Owing to the Parallel
versus Anti-Parallel Alignment of
Backbone Dipoles
Leung, Chui-Fan; Chow, Hak-Fun
Chemistry - A European Journal
Volume 23
Issue 20
Pages 4827-4836
Journal; Online Computer File
2017
Department of Chemistry and Center
of Novel Functional Molecules
The Chinese University of Hong Kong
Hong Kong SAR, Peop. Rep. China
Number of Steps
4
59. Single Step

1 Stille coupling (stage 1), Reactants: 2,
1.1 R:LiCl, C:PdCl2(PPh3)2, 20 h, 50°C; 8 h, 90°C Reagents: 2, Catalysts: 1, Solvents: 2,
Steps: 1, Stages: 2
1.2 R:KF, S:H2O, S:CH2Cl2, overnight, rt
Transformation:
1. Arylation and Alkylation of Alkenes/
Heck Reaction
Preparation of 1-chloro-3-methy2-vinynaphthalene: To a solution of trifluoromethanesulfonic acid 1-
chloro-3-methynaphthalen-2-yl ester (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol)
and lithium chloride (5.78 g, 136.29 mmol) was added dichlorobis(triphenylphosphine) palladium(II)
under argon. The reaction mixture was heated at 50 °C for 20 h, then heated at 90 °C for 8 h. The
reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5%
lithium chloride solution (3x), brine and dried (MgSO4), filtered and then concentrated and purified by
flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methy2-
vinylnaphthalene contaminated by organotin. The residue was dissolved in dichloromethane and
stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite
and extracted with dichloromethane (2x). The organic layer was concentrated and purified by flash
column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methy2-
vinynaphthalene. 1-chloro-3-methy2-vinynaphthalene. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.2
Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.59-7.48 (m, 2H), 6.90 (dd, J = 18.0, 11.8 Hz, 1H),
5.73 (d, J = 11.8 Hz, 1H), 5.53 (d, J = 18.0 Hz, 1H), 2.50 (s, 3H).
Source
Naphthalenylacetic acid derivatives
against HIV infection and their
preparation
Babaoglu, Kerim; Brizgys, Gediminas;
Guo, Hongyan; Hrvatin, Paul;
Lansdon, Eric; Link, John O.; Liu,
Hongtao; McFadden, Ryan; Mitchell,
Michael L.; Qi, Yingmei; Roethle, Paul
A.; Vivian, Randall W.; Xu, Lianhong;
Yang, Hong
Assignee Gilead Sciences, Inc., USA
2013
Patent Information
Jul 11, 2013
WO 2013103738
A1
Number of Steps
1
60. Single Step

1 Stille coupling, Reactants: 2, Reagents:
1.1 R:LiCl, C:PdCl2(PPh3)2, 20 h, 50°C; 8 h, 90°C 1, Catalysts: 1, Steps: 1, Stages: 1
Transformation:
1. Arylation and Alkylation of Alkenes/
Heck Reaction
Preparation of 1-chloro-3-methyl-2-vinylnaphthalene (4D): To a solution of 1-chloro-3-
methylnaphthalen-2-yl trifluoromethanesulfonate (4C) (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59
mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added
bis(triphenylphosphine)palladium(II) dichloride under Ar. The reaction mixture was heated at 50 °C for
20 h, then heated at 90 °C for 8 h. The reaction mixture was than cooled to room temperature, diluted
with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgSO4), filtered and
then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl
acetate/hexanes) to give 4D contaminated by organotin. The residue was dissolved in
dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered
through a pad of Celite and extracted with dichloromethane (2x). The organic layer was concentrated
and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4D.
Pale yellow oil, yield 10.1 g.
Source
2-(Naphth-2-yl)acetic acid derivatives
as HIV antiviral agents and their
preparation and use for the treatment
of AIDS
Babaoglu, Kerim; Bjornson, Kyla;
Guo, Hongyan; Halcomb, Randall L.;
Link, John O.; Mcfadden, Ryan;
Mitchell, Michael L.; Roethle, Paul;
Trenkle, James D.; Vivian, Randall
W.; Xu, Lianhong
Assignee Gilead Sciences, Inc., USA
2012
Patent Information
Jan 05, 2012
WO 2012003497
A1
Number of Steps
1
61. Single Step

1 sealed tube used, stereoselective,
1.1 R:Me3SiCl, S:DMF, rt; 6 h, 100°C 95%
ultrasound (stage 2), Reactants: 2,
1.2 S:H2O, 1 h, 20°C Reagents: 1, Solvents: 2, Steps: 1,
Stages: 2
Transformations:
1. Allylic, Benzylic and Vinylic
Halogenations/ Wohl-Ziegler
Reaction
2. Condensation Reaction between
Compounds with Active Hydrogen
and Aldehydes or Ketones/
Knoevenagel Reaction
General/Typical Procedure: 2-Aryl-1-chloro-1-heteroarylalkenes 38 and 43; General Procedure. 2-
(Tosyloxymethyl)hetarenes 42 or 46 (2 mmol) and an appropriate aromatic aldehyde 23b,c (2 mmol)
were placed in a 15-mL pressure tube and dissolved in DMF (2-3 mL). TMSCl (6 mmol) was added
dropwise to the soln. The tube was thoroughly sealed and heated on a water bath for 8 h. After
cooling the flask was opened (Caution! Excessive pressure.) and the mixture was poured into H2O (15
mL) and allowed to stand at 20 °C in an ultrasonic bath for 1 h. The precipitate formed was filtered
and washed with small amount of i-PrOH. Recrystallization from an appropriate solvent yielded target
compound. 2-[(Z)-1-Chloro-2-(4-chlorophenyl)vinyl]quinoline Hydrochloride (38). Yield 95%. Mp 95-96
°C (MeCN). 1H NMR (400 MHz, DMSO-d6): δ = 7.56 (d, 3JH,H = 8.5 Hz, 2 H, 3,5-HAr), 7.65 (t, 3JH,H =
8.0 Hz, 1 H, 6-HQn), 7.82 (t, 3JH,H = 8.0 Hz, 1 H, 7-HQn), 7.96 (d, 3JH,H = 8.5 Hz, 2 H, 2,6-HAr), 8.03 (d,
3J 3 3
H,H = 8.4 Hz, 1 H, 5-HQn), 8.08 (d, JH,H = 8.4 Hz, 1 H, 8-HQn), 8.12 (d, JH,H = 8.8 Hz, 1 H, 3-HQn),
8.15 (s, 1 H, CH), 8.51 (d, 3JH,H = 8.8 Hz, 1 H, 4-HQn). 13C NMR (125 MHz, DMSO-d6): δ = 119.1,
127.7, 127.8, 128.3, 128.8, 129.1, 129.5, 130.9, 131.5, 132.1, 133.7, 133.9, 137.9, 147.3, 154.0. MS
(APSI): m/z = 300 [M + 1]+.
Reaction Protocol
Step 1
Procedure 1. Place 2- ( Tosyloxymethyl ) hetarenes ( 2 mmol ) and an appropriate aromatic aldehyde ( 2 mmol )
in a 15-mL pressure tube and dissolve in DMF ( 2-3 mL ) .
2. Add TMSCl ( 6 mmol ) dropwise to the solution and seal the tube thoroughly.
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Experimental
Data
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Source
Chlorotrimethylsilane-mediated
synthesis of 2-aryl-1-chloro-1-
heteroarylalkenes
Ryabukhin, Sergey V.; Plaskon,
Andrey S.; Volochnyuk, Dmitriy M.;
Tolmachev, Andrey A.
Synthesis
Issue 20
Pages 3163-3170
Journal
2007
Enamine Ltd.
Kiev, Ukraine 01103
Number of Steps
1
62. Single Step
1 prophetic reaction, Reactants: 1,
1.1 R:SOCl2, S:CH2Cl2, rt Reagents: 1, Solvents: 1, Steps: 1,
Stages: 1
Transformation:
Uncategorized
7-(Chloromethyl)-5-methyl-1,2,3,4-tetrahydronaphthalene (46.6). Alcohol 46.5 (1.0 g, 5.7 mmol) is
dissolved in anhydrous DCM (50 mL). Thionyl chloride (619 µL, 8.5 mmol) is slowly added dropwise to
the solution. The resulting mixture is stirred until TLC confirms consumption of the starting material.
The organic solvent is removed in vacuo. The residue is purified by column chromatography (silica,
EtOAc/Hexane), to afford chloride 46.6.
Source
Preparation of benzo-fused
compounds for use in treating
metabolic disorders
Brown, Sean P.; Dransfield, Paul;
Houze, Jonathan B.; Liu, Jinqian; Liu,
Jiwen; Ma, Zhihua; Medina, Julio C.;
Pattaropong, Vatee; Schmitt, Michael
J.; Sharma, Rajiv; Wang, Yingcai
Assignee Amgen Inc., USA
2008
Patent Information
Mar 13, 2008
WO 2008030618
A1
Number of Steps
1
63. Single Step

1.1 R:LiOH, 2 h, rt Stages: 1
Transformation:
Source
Preparation method for velpatasvir
intermediates
Wu, Chenglong; Zeng, Wen; Liu,
Shaoli; Gong, Jiafu; Huang, Jinkun;
Xie, Dejian
Assignee Xiling Lab Co., Ltd., Peop.
Rep. China
2018
Patent Information
Jun 14, 2018
WO 2018103239
A1
Number of Steps
1
64. Single Step

1.1 R:LiOH, 2 h, rt Stages: 1
Transformation:
Source
Preparation of velpatasvir and
intermediates thereof
Wu, Chenglong; Zeng, Wen; Liu,
Shaoli; Gong, Jiafu; Huang, Jinkun;
Xie, Dejian
Assignee Chengdu Xilingyuan
Pharmaceutical Co., Ltd., Peop. Rep.
China
2018
Patent Information
Jun 12, 2018
CN 108147972
A
Number of Steps
1
65. Single Step

1 alternate method may also be used,
1.1 R:LiCl, 0°C → rt; 2 h, rt Reactants: 1, Reagents: 1, Steps: 1,
Stages: 1
Transformation:
Source
Processes for preparing peptide
analog as antiviral agent
Allan, Kevin M.; Fujimori, Shinji;
Heumann, Lars V.; Huynh, Grace
May; Keaton, Katie Ann; Levins,
Christopher M.; Pamulapati, Ganapati
Reddy; Roberts, Benjamin James;
Sarma, Keshab; Teresk, Martin
Gerald; Wang, Xiang; Wolckenhauer,
Scott Alan
Assignee Gilead Pharmasset LLC,
USA
2015
Patent Information
Dec 17, 2015
WO 2015191437
A1
Number of Steps
1
66. 3 Steps

1 Suzuki coupling, Reactants: 2,
1.1 R:Cs2CO3, C:Pd(PPh3)4, S:H2O, S:PhMe, Reagents: 1, Catalysts: 1, Solvents: 2,
overnight, 80°C Steps: 1, Stages: 1
(6) 3-Isobutyl-4-trifluoromethyl benzoic acid methyl ester Under a nitrogen stream, 3-
trifluoromethanesulfonyloxy-4-trifluoromethylbenzoic acid methyl ester (0.40 g),
tetrakis(triphenylphosphine)palladium (0) (0.13 g), 2-methyl propyl boric acid (0.35 g), cesium
carbonate (1.9 g), water (2.5 ml) and toluene (5 ml) were added, heated and stirred overnight at 80
°C. The reaction mixture was cooled to room temperature, water was added and extracted 3 times
with diethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, the
insoluble substance was filtered, the filtrate was concentrated. The residue was purified by silica gel
column chromatography and the title compound (0.24 g) was obtained. 1H-NMR (CDCl3) δ : 0.94 (6H,
d, J=6.6Hz), 1.97-2.04 (1H, m), 2.70 (2H, d, J=6.9Hz), 3.95 (3H, s), 7.69-7.70 (1H, m), 7.93-7.94 (1H,
m), 7.98 (1H, s).

2.1 R:LiBH4, S:THF, 3 h, reflux; reflux → rt Steps: 1, Stages: 2
2.2 R:HCl, S:H2O, rt
(7) (3-Isobutyl-4-trifluoromethylphenyl)methanol 3-Isobutyl-4-trifluoromethyl benzoic acid methyl ester
(0.24 g) was dissolved in THF (10 ml), lithium borohydride (0.060 g) was added and heated under
reflux for 3 hours with stirring. The reaction mixture was cooled to room temperature, 1 N hydrochloric
acid was added and extracted 3 times with ethyl acetate. The combined extracts were washed with
brine, dried over sodium sulfate, the insoluble substance was filtered and the filtrate was
concentrated. The residue was purified by silica gel column chromatography and the title compound
(0.16 g) was obtained. 1H-NMR (CDCl3) δ : 0.93 (6H, d, J=6.6Hz), 1.72 (1H, t, J=5.9Hz), 1.92-2.02
(1H, m), 2.66 (2H, d, J=7.4Hz), 4.74 (2H, d, J=5.9Hz), 7.28-7.31 (2H, m), 7.61 (1H, d, J=8.1Hz).

3 Reactants: 1, Reagents: 1, Catalysts: 1,
3.1 R:SOCl2, C:DMF, S:ClCH2CH2Cl, 1 h, 60°C Solvents: 1, Steps: 1, Stages: 1
(8) 3-[N-[2-[5-(3-isobutyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2-oxoethyl]amino]propionic
acid [0651] To a 1,2-dichloroethane (7 ml) solution of (3-isobutyl-4-trifluoromethylphenyl)methanol
(0.16 g), thionyl chloride (0.26 ml), DMF (trace) were added, heated and stirred for 1 hour at 60 °C.
The reaction mixture was cooled to room temperature and concentrated.
Source
Preparation of heteroarylamide
derivatives as immunosuppressants
with S1P agonist activity
Machinaga, Nobuo; Yoshino,
Toshiharu; Chiba, Atsushi; Watabe,
Jun; Suzuki, Takashi; Kimura, Yoichi
Assignee Daiichi Sankyo Co., Ltd.,
Japan
2009
Patent Information
May 28, 2009
JP 2009114107
A
Number of Steps
3
67. 3 Steps

[1036] (6) 3-Isobutyl-4-trifluoromethylbenzoic acid methyl ester [1038] Water (2.5 mL) and toluene (5
mL) were added to 3-trifluoromethanesulfonyloxy-4-trifluoromethylbenzoic acid methyl ester (0.40 g),
tetrakis(triphenylphosphine)palladium(0) (0.13 g), 2-methylpropylboric acid (0.35 g) and cesium
carbonate (1.9 g) and the mixture was stirred under a stream of nitrogen at 80 °C overnight. The
reaction mixture was cooled to room temperature and water was added thereto, followed by extraction
thrice, each with diethyl ether. The extracts were combined and washed with saturated brine, followed
by drying over sodium sulfate. Insoluble matter was removed through filtration and then the filtrate
was concentrated. The residue was purified by silica gel column chromatography, whereby the title
compound (0.24 g) was yielded. 1H-NMR (CDCl3) δ: 0.94 (6H, d, J=6.6 Hz), 1.97-2.04 (1H, m), 2.70
(2H, d, J=6.9 Hz), 3.95 (3H, s), 7.69-7.70 (1H, m), 7.93-7.94 (1H, m), 7.98 (1H, s).

[1039] (7) (3-Isobutyl-4-trifluoromethylphenyl)methanol [1041] 3-Isobutyl-4-trifluoromethylbenzoic acid
methyl ester (0.24 g) was dissolved in THF (10 mL) and lithium borohydride (0.060 g) was added to
the solution, followed by reflux with stirring for 3 hours. The reaction mixture was cooled to room
temperature and 1N hydrochloric acid was added thereto, followed by extraction thrice, each with
ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over
sodium sulfate. Insoluble matter was removed by filtration and then the filtrate was concentrated. The
residue was purified by silica gel column chromatography, whereby the title compound (0.16 g) was
yielded. 1H-NMR (CDCl3) δ: 0.93 (6H, d, J=6.6 Hz), 1.72 (1H, t, J=5.9 Hz), 1.92-2.02 (1H, m), 2.66
(2H, d, J=7.4 Hz), 4.74 (2H, d, J=5.9 Hz), 7.28-7.31 (2H, m), 7.61 (1H, d, J=8.1 Hz).
3
[1042] (8) 3-[N-[2-[5-(3-Isobutyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2-
oxoethyl]amino]propionic acid [1044] To a 1,2-dichloroethane solution (7 mL) of (3-isobutyl-4-
trifluoromethylphenyl)methanol (0.16 g), thionyl chloride (0.26 mL) and DMF (trace) were added and
the mixture was stirred with heating at 60 °C for 1 hour. The reaction mixture was cooled to room
temperature and concentrated.
Source
Toshiharu; Chiba, Jun; Watanabe,
Jun; Suzuki, Takashi; Kimura, Youichi
Assignee Daiichi Sankyo Company,
Limited, Japan
2007
Patent Information
Nov 15, 2007
WO 2007129745
A1
Number of Steps
3
68. 2 Steps

1.1 R:NaN3, S:DMF, 3.5 h, 60°C Steps: 1, Stages: 1

2.1 R:SnCl2, S:MeOH, 30 min, 0°C; overnight, rt 95%
Steps: 1, Stages: 2
2.2 R:NaOH, S:H2O, S:CH2Cl2, pH 13
Source
Preparation. of heterocyclic compds.
as class I phosphatidylinositol 3-
kinase selective inhibitors
Ruan, Fuqiang
2017
Patent Information
Aug 03, 2017
WO 2017132157
A1
Number of Steps
2
69. 2 Steps


2.1 R:SnCl2, S:MeOH, 30 min, 0°C; overnight, rt 95%
Steps: 1, Stages: 2
2.2 R:NaOH, S:H2O, S:CH2Cl2, rt, pH 13
Source
Ruan, Fuqiang
2016
Patent Information
Aug 04, 2016
US 20160222012
A1
Number of Steps
2
70. 4 Steps

[Production Example 71] 3-[N-[2-[5-(3-isopropyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2-
oxoethyl]amino]propionic acid (1) 3-Isopropenyl-4-trifluoromethylbenzoic acid methyl ester Under a
nitrogen stream, water (2.5 ml) and toluene (5 ml) were added to 3-trifluoromethanesulfonyloxy-4-
trifluoromethylbenzoic acid methyl ester (0.40 g), tetrakis(triphenylphosphine)palladium (0) (0.13 g),
isopropenyl boric acid (0.43 ml) and cesium carbonate (1.9 g) and heated and stirred overnight at 80
°C. The reaction mixture was cooled to room temperature, water was added and extracted 3 times
with diethyl ether. The combined extracts were washed with saturated brine and dried over sodium
sulfate. The insoluble substance was filtered and the filtrate was concentrated. The residue was
purified by silica gel column chromatography and the title compound (0.28 g) was obtained. 1H-NMR
(CDCl3) δ : 2.09 (3H, s), 3.95 (3H, s), 4.91 (1H, s), 5.27-5.2(1H, m), 7.72 (1H, d, J=8.2Hz), 7.92 (1H,
s), 8.01 (1H, d, J=8.2Hz).

2.1 R:H2, C:H2O, C:Pd, S:MeOH, rt Solvents: 1, Steps: 1, Stages: 1
(2) 3-Isopropyl-4-trifluoromethylbenzoic acid methyl ester Methanol (10 ml) was added to 3-
isopropenyl-4-trifluoromethyl benzoic acid methyl ester (0.28 g), 5% Pd/C catalyst (wet) (0.060 g) and
stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was
filtered, the filtrate was concentrated and the title compound (0.28 g) was obtained. 1H-NMR (CDCl3)
δ : 1.30 (6H, d, J=6.9Hz), 3.3,5-3.42 (1H, m), 3.95 (3H, s), 7.67 (1H, d, J=8.1Hz), 7.91 (1H, d,
J=8.3Hz), 8.14 (1H, s).

(3) (3-Isopropyl-4-trifluoromethylphenyl)methanol (3-Isopropyl-4-trifluoromethyl benzoic acid methyl
ester (0.28 g) was dissolved in THF (10 ml), lithium borohydride (0.070 g) was added and heated
under reflux for 3 hours. The reaction mixture was cooled to room temperature, 1 N hydrochloric acid
was added and extracted 3 times with ethyl acetate. The combined extracts were washed with brine,
dried over sodium sulfate, the insoluble substance was filtered and the filtrate was concentrated. The
residue was purified by silica gel column chromatography and the title compound (0.19 g) was
obtained. 1H-NMR (CDCl3) δ : 1.27-1.28 (6H, m), 1.74 (1H, t, J=5.9Hz), 3.3,5-3.38 (1H, m), 4.76 (2H,
d, J=5.9Hz), 7.23-7.26 (1H, m), 7.46 (1H, s), 7.59 (1H, d, J=8.1Hz).

(4) 3-[N-[2-[5-(3-isopropyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2-
oxoethyl]amino]propionic acid To a 1,2-dichloroethane (10 ml) solution of (3-isopropyl-4-
trifluoromethylphenyl)methanol (0.19 g), thionyl chloride (0.37 ml), DMF (trace) were added, heated
and stirred for 1 hour at 60 °C. The reaction mixture was cooled to room temperature and
concentrated.
Source
Toshiharu; Chiba, Atsushi; Watabe,
Jun; Suzuki, Takashi; Kimura, Yoichi
Assignee Daiichi Sankyo Co., Ltd.,
Japan
2009
Patent Information
May 28, 2009
JP 2009114107
A
Number of Steps
4
71. 4 Steps

[1054] [Example 71] 3-[N-[2-[5-(3-Isopropyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2-
oxoethyl]amino]propionic acid (1) 3-Isopropenyl-4-trifluoromethylbenzoic acid methyl ester [1056]
Water (2.5 mL) and toluene (5 mL) were added to 3-trifluoromethanesulfonyloxy-4-
trifluoromethylbenzoic acid methyl ester (0.40 g), tetrakis(triphenylphosphine)palladium(0) (0.13 g),
isopropenylboric acid (0.43 mL) and cesium carbonate (1.9 g). Under a stream of nitrogen gas, the
resultant mixture was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature
and water was added thereto, followed by extraction thrice, each with diethyl ether. The extracts were
combined and washed with saturated brine, followed by drying over sodium sulfate. Insoluble matter
was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel
column chromatography, whereby the title compound (0.28 g) was yielded. 1H-NMR (CDCl3) δ: 2.09
(3H, s), 3.95 (3H, s), 4.91 (1H, s), 5.27-5.2 (1H, m), 7.72 (1H, d, J=8.2 Hz), 7.92 (1H, s), 8.01 (1H, d,
J=8.2 Hz).
2

2.1 R:H2, C:H2O, C:Pd, S:MeOH, rt Solvents: 1, Steps: 1, Stages: 1
[1057] (2) 3-Isopropyl-4-trifluoromethylbenzoic acid methyl ester [1059] Methanol (10 mL) was added
to 3-isopropenyl-4-trifluoromethylbenzoic acid methyl ester (0.28 g) and 5% Pd/C catalyst (wet) (0.060
g) and the resultant mixture was stirred overnight under a hydrogen atmosphere at room temperature.
The reaction mixture was filtered and the filtrate was concentrated, whereby the title compound (0.28
g) was yielded. 1H-NMR (CDCl3) δ: 1.30 (6H, d, J=6.9 Hz), 3.35-3.42 (1H, m), 3.95 (3H, s), 7.67 (1H,
d, J=8.1 Hz), 7.91 (1H, d, J=8.3 Hz), 8.14 (1H, s).

[1060] (3) (3-Isopropyl-4-trifluoromethylphenyl)methanol [1062] (3-Isopropyl-4-trifluoromethylbenzoic
acid methyl ester (0.28 g) was dissolved in THF (10 mL). Lithium borohydride (0.070 g) was added to
the solution and the resultant mixture was refluxed for 3 hours. The reaction mixture was cooled to
room temperature and 1N hydrochloric acid was added to the mixture, followed by extraction thrice,
each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by
drying over sodium sulfate. Insoluble matter was removed by filtration and the filtrate was
concentrated. The residue was purified by silica gel column chromatography, whereby the title
compound (0.19 g) was yielded. 1H-NMR (CDCl3) δ: 1.27-1.28 (6H, m), 1.74 (1H, t, J=5.9 Hz), 3.35-
3.38 (1H, m), 4.76 (2H, d, J=5.9 Hz), 7.23-7.26 (1H, m), 7.46 (1H, s), 7.59 (1H, d, J=8.1 Hz).
4

[1063] (4) 3-[N-[2-[5-(3-Isopropyl-4-trifluoromethylbenzyloxy)-2,3-dihydroindol-1-yl]-2-
oxoethyl]amino]propionic acid [1065] Thionyl chloride (0.32 mL) and DMF (trace) were added to a
solution (10 mL) of (3-isopropyl-4-trifluoromethylphenyl)methanol (0.19 g) in 1,2-dichloroethane. The
resultant mixture was stirred for 1 hour at 60 °C. The reaction mixture was cooled to room
temperature and then concentrated.
Source
Toshiharu; Chiba, Jun; Watanabe,
Jun; Suzuki, Takashi; Kimura, Youichi
Assignee Daiichi Sankyo Company,
Limited, Japan
2007
Patent Information
Nov 15, 2007
WO 2007129745
A1
Number of Steps
4
72. Single Step

1 stereoselective, Reactants: 2, Reagents: 51%
1.1 R:NaOH, S:H2O, S:EtOH, rt; 6 h, rt 1, Solvents: 2, Steps: 1, Stages: 1
Transformation:
1. Aldol Reaction
Source
Preparation of 1,4-pentadien-3-one
derivatives as antitumor agents
Song, Baoan; Wu, Qin
Assignee Guizhou University, Peop.
Rep. China
2011
Patent Information
Nov 02, 2011
CN 102229546
A
Number of Steps
1
73. Single Step

1 stereoselective, Reactants: 2, Reagents: 62%
1.1 R:NaOH, S:H2O, S:EtOH, rt; 6 h, rt 1, Solvents: 2, Steps: 1, Stages: 1
Transformation:
1. Aldol Reaction
Source
Preparation of 1,4-pentadien-3-one
derivatives as antitumor agents
Song, Baoan; Wu, Qin
Assignee Guizhou University, Peop.
Rep. China
2011
Patent Information
Nov 02, 2011
CN 102229546
A
Number of Steps
1
74. 6 Steps

1.1 R:Bu3SnH, C:Pd(PPh3)4, S:DMF, rt Reagents: 1, Catalysts: 1, Solvents: 1,
Steps: 1, Stages: 1
1-Bromo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (47.3). The bromide is formed according to the
method of Kasibhatla et al; (J. Med. Chem., 44, 613, (2001)). A solution of triflate 47.2 (2.2 g, 5.1
mmol) in 40 mL of DMF under nitrogen is stirred and tetrakis(triphenylphosphone) palladium (294 mg,
0.26 mmol) and tributyltin hydride (1.65 mL, 6.1 mmol) are added. The mixture is stirred until TLC
confirms consumption of the starting material. After cooling to room temperature, the mixture is diluted
with EtOAc (30 mL), washed with water and brine, dried over MgSO4 and concentrated in vacuo. The
residue is purified by column chromatography (silica, EtOAc/Hexane), to afford ester 47.3.

2.1 R:AlH(Bu-i)2, S:CH2Cl2, S:PhMe, -78°C Reagents: 2, Solvents: 2, Steps: 1,
Stages: 2
2.2 R:Rochelle salt, 2 h
(1-Bromo-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (47.4). The alcohol 47.4 is formed according to
the method of Basabe et al. (Tetrahedron, 46, 9173, (2003)). To a stirring solution of the ester 47.3
(1.5 g, 5.3 mmol) in dry DCM (40 mL) at -78°C, is added dropwise a solution of DIBALH in toluene
(1.5 M, 7.1 mL, 10.6 mmol). The mixture is stirred until TLC confirms consumption of the starting
material. The reaction is slowly quenched with a solution of Na/K tartrate (10 mL). The mixture is
further stirred for 2 hours. The aqueous layer is extracted with EtOAc (3 × 50 mL), dried over MgSO4
and concentrated in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane),
to afford alcohol 47.4.
[Reactant]

3 3.1 C:Py •p-MePhSO3H, S:CH2Cl2, 23°C prophetic reaction, Reactants: 2,
Catalysts: 1, Solvents: 1, Steps: 1,
Stages: 1
2-((1-Bromo-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)-tetrahydro-2H-pyran (47.5). To a stirring
solution of alcohol 47.4 (1.0 g, 4.1 mmol) in DCM at 23 °C, is added 3,4-dihydro-2H-pyran (757 µL,8.3
mmol) followed by PPTS (catalytic). The mixture is stirred until TLC confirms consumption of the
starting material. The mixture is concentrated in vacuo. The residue is purified by column
chromatography (silica, EtOAc/Hexane), to afford the THP protected alcohol 47.5.

4.1 R:BuLi, S:THF, 1 h, -78°C Reagents: 3, Solvents: 1, Steps: 1,
Stages: 3
4.2 R:NFSI, -78°C → 23°C
4.3 R:H2O
2-((1-Fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)-tetrahydro-2H-pyran (47.6). To stirring
solution of bromide 47.5 (1.0 g, 3.1 mmol) in THF at -78°C is added n-BuLi (1.6M, 2.11 mL, 3.4
mmol), and stirring is continued for 1hour. N-Fluorobenzene sulfonimide (3.7 mmol) is added and the
mixture is allowed to warm to 23°C. Water is added to quench the reaction. The aqueous layer is
extracted with EtOAc (3 × 100 mL), and the organic layer is dried over MgSO4 and concentrated in
vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford fluoride
47.6.

5 5.1 C:Py •p-MePhSO3H, S:EtOH, 23°C prophetic reaction, Reactants: 1,
Catalysts: 1, Solvents: 1, Steps: 1,
Stages: 1
(1-Fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (47.7). To a stirring solution of 47.6 (0.75 g, 2.8
mmol) in EtOH (25 mL) at 23 °C, is added PPTS (catalytic). The mixture is stirred until TLC confirms
consumption of the starting material. The mixture is concentrated in vacuo. The residue is purified by
column chromatography (silica, EtOAc/Hexane), to afford alcohol 47.7.

6.1 R:SOCl2, S:CH2Cl2, rt Reagents: 1, Solvents: 1, Steps: 1,
Stages: 1
6-(Chloromethyl)-5-fluoro-1,2,3,4-tetrahydronaphthalene. (47.8). The alcohol 47.7 (0.5 g, 2.77 mmol)
is dissolved in anhydrous DCM (50 mL). Thionyl chloride (302 µL, 4.2 mmol) is slowly added dropwise
to the above solution. The resulting mixture is stirred until TLC confirms the consumption of the
starting material. The organic solvent is removed in vacuo. The residue is purified by column
chromatography (silica, EtOAc/Hexane), to afford chloride 47.8.
Source
Preparation of benzo-fused
compounds for use in treating
metabolic disorders
Brown, Sean P.; Dransfield, Paul;
Houze, Jonathan B.; Liu, Jinqian; Liu,
Jiwen; Ma, Zhihua; Medina, Julio C.;
Pattaropong, Vatee; Schmitt, Michael
J.; Sharma, Rajiv; Wang, Yingcai
Assignee Amgen Inc., USA
2008
Patent Information
Mar 13, 2008
WO 2008030618
A1
Number of Steps
6
75. 3 Steps

1 incremental addition of TBAC,
1.1 R:Bu4NCl, S:PhMe, 36 h, 40°C; 40°C → rt Reactants: 1, Reagents: 2, Solvents: 1,
Steps: 1, Stages: 2
1.2 R:H2O
Additional Product(s):
Compound 8. TBAC (63mg, 0.228mmol) was added to a solution of mesylate 7 (28mg, 0.046mmol) in
toluene (5mL). The mixture was stirred at 40°C for 16 hours, and TLC revealed the presence of
starting material. An additional portion of TBAC (63mg, 0.228mmol) was added and stirring at 40°C
was continued for an additional 20 hours. The reaction was cooled to rt, quenched with water, and
extracted with EtOAc (3x). The combined organics were washed with brine, dried (Na2SO4) and FCC
followed by HPLC provided 5mg of the elimination product alkene 14, and 10mg of chloride 8. 8, yield
10mg

2.1 R:HF-pyridine, S:MeCN, 4 h, rt Reagents: 2, Solvents: 2, Steps: 1,
Stages: 2
2.2 R:NaHCO3, S:H2O
Compound 9. HFpyr (0.2mL) was added to a solution of chloride 8 (10mg 0.018mmol) in MeCN (2mL)
in a plastic vial. After stirring 4 hours, the mixture was quenched with NaHCO3 (sat), and extracted
with EtOAc (3x). The combined organics were washed with copper sulfate (sat), brine, and dried
(Na2SO4). FCC afforded alcohol 9. 9

3.1 R:LiOH, S:H2O, S:THF, 48 h, rt Steps: 1, Stages: 1
Compound 10. LiOH (3mg, 0.071mmol) was added to a solution of ester 9 (3mg, 0.068mmol) in a 1:1
THF/water solution (2mL). After having stirred 48h, FCC provided 2.3mg of acid 10. 10, yield 2.3mg
Source
Substituted cyclopentanes having
prostaglandin activity and their
preparation
Holoboski, Mark; Burk, Robert M.;
Posner, Mari; Donde, Yariv; Old,
David W.
Assignee Allergan, Inc., USA
2009
Patent Information
Sep 11, 2009
WO 2009111322
A1
Number of Steps
3
76. Single Step

1.1 R:NaN3, S:DMF, rt; rt → 60°C; 2 h, 60°C; 60°C Steps: 1, Stages: 2
→ rt
Transformation:
1.2 R:H2O, rt 1. Formation of Azides
Source
Synthesis and Pharmacological
Properties of 5-Alkyl Substituted
Nicotine Analogs
Wang, Jing; Li, Xi; Yuan, Qianjia;
Ren, Jiangmeng; Huang, Jin; Zeng,
Bubing
Chinese Journal of Chemistry
Volume 30
Issue 12
Pages 2813-2818
2012
Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy
East China University of Science and
Technology
Shanghai, Peop. Rep. China 200237
Number of Steps
1
77. 4 Steps

Steps: 1, Stages: 1
General/Typical Procedure: Compound 2. TBAC (839mg, 3.0mmol) was added a solution of mesylate
1 (473mg, 0.6mmol) in 20mL toluene. The mixture was then stirred at 45°C for 6 hours, at which time
another portion of TBAC (3 equivalents) was added. After stirring another 14 hours at 45°C, the
mixture was cooled to room temperature and water was added. The toluene layer was separated and
the aqueous layer was extracted 3x with EtOAc. The combined organics were washed with brine,
dried (Na2SO4) and concentrated. Flash chromatography (FCC) provided chloride 2 (320mg).
Compound 47. The procedure of Example 2 was employed with mesylate 38 (19mg, 0.031mmol) to
afford 12.5mg of chloride 47.

2.1 R:HF-pyridine, S:MeCN, 4 h, rt Steps: 1, Stages: 2
2.2 R:NaHCO3, S:H2O
General/Typical Procedure: Compound 9. HFpyr (0.2mL) was added to a solution of chloride 8 (10mg
0.018mmol) in MeCN (2mL) in a plastic vial. After stirring 4 hours, the mixture was quenched with
NaHCO3 (sat), and extracted with EtOAc (3x). The combined organics were washed with copper
sulfate (sat), brine, and dried (Na2SO4). FCC afforded alcohol 9. Compound 48. The procedure of
Example 9 was employed with alkene 47 (12.5mg, 0.141mmol) to afford 9mg of alcohol 48.

3.1 R:H2, C:Pd, S:MeOH, 16 h, rt Solvents: 1, Steps: 1, Stages: 1
General/Typical Procedure: Compound 13. To a stirred mixture of alkene 12 and MeOH (2mL), was
added 5% Pd/C (1mg). The flask was then placed under an atmosphere of H2 (g) and the reaction
was stirred for 16 hours. The mixture was then concentrated and FCC provided 0.8mg of acid 13.
Compound 49. The procedure of Example 13 was employed with alcohol 48 (5mg, 0.017mmol) to
afford 3.4mg of acid 49.

4.1 R:LiOH, S:H2O, S:THF, 48 h, rt Steps: 1, Stages: 1
General/Typical Procedure: Compound 10. LiOH (3mg, 0.071mmol) was added to a solution of ester
9 (3mg, 0.068mmol) in a 1:1 THF/water solution (2mL). After having stirred 48h, FCC provided 2.3mg
of acid 10. Compound 50. The procedure of Example 10 was employed with alkene 48 (4mg,
0.01mmol) to afford 2.4mg of chloride 50.
Source
preparation
David W.
2009
Patent Information
Sep 11, 2009
WO 2009111322
A1
Number of Steps
4
78. 5 Steps

1.1 R:Ph2P(CH2)3PPh2, C:Pd(OAc)2, S:DMF, rt → Solvents: 1, Steps: 1, Stages: 2
60°C
1.2 R:Et3SiH, 12 h, 70°C
1-Methyl-2-fluoro-4-tert-butylbenzene. 2-tert-Butyl-4-fluoro-5-methylphenyl trifluoromethylsulphonate
(Intermediate 17; 20.7 g) in dry dimethylformamide (100 mL) was stirred under nitrogen at room
temperature. Palladium acetate (300 mg) and 1,3-bis(diphenylphosphino)propane (540 mg) were
added and the mixture was heated to 60°C. Triethylsilane (26.3 mL) was added and the mixture was
stirred at 70°C for 12 hours. The mixture was diluted with water and extracted with ether. The
combined extracts were washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The
residue was purified by chromatography on silica gel using cyclohexane as eluent to give the title
compound, admixed with ca 3 mol equivalents of residual triethylsilane. This material was used in the
subsequent stage without further purification. 1H NMR (CDCl3): δ 7.01-7.11 (m, 3H), 2.24 (s, 3H) and
1.30 (s, 9H); together with triethylsilane peaks.

2 incremental addition of potassium
2.1 R:KMnO4, S:H2O, S:C5H5N, 21 h, reflux permanganate in stage 1, Reactants: 1,
Reagents: 2, Solvents: 2, Steps: 1,
2.2 R:HCl, S:H2O, pH 6 Stages: 2
4-tert-Butyl-2-fluorobenzoic acid. 1-Methyl-2-fluoro-4-tert-butylbenzene (Intermediate 18;
contaminated with triethylsilane, sample estimated to contain ca 8.3g of desired compound) in
pyridine (200 mL) and water (50 mL) was treated with potassium permanganate (26.7 g), and heated
under reflux for 3 hours. A further portion of potassium permanganate (26.7 g) was added and the
mixture was heated under reflux for 18 hours. The cooled mixture was filtered through Celite, and the
filter cake was washed with 2 M sodium hydroxide solution. The combined filtrates were acidified to
pH 6 with 2 M hydrochloric acid and extracted with ethyl acetate (2 ×). Combined extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using
cyclohexane-ethyl acetate as eluent (gradient elution from 90:10 v/v to 0:100 v/v) to give the title
compound as a solid. MS calcd for (C11H13FO2 + H)+: 197. MS found (electrospray): (M+H)+ = 197.

3 regioselective, Reactants: 1, Reagents:
3.1 R:H2SO4, R:F3CCO2H, R:Bromosuccinimide, 3, Solvents: 1, Steps: 1, Stages: 1
S:H2O, 16 h, 40°C
5-Bromo-4-tert-butyl-2-fluorobenzoic acid. A mixture of 4-tert-butyl-2-fluorobenzoic acid (Intermediate
19; 3.5 g), trifluoroacetic acid (11 mL), N-bromosuccinimide (3.8 g) and concentrated sulphuric acid (2
mL) was heated under nitrogen at 40°C for 16 hours. The mixture was diluted with dichloromethane
and washed with water. The organic phase was passed through a hydrophobic frit and concentrated
in vacuo. The residue was purified by chromatography on silica gel using cyclohexane-ethyl acetate
as eluent (gradient elution from 70:30 v/v to 0:100 v/v) to give the title compound as a solid. MS calcd
for (C11H12BrFO2 - H)-: 273/275. MS found (electrospray): (M-H)- = 273/275.
[Reactant]

4 chemoselective, Reactants: 2,
4.1 R:Cs2CO3, C:95464-05-4, S:H2O, S:THF, 6 h, Reagents: 1, Catalysts: 1, Solvents: 2,
reflux; 18 h, 20°C Steps: 1, Stages: 1
4-tert-Butyl-5-ethenyl-2-fluorobenzoic acid. A mixture of 5-bromo-4-tert-butyl-2-fluorobenzoic acid
(Intermediate 20; 2.30 g), potassium ethenyltrifluoroborate (1.34 g), [1,1'-
bis(diphenylphosphino)ferrocene]dichloro-paliadium(II), complex with CH2Cl2 (0.55 g) and cesium
carbonate (10.9 g) in THF (60 mL) and water (6 mL) was heated under reflux for 6 hours. The mixture
was set aside for 18 hours at 20°C, diluted with ethyl acetate and washed with 2 M hydrochloric acid.
The organic phase was washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The
residue was dissolved in dichloromethane, filtered through a hydrophobic frit and the filtrate was
purified by chromatography on silica gel using cyclohexane-ethyl acetate as eluent (gradient elution
from 100:0 v/v to 50:50 v/v) to give the title compound as a solid. MS calcd for (C13H15FO2 + H)+: 223.
MS found (electrospray): (M+H)+ = 223.

5.1 R:Cl(O=)CC(=O)Cl, C:DMF, S:CH2Cl2, 3 h, Reagents: 1, Catalysts: 1, Solvents: 1,
20°C Steps: 1, Stages: 1
4-tert-Butyl-5-ethenyl-2-fluorobenzoyl chloride. To a solution of 4-tert-butyl-5-ethenyl-2-fluorobenzoic
acid (Intermediate 21; 400 mg) in dry dichloromethane (2 mL) was added oxalyl chloride (1.6 mL) and
diethylformamide (2 drops). The mixture was stirred at 20°C for 3 hours. The solvent was removed in
vacuo to give the crude title compound, an oil, which was used without further purification.
Source
2-Heteroarylmethyl-4-pyrazin-2-yl-N-
acyl pyrrolidine compounds as
antiviral agents, their preparation,
pharmaceutical compositions, and
use for treatment of hepatitis C
Haigh, David; Hartley, Charles David;
Howes, Peter David; Lazarides,
Linos; Nerozzi, Fabrizio; Smith,
Stephen Allan
Assignee Glaxo Group Limited, UK
2007
Patent Information
Apr 12, 2007
WO 2007039143
A1
Number of Steps
5
79. 5 Steps

1 1.1 C:Ph2P(CH2)3PPh2, C:Pd(OAc)2, S:DMF, rt; rt Reactants: 1, Reagents: 1, Catalysts: 2,
→ 60°C Solvents: 1, Steps: 1, Stages: 2
1.2 R:Et3SiH, 12 h, 70°C
Intermediate 22. 1-Methyl-2-fluoro-4-tert-butylbenzene. 2-tert-Butyl-4-fluoro-5-methylphenyl
trifluoromethylsulphonate (Intermediate 21; 20.7 g) in dry dimethylformamide (100 mL) was stirred
under nitrogen at room temperature. Palladium acetate (300 mg) and 1,3-
bis(diphenylphosphino)propane (540 mg) were added and the mixture was heated to 60°C.
Triethylsilane (26.3 mL) was added and the mixture was stirred at 70°C for 12 hours. The mixture was
diluted with water and extracted with ether. The combined extracts were washed with saturated brine,
dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel
using cyclohexane as eluent to give the title compound, admixed with ca 3 mol equivalents of residual
triethylsilane. This material was used in the subsequent stage without further purification. 1H NMR
(CDCl3): δ 7.01-7.11 (m, 3H), 2.24 (s, 3H) and 1.30 (s, 9H); together with triethylsilane peaks.

2 incremental addition of potassium
2.1 R:KMnO4, R:Et3SiH, S:H2O, S:C5H5N, 21 h, permanganate in stage 1, Reactants: 1,
reflux Reagents: 3, Solvents: 2, Steps: 1,
Stages: 2
2.2 R:HCl, S:H2O, pH 6
Intermediate 23. 4-tert-Butyl-2-fluorobenzoic acid. 1-Methyl-2-fluoro-4-tert-butylbenzene (Intermediate
22; contaminated with triethylsilane, sample estimated to contain ca 8.3g of desired compound) in
pyridine (200 mL) and water (50 mL) was treated with potassium permanganate (26.7 g), and heated
under reflux for 3 hours. A further portion of potassium permanganate (26.7 g) was added and the
mixture was heated under reflux for 18 hours. The cooled mixture was filtered through Celite, and the
filter cake was washed with 2 M sodium hydroxide solution. The combined filtrates were acidified to
pH 6 with 2 M hydrochloric acid and extracted with ethyl acetate. Combined extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using
cyclohexane-ethyl acetate as eluent (gradient elution from 90:10 v/v to 0:100 v/v) to give the title
compound as a solid. MS calcd for (C11H13FO2+H)+ : 197. MS found (electrospray): (M+H)+ = 197.

3.1 R:H2SO4, R:F3CCO2H, R:Bromosuccinimide, 3, Solvents: 1, Steps: 1, Stages: 1
S:H2O, 16 h, 40°C
Intermediate 24. 5-Bromo-4-tert-butyl-2-fluorobenzoic acid. A mixture of 4-tert-butyl-2-fluorobenzoic
acid (Intermediate 23; 3.5 g), trifluoroacetic acid (11 mL), N-bromosuccinimide (3.8 g) and
concentrated sulphuric acid (2 mL) was heated under nitrogen at 40°C for 16 hours. The mixture was
diluted with dichloromethane and washed with water. The organic phase was passed through a
hydrophobic frit and concentrated in vacuo. The residue was purified by chromatography on silica gel
using cyclohexane-ethyl acetate as eluent (gradient elution from 70:30 v/v to 0: 100 v/v) to give the
title compound as a solid. MS calcd for (C11H12BrFO2-H)-: 273/275. MS found (electrospray): (M-H)- =
273/275.
[Reactant]

4 chemoselective, Reactants: 2,
4.1 R:Cs2CO3, C:95464-05-4, S:H2O, S:THF, 6 h, Reagents: 1, Catalysts: 1, Solvents: 2,
reflux; 18 h, 20°C Steps: 1, Stages: 1
Intermediate 25. 4-tert-Butyl-5-ethenyl-2-fluorobenzoic acid. A mixture of 5-bromo-4-tert-butyl-2-
fluorobenzoic acid (Intermediate 24; 2.30 g), potassium ethenyltrifluoroborate (1.34 g),[1,1'-
bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with CH2Cl2 (0.55 g) and cesium
carbonate (10.9 g) in THF (60 mL) and water (6 mL) was heated under reflux for 6 hours. The mixture
was set aside for 18 hours at 20°C, diluted with ethyl acetate and washed with 2 M hydrochloric acid.
The organic phase was washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The
residue was dissolved in dichloromethane, filtered through a hydrophobic frit and the filtrate was
purified by chromatography on silica gel using cyclohexane-ethyl acetate as eluent (gradient elution
from 100:0 v/v to 50:50 v/v) to give the title compound as a solid. MS calcd for (C13H15FO2+H)+: 223.
MS found (electrospray): (M+H)+ = 223.

5.1 R:Cl(O=)CC(=O)Cl, C:Et2NCHO, S:CH2Cl2, 3 Reagents: 1, Catalysts: 1, Solvents: 1,
h, 20°C Steps: 1, Stages: 1
Intermediate 26. 4-tert-Butyl-5-ethenyl-2-fluorobenzoyl chloride. To a solution of 4-tert-butyl-5-ethenyl-
2-fluorobenzoic acid (Intermediate 25; 400 mg) in dry dichloromethane (2 mL) was added oxalyl
chloride (1.6 mL) and diethylformamide (2 drops). The mixture was stirred at 20°C for 3 hours. The
solvent was removed in vacuo to give the crude title compound, an oil, which was used without further
purification.
Source
2-Heteroarylmethyl-4-
(methoxymethyl)-N-acyl pyrrolidine
compounds as antiviral agents, their
preparation, pharmaceutical
compositions, and use for treatment
of hepatitis C
Haigh, David; Hartley, Charles David;
Howes, Peter David; Jarvest, Richard
Lewis; Lazarides, Linos; Nerozzi,
Fabrizio; Smith, Stephen Allan
Assignee Glaxo Group Limited, UK
2007
Patent Information
Apr 12, 2007
WO 2007039142
A1
Number of Steps
5
80. Single Step

1.1 R:LiCl Stages: 1
Transformation:
Source
Factors influencing conformational
preferences in cyclohexenes
Lambert, Joseph B.; Marko, Dale E.
Journal of the American Chemical
Society
Volume 107
Issue 26
Pages 7978-82
Journal
1985
Dep. Chem.
Northwestern Univ.
Evanston, USA 60201
Number of Steps
1
81. 2 Steps

Steps: 1, Stages: 1

2.1 R:HF-pyridine, S:MeCN, 4 h, rt Steps: 1, Stages: 2
2.2 R:NaHCO3, S:H2O
General/Typical Procedure: Compound 9. HFpyr (0.2mL) was added to a solution of chloride 8 (10mg
0.018mmol) in MeCN (2mL) in a plastic vial. After stirring 4 hours, the mixture was quenched with
NaHCO3 (sat), and extracted with EtOAc (3x). The combined organics were washed with copper
sulfate (sat), brine, and dried (Na2SO4). FCC afforded alcohol 9. Compound 48. The procedure of
Example 9 was employed with alkene 47 (12.5mg, 0.141mmol) to afford 9mg of alcohol 48.
Source
preparation
David W.
2009
Patent Information
Sep 11, 2009
WO 2009111322
A1
Number of Steps
2
82. 2 Steps

Steps: 1, Stages: 2
1.2 R:H2O
Additional Product(s):
Compound 8. TBAC (63mg, 0.228mmol) was added to a solution of mesylate 7 (28mg, 0.046mmol) in
toluene (5mL). The mixture was stirred at 40°C for 16 hours, and TLC revealed the presence of
starting material. An additional portion of TBAC (63mg, 0.228mmol) was added and stirring at 40°C
was continued for an additional 20 hours. The reaction was cooled to rt, quenched with water, and
extracted with EtOAc (3x). The combined organics were washed with brine, dried (Na2SO4) and FCC
followed by HPLC provided 5mg of the elimination product alkene 14, and 10mg of chloride 8. 8, yield
10mg

2.1 R:HF-pyridine, S:MeCN, 4 h, rt Reagents: 2, Solvents: 2, Steps: 1,
Stages: 2
2.2 R:NaHCO3, S:H2O
Compound 9. HFpyr (0.2mL) was added to a solution of chloride 8 (10mg 0.018mmol) in MeCN (2mL)
in a plastic vial. After stirring 4 hours, the mixture was quenched with NaHCO3 (sat), and extracted
with EtOAc (3x). The combined organics were washed with copper sulfate (sat), brine, and dried
(Na2SO4). FCC afforded alcohol 9. 9
Source
preparation
David W.
2009
Patent Information
Sep 11, 2009
WO 2009111322
A1
Number of Steps
2
83. Single Step

1 reactant assumed (stage 1), Reactants:
1.1 R:H2SO4, S:H2O, S:MeCN, 15 min, cooled; 20 3, Reagents: 9, Solvents: 6, Steps: 1,
min, cooled Stages: 11
1.2 R:NaNO2, S:H2O, 7 min, cooled; 15 min, Transformation:
cooled Uncategorized
1.3 R:KI, S:H2O, 50 min, cooled
1.4 R:NaOH, S:MeOH, S:H2O, cooled; 1 h, rt
1.5 R:HCl, S:H2O, rt, acidify
1.6 R:Cs2CO3, S:MeCN, 4 h, rt
1.7 R:(S)-Proline, S:DMF, rt → 80°C; 24 h, 80°C;

80°C → rt
1.8 R:NH3, S:H2O, S:AcOEt, 30 min, rt
1.9 R:AlH(Bu-i)2, S:PhMe, 5 min, cooled; 50 min,

cooled
1.10 S:MeOH, cooled; rt
1.11 R:H2SO4, S:AcOEt, 1 h, rt
Source
Preparation of pyridine derivatives
as thyroid hormone β receptor
agonists
Kawada, Shinji; Matsumoto, Koji;
Arashima, Maki; Takahashi, Taichi
Assignee Tanabe Seiyaku Co., Ltd.,
Japan; Mitsubishi Tanabe Pharma
Corporation
2012
Patent Information
Jun 07, 2012
JP 2012106996
A
Number of Steps
1
84. Single Step

Transformation:
1. Formation of Azides
Source
Ruan, Fuqiang
2017
Patent Information
Aug 03, 2017
WO 2017132157
A1
Number of Steps
1
85. Single Step

Transformation:
1. Formation of Azides
Source
Ruan, Fuqiang
2016
Patent Information
Aug 04, 2016
US 20160222012
A1
Number of Steps
1
86. Single Step

1.1 R:KOH, S:H2O, S:EtOH, 2.5 h, reflux; reflux → Steps: 1, Stages: 1
rt
Transformation:
1. Hydrolysis of Alkyl Esters of
Inorganic Acids
Step E Synthesis of 5-chloro-6-methyl-1-naphthol as an intermediate. A solution of 0.37 gram (0.0059
mole) of potassium hydroxide (85%) in 10 mL of water was added to a stirred mixture of 0.87 gram
(0.0025 mole) of (5-chloro-6-methylnaphthyl)-4-methylbenzenesulfonate in 75 mL of ethanol. The
reaction mixture was then heated at reflux for 2.5 hours, after which time the mixture was allowed to
cool to ambient temperature. The reaction mixture was diluted with 100 mL of water and then
extracted with two 100 mL portions of diethyl ether. The extracts were combined, washed with 100 mL
of an aqueous lithium chloride solution and dried with anhydrous magnesium sulfate. The mixture was
filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was
purified by column chromatography on silica gel, eluted with mixtures of 50% to 99% methylene
chloride in petroleum ether. The appropriate fractions were combined and concentrated under
reduced pressure, yielding 0.27 gram of the title compound. The NMR spectrum was consistent with
the proposed structure.
Source
Preparation of nonaromatic
heterocyclic N-oxides as insecticides.
Theodoridis, George; Yeager, Walter
Assignee FMC Corporation, USA
2006
Patent Information
Jul 27, 2006
WO 2006078619
A1
Number of Steps
1
87. Single Step

1.1 R:MgCl2, S:MeCN, 1 h, 90°C 94%
Steps: 1, Stages: 2
1.2 R:H2O Transformation:
Synthesis of 2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7).32 Tosylate 6 (1.84 g; 5.15 mmol) was
dissolved in MeCN (50 mL). MgCl2 (0.74 g; 7.73mmol) was added, and the stirred solution was
heated to reflux (90 °C). After 1 h, the reaction was quenched by dilution with water. MeCN was
evaporated under reduced pressure, and the remaining aqueous phase was extracted with DCM (4 x
50 mL). The combined organic phase was washed with brine (1 x 100 mL), dried over Na2SO4,
filtered, and evaporated, yielding 2-chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7) as a brown solid
(1.08 g; 94%): 2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7), yield 1.08 g; 94% 1H NMR (400 MHz,
CDCl3) δ 1.40 (t, J = 7.5 Hz, 3H), 3.01 (q, J = 7.5 Hz, 2H), 4.75 (s, 2H, CH2Cl), 7.28-7.38 (m, 2H),
7.59 (dd, J = 6.5Hz, J = 1.3 Hz, 1H), 7.68 (s, 1H); 13C (100MHz, CDCl3) δ 13.9 (CH3), 22,7 (CH2),
30.2 (CH2), 115.0 (CH), 120.9 (CH), 124.4 (CH), 126.6 (C), 127.8 (CH), 129.0 (C), 149.9 (C), 154.6
(C), 182.2 (CO).
Reaction Protocol
Step 1
Procedure 1. Dissolve 2-tosyloxy-1-(7-ethylbenzofuran-2-yl)ethanone (5.15 mmol) in MeCN (50 mL).
2. Add MgCl2 (0.74 g; 7.73mmol) to the mixture.
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Enantioselective Synthesis of (R)-
Bufuralol via Dynamic Kinetic
Resolution in the Key Step
Johnston, Eric V.; Bogar, Krisztian;
Baeckvall, Jan-E.
Volume 75
Issue 13
Pages 4596-4599
Journal
2010
Department of Organic Chemistry,
Arrhenius Laboratory
Stockholm University
Stockholm, Swed. SE-106 91
Number of Steps
1
88. 2 Steps

1.1 R:i-Pr2NH, C:Pd(PPh3)4, C:CuI, S:DMF, rt → Solvents: 1, Steps: 1, Stages: 1
100°C; 14 h, 100°C

2 stereoselective, ultrasound (in stage 2), 70%
2.1 R:H2, C:Pd, S:C5H5N, 2.25 h, rt Reactants: 1, Reagents: 3, Catalysts: 1,
2.2 R:KHCO3, R:Martin's reagent, S:CDCl3, 1 min,
rt; 1 h, rt; 10 min, rt
Source
Stereoselective arene-forming aldol
condensation: Synthesis of axially
chiral aromatic amides
Faeseke, Vincent C.; Sparr, Christof
Angewandte Chemie, International
Edition
Volume 55
Issue 25
Pages 7261-7264
2016
Department of Chemistry
University of Basel
Basel, Switz. 4056
Number of Steps
2
89. 2 Steps

1.1 R:AcOK, C:Pd(OAc)2, C:(Ph2P)2-ferrocene, Solvents: 2, Steps: 1, Stages: 2
S:DMSO, 5 min, rt; overnight, 60°C; 60°C → rt
1.2 R:HCl, S:H2O, rt, < pH 3
Reaction Protocol
Step 1
Procedure 1. Add Pd (OAc)2 (0.125 mmol, 5 mol % equiv), dppf (0.5 mmol, 20 mol %), and potassium acetate
(10 mmol, 4 equiv) to the crude phenyl trifluoromethanesulfonate in DMSO (25 mL).
2. Bubble CO through the mixture for 5 minutes.
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2.1 R:Cl(O=)CC(=O)Cl, C:DMF, S:CH2Cl2, 4 h, rt Solvents: 1, Steps: 1, Stages: 1
Reaction Protocol
Step 2
Procedure 1. Add dropwise oxalyl chloride (6.0 mmol, 1.2 equiv) followed by a catalytic amount of dry DMF (2
drops) to a solution of the carboxylic acid (5.0 mmol, 1.0 equiv) in dry DCM (16 mL) at 0 °C under Ar.
2. Allow the reaction to stir at room temperature.
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Iodoarene-Catalyzed Stereospecific
Intramolecular sp3 C-H Amination:
Reaction Development and
Mechanistic Insights
Zhu, Chendan; Liang, Yong; Hong,
Xin; Sun, Heqing; Sun, Wei-Yin;
Houk, K. N.; Shi, Zhuangzhi
Journal of the American Chemical
Society
Volume 137
Issue 24
Pages 7564-7567
2015
State Key Laboratory of Coordination
Chemistry, Collaborative Innovation
Center of Chemistry for Life Sciences,
School of Chemistry and Chemical
Engineering
Nanjing University
Nanjing, Peop. Rep. China 210093
Number of Steps
2
90. Single Step

1.1 R:HCl 97%
Stages: 1
Transformation:
Source
Reactive troponoids and o-
aminophenol. II. The formation of
cyclohepta[b][1,4]benzoxazine and
11H-cyclohepta[b][1,4]benzoxazin-10-
one derivatives from isomeric
isopropyl-2-chlorotropones
Nozoe, Tetsuo; Someya, Taichi
Bulletin of the Chemical Society of
Japan
Volume 51
Issue 11
Pages 3316-19
Journal
1978
Cent. Res. Lab.
Takasago Perfum. Co., Ltd.
Tokyo, Japan
Number of Steps
1
91. 2 Steps

1.1 R:MgCl2, S:MeCN, 1 h, 90°C 94%
Steps: 1, Stages: 2
1.2 R:H2O
Synthesis of 2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7).32 Tosylate 6 (1.84 g; 5.15 mmol) was
dissolved in MeCN (50 mL). MgCl2 (0.74 g; 7.73mmol) was added, and the stirred solution was
heated to reflux (90 °C). After 1 h, the reaction was quenched by dilution with water. MeCN was
evaporated under reduced pressure, and the remaining aqueous phase was extracted with DCM (4 x
50 mL). The combined organic phase was washed with brine (1 x 100 mL), dried over Na2SO4,
filtered, and evaporated, yielding 2-chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7) as a brown solid
(1.08 g; 94%): 2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7), yield 1.08 g; 94% 1H NMR (400 MHz,
CDCl3) δ 1.40 (t, J = 7.5 Hz, 3H), 3.01 (q, J = 7.5 Hz, 2H), 4.75 (s, 2H, CH2Cl), 7.28-7.38 (m, 2H),
7.59 (dd, J = 6.5Hz, J = 1.3 Hz, 1H), 7.68 (s, 1H); 13C (100MHz, CDCl3) δ 13.9 (CH3), 22,7 (CH2),
30.2 (CH2), 115.0 (CH), 120.9 (CH), 124.4 (CH), 126.6 (C), 127.8 (CH), 129.0 (C), 149.9 (C), 154.6
(C), 182.2 (CO).
Reaction Protocol
Step 1
Procedure 1. Dissolve 2-tosyloxy-1-(7-ethylbenzofuran-2-yl)ethanone (5.15 mmol) in MeCN (50 mL).
2. Add MgCl2 (0.74 g; 7.73mmol) to the mixture.
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2.1 R:NaBH4, S:MeOH, 0°C; 0°C → rt; overnight, 94%
Steps: 1, Stages: 1
rt
Synthesis of rac-2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanol (8). NaBH4 (63 mg, 1.65 mmol) was
added portionwise to a solution of chloro ketone 7 (666 mg, 3 mmol) in MeOH (75 mL) stirred at 0 °C
under argon. The stirring was continued while the mixture was allowed to warm to ambient
temperature.When the reaction was complete, it was stopped and the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc (80 mL) and extracted with water (3 x 50 mL).
The separated organic phases were washed with brine (1 x 50mL), dried over anhydrous Na2SO4,
filtered, and concentrated to give a light yellow oil was (626 mg, 94% yield). rac-2-Chloro-1-(7-
ethylbenzofuran-2-yl)ethanol (8), yield 626 mg, 94% Spectral data were in accordance with those
reported in the literature.27b
Reaction Protocol
Step 2
Procedure 1. Add NaBH4 (63 mg, 1.65 mmol) portionwise to a solution of 2-chloro-1-(7-ethylbenzofuran-2-
yl)ethanone (3 mmol) in MeOH (75 mL) stirred at 0 °C under argon.
2. Continue the stirring while the mixture.
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Enantioselective Synthesis of (R)-
Bufuralol via Dynamic Kinetic
Resolution in the Key Step
Johnston, Eric V.; Bogar, Krisztian;
Baeckvall, Jan-E.
Volume 75
Issue 13
Pages 4596-4599
Journal
2010
Department of Organic Chemistry,
Arrhenius Laboratory
Stockholm University
Stockholm, Swed. SE-106 91
Number of Steps
2
92. Single Step

1.1 R:HCl 24%
Stages: 1
Transformation:
Uncategorized
Source
Synthesis of functionalized
cycloprop[f]indenes via the carbene
addition route
Mueller, Paul; Miao, Zhongshan
Helvetica Chimica Acta
Volume 77
Issue 7
Pages 2051-9
Journal
1994
Dep. Chimie Organique
Univ. Geneve
Geneva, Switz. CH-1211
Number of Steps
1
93. 4 Steps

1 1.1 48 h, rt Reactants: 2, Steps: 1, Stages: 1 84%
General/Typical Procedure: 1.4 3-Propyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 22.6 g (70.1 mmol) of
1,2-bis(2-methylsulfonyloxyethyl)benzene were dissolved in 28.8 ml (350.5 mmol) of n-propylamine
and stirred at room temperature for 48 hours. The reaction solution was mixed with 150 ml of diethyl
ether and extracted with 2 × 35 ml of water. The organic phase was dried with magnesium sulfate,
filtered and evaporated. Yield: 14.6 g (84% of theory). MS [m+1]: 190 1H-NMR (360 MHz, CDCl3): 7.1
(m, 4H); 2.9 (m, 4H); 2.7 (m, 4H); 2.5 (m, 2H); 1.5 (m, 2H); 0.9 (m, 3H).
[Reactant] [Reactant]
2.1 R:AlCl3, S:CH2Cl2, 0-5°C; overnight, rt 36%
1, Solvents: 1, Steps: 1, Stages: 2
2.2 30 min, rt
Example 36: 7-(4-Isopropylbenzenesulfonylmethyl)-3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
36.1 Methyl 3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylate. 2.99 g (22.43 mmol) of
aluminum trichloride were added to 1.9 g (7.48 mmol) of 3-propyl-2,3,4,5-tetrahydro-1H-3-
benzazepine and 1.29 ml (14.95 mmol) of oxalyl chloride in 40 ml of dichloromethane under a
nitrogen atmosphere at 0- 5°C and then stirred at room temperature overnight. 2 ml of methanol were
added, and stirring was continued for 30 minutes. The reaction solution was concentrated and the
residue was mixed with 25 ml of water and extracted with 25 ml of diethyl ether. The aqueous phase
was then saturated with sodium chloride and extracted twice with ethyl acetate. The combined organic
phases were dried with magnesium sulfate, filtered and evaporated. Yield: 720 mg (36% of theory).
MS [m+1]: 248.

3 incremental addition of LAH, Reactants:
3.1 R:LiAlH4, S:THF, 1 h, 0-5°C 1, Reagents: 1, Solvents: 1, Steps: 1,
Stages: 1
36.2 (3-Propyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methanol. 720 mg (2.67 mmol) of methyl 3-
propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylate were dissolved in 10 ml of tetrahydrofuran
under a nitrogen atmosphere and, at 0-5°C, 202 mg (5.34 mmol) of lithium aluminum hydride were
added in portions. After stirring for 1 hour, the reaction mixture was worked up and then employed in
the following reaction. MS [m+1]: 220.

4.1 R:Et3N, R:p-Tosyl chloride, S:CH2Cl2, 30 min, 77%
Steps: 1, Stages: 1
rt
36.3 7-Chloromethyl-3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 180 mg (0.82 mmol) of (3-propyl-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methanol were dissolved in 25 ml of dichloromethane under
a nitrogen atmosphere, and 0.34 ml (2.46 mmol) of triethylamine was added. Then 0.19 ml (2.46
mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was extracted twice with 10 ml of aqueous sodium bicarbonate
solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. Yield: 175
mg (77% of theory). MS [m+1]: 238.
Source
Tetrahydrobenzazepines as
dopamine D3 receptor modulators,
their preparation, pharmaceutical
compositions and use in the treatment
of CNS disorders and renal function
disorders
Braje, Wilfried; Haupt, Andreas;
Lubisch, Wilfried; Grandel, Roland;
Drescher, Karla; Geneste, Herve;
Unger, Liliane; Sauer, Daryl R.
Assignee Abbott G.m.b.H. & Co. K.-
G., Germany
2005
Patent Information
Jun 30, 2005
WO 2005058328
A1
Number of Steps
4
94. 4 Steps

1 1.1 48 h, rt Reactants: 2, Steps: 1, Stages: 1 84%
1,4 3-Propyl-2,3,4,5-tetrahydro-1H-3-benzazepine 22.6 g (70.1 mmol) of 1,2-bis(2-
methylsulfonyloxyethyl)benzene were dissolved in 28.8 ml (350.5 mmol) of n-propylamine and stirred
at room temperature for 48 hours. The reaction solution was mixed with 150 ml of diethyl ether and
extracted with 2×35 ml of water. The organic phase was dried with magnesium sulfate, filtered and
evaporated. Yield: 14.6 g (84% of theory). MS [m+1]190 1H-NMR (360 MHz, CDCl3): 7.1(m,4H);
2.9(m,4H); 2.7(m, 4H); 2.5(m,2H); 1.5(m,2H); 0.9(m,3H).
[Reactant] [Reactant]
2.1 R:AlCl3, S:CH2Cl2, 0-5°C; overnight, rt 36%
Steps: 1, Stages: 2
2.2 30 min, rt
36.1 Methyl 3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylate 2.99 g (22.43 mmol) of
aluminum trichloride were added to 1.9 g (7.48 mmol) of 3-propyl-2,3,4,5-tetrahydro-1H-3-
benzazepine and 1.29 ml (14.95 mmol) of oxalyl chloride in 40 ml of dichloromethane under a
nitrogen atmosphere at 0-5° C. and then stirred at room temperature overnight. 2 ml of methanol were
added, and stirring was continued for 30 minutes. The reaction solution was concentrated and the
residue was mixed with 25 ml of water and extracted with 25 ml of diethyl ether. The aqueous phase
was then saturated with sodium chloride and extracted twice with ethyl acetate. The combined organic
phases were dried with magnesium sulfate, filtered and evaporated. Yield: 720 mg (36% of theory).
MS [m+1]: 248

3 incremental addition of LAH, Reactants:
3.1 R:LiAlH4, S:THF, 1 h, 0-5°C; 1 h 1, Reagents: 1, Solvents: 1, Steps: 1,
Stages: 1
36.2 (3-Propyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methanol 720 mg (2.67 mmol) of methyl 3-
propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylate were dissolved in 10 ml of tetrahydrofuran
under a nitrogen atmosphere and, at 0-5° C., 202 mg (5.34 mmol) of lithium aluminum hydride were
added in portions. After stirring for 1 hour, the reaction mixture was worked up and then employed in
the following reaction. MS [m+1]: 220

4.1 R:Et3N, R:MeSO2Cl, S:CH2Cl2, 30 min, rt 77%
Steps: 1, Stages: 1
36.3 7-Chloromethyl-3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine 180 mg (0.82 mmol) of (3-propyl-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methanol were dissolved in 25 ml of dichloromethane under
a nitrogen atmosphere, and 0.34 ml (2.46 mmol) of triethylamine was added. Then 0.19 ml (2.46
mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was extracted twice with 10 ml of aqueous sodium bicarbonate
solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. Yield: 175
mg (77% of theory). MS [m+1]: 238
Source
A preparation of
tetrahydrobenzazepine derivatives,
useful as dopamine D3 receptor
ligands
Braje, Wilfried M.; Haupt, Andreas;
Lubisch, Wilfried; Grandel, Roland;
Drescher, Karla; Geneste, Herve;
Unger, Liliane; Sauer, Daryl R.
Assignee Abbott G.m.b.H. & Co. Kg.,
Germany
2005
Patent Information
Jun 23, 2005
US 20050137186
A1
Number of Steps
4
95. 2 Steps

1 acidified using unspecified reagent
1.1 R:NaOH, S:H2O, S:MeOH, 2 h, rt → reflux (PH=3), Reactants: 1, Reagents: 1,
Step 79d. To a solution of the compound from step 79c (72.0 mg, NMR 75% purity) in MeOH (6 mL)
was added 50% aqueous NaOH (0.13 mL). The reaction was heated to reflux for 2 hours before being
acidified to pH 3. The mixture was partitioned between CH2Cl2 and water, and the organics were
washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed
(silica, CH2Cl2-MeOH) to give the desired compound (60.2 mg, NMR 75% purity) as a white solid.
Yield 60.2 mg.

2.1 R:SOCl2, 2 h, reflux Stages: 1
General/Typical Procedure: Step 65b. A solution of the compound from step 65a (500 mg, 1.95 mmol)
in SOCl2 (6 mL) was refluxed for 2 hours. It was cooled down and the volatiles were evaporated to
afford the desired crude compound as a light yellow oil which was directly used in the next step. Step
79e. The crude desired compound (0.220 mmol at most) as a light yellow oil was prepared from the
compound from step 79d (60.2 mg, NMR 75% purity) following a similar procedure to that described in
step 65b.
Source
Acylsulfonamide derivatives as
antiviral agents and their preparation
and use in the treatment of HCV
infection
Or, Yat Sun; Ying, Lu; Wang, Ce;
Peng, Xiaowen; Qiu, Yao-Ling
Assignee Enanta Pharmaceuticals,
Inc., USA
2010
Patent Information
Jun 03, 2010
US 20100135960
A1
Number of Steps
2
96. 2 Steps

1.1 R:NaOH, S:H2O, S:MeOH, 2 h, reflux 98%
(pH=3), Reactants: 1, Reagents: 1,
General/Typical Procedure: Step 69e. To a solution of the compound from step 69d (0.116 g, 0.450
mmol) in MeOH (5 mL) was added 50% aqueous NaOH (1.8 mL). It was refluxed for 2 hours before
being acidified to pH 3. The mixture was partitioned between CH2Cl2 and water, and the organics
were washed with brine, dried over sodium sulfate and evaporated. The residue was
chromatographed (silica, CH2Cl2-MeOH) to give the desired compound (99.6 mg, 91%) as a white
solid. Step 78e. The desired compound (0.301 g, 98%) as a white solid was prepared from the
compound from step 78d (0.301 g, 1.11 mmol) following a similar procedure to that described in step
69e.

78f. The crude desired compound (0.174 mmol at most) as a light yellow oil was prepared from the
compound from step 78e (0.301 g, 1.09 mmol) following a similar procedure to that described in step
65b.
Source
infection
Inc., USA
2010
Patent Information
Jun 03, 2010
US 20100135960
A1
Number of Steps
2
97. Single Step

Steps: 1, Stages: 1
Transformation:
Source
preparation
David W.
2009
Patent Information
Sep 11, 2009
WO 2009111322
A1
Number of Steps
1
98. 3 Steps

1.1 R:BF3-Et2O, S:(CH2OMe)2, -10°C; 30 min, - Steps: 1, Stages: 2
10°C
1.2 R:t-BuONO, S:(CH2OMe)2, -10°C; -10°C →

0°C; 1.5 h, 0°C
Step 79c. To a solution of BF3.Et2O (38.0 µL, 0.378 mmol) in DME (4 mL) at -10°C. was added the
compound from step 79b (80.5 mg, 0.280 mmol) in DME (6 mL) dropwise. The reaction was kept
stirring at this temperature for 30 minutes before the slow addition of tert-butyl nitrite (41.0 µL, 90%,
0.308 mmol) in DME (10 mL). The mixture was warmed up to 0°C. and kept stirring for 1.5 hours
before being evaporated to dryness. The residue was dissolved into xylene (10 mL) and was heated
up to 135°C. for 30 minutes. The reaction was cooled down and the volatiles were evaporated. The
residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (72.0 mg, NMR
75% purity) as a light yellow oil. Yield 72.0 mg.

Yield 60.2 mg.

step 65b.
Source
infection
Inc., USA
2010
Patent Information
Jun 03, 2010
US 20100135960
A1
Number of Steps
3
99. 3 Steps

10°C
1.2 R:t-BuONO, S:(CH2OMe)2, -10°C; 1.5 h, -10°C

→ 0°C
Step 73d. To a solution of boron trifluoride etherate (0.41 mL, 4.06 mmol) in 1,2-dimethoxyethane
(DME, 15 mL) at -10°C. was added the compound from step 73c (0.770 g, 3.25 mmol) in DME (21
mL) dropwise. The reaction was stirred at this temperature for 30 minutes before the slow addition of
tert-butyl nitrite (0.45 mL, 90%, 3.41 mmol) in DME (15 mL). The mixture was warmed up to 0°C. and
stirred for 1.5 hours before being evaporated to dryness. The residue was dissolved into
chlorobenzene (40 mL) and was heated up to 135°C. for 1.5 hours. The reaction was cooled down
and the volatiles were evaporated. The residue was chromatographed (silica, hexanes-EtOAc) to give
the desired compound (0.232 g) as a yellow oil. Step 78d. The desired compound (0.322 g) was
prepared from the compound of step 78c (0.475 g, 1.66 mmol) following a procedure similar to that
described in step 73d.

2.1 R:NaOH, S:H2O, S:MeOH, 2 h, reflux 98%
(pH=3), Reactants: 1, Reagents: 1,
General/Typical Procedure: Step 69e. To a solution of the compound from step 69d (0.116 g, 0.450
mmol) in MeOH (5 mL) was added 50% aqueous NaOH (1.8 mL). It was refluxed for 2 hours before
being acidified to pH 3. The mixture was partitioned between CH2Cl2 and water, and the organics
were washed with brine, dried over sodium sulfate and evaporated. The residue was
chromatographed (silica, CH2Cl2-MeOH) to give the desired compound (99.6 mg, 91%) as a white
solid. Step 78e. The desired compound (0.301 g, 98%) as a white solid was prepared from the
compound from step 78d (0.301 g, 1.11 mmol) following a similar procedure to that described in step
69e.

78f. The crude desired compound (0.174 mmol at most) as a light yellow oil was prepared from the
compound from step 78e (0.301 g, 1.09 mmol) following a similar procedure to that described in step
65b.
Source
infection
Inc., USA
2010
Patent Information
Jun 03, 2010
US 20100135960
A1
Number of Steps
3
100. 4 Steps

1.1 R:SnCl2 •2H2O, S:MeOH, S:AcOEt, 20 h, 70°C Steps: 1, Stages: 1 25%
Step 79b. To a solution of the compound from step 79a (0.355 g, 1.12 mmol) in EtOH (8 mL) and
EtOAc (8 mL) was added SnCl2.2H2O (2.03 g, 8.99 mmol). It was heated at 70°C. for 20 hours before
being evaporated to dryness. The residue was partitioned between EtOAc and water, and the
organics were washed with saturated NaHCO3, brine, dried over sodium sulfate and evaporated. The
residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (80.5 mg, 25%)
as a colorless oil. Yield 80.5 mg, 25%.
2

10°C
2.2 R:t-BuONO, S:(CH2OMe)2, -10°C; -10°C →

0°C; 1.5 h, 0°C
Step 79c. To a solution of BF3.Et2O (38.0 µL, 0.378 mmol) in DME (4 mL) at -10°C. was added the
compound from step 79b (80.5 mg, 0.280 mmol) in DME (6 mL) dropwise. The reaction was kept
stirring at this temperature for 30 minutes before the slow addition of tert-butyl nitrite (41.0 µL, 90%,
0.308 mmol) in DME (10 mL). The mixture was warmed up to 0°C. and kept stirring for 1.5 hours
before being evaporated to dryness. The residue was dissolved into xylene (10 mL) and was heated
up to 135°C. for 30 minutes. The reaction was cooled down and the volatiles were evaporated. The
residue was chromatographed (silica, hexanes-EtOAc) to give the desired compound (72.0 mg, NMR
75% purity) as a light yellow oil. Yield 72.0 mg.

Yield 60.2 mg.
4

step 65b.
Source
infection
Inc., USA
2010
Patent Information
Jun 03, 2010
US 20100135960
A1
Number of Steps
4

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Step Stages Notes Yield

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

1.3 R:NH4Cl, S:H2O, rt

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

4.2 R:NH4Cl, S:H2O

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

5.3 R:NH4Cl, S:H2O

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec

Step Stages Notes Yield

Step Stages Notes Yield

Step Stages Notes Yield

1.3 R:NH4Cl, S:H2O, rt

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

4.2 R:NH4Cl, S:H2O

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

5.3 R:NH4Cl, S:H2O

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

1.3 R:NH4Cl, S:H2O, rt

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

5.2 R:NH4Cl, S:H2O

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

6.3 R:NH4Cl, S:H2O

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State

Step Stages Notes Yield

Available 1H NMR, 13C NMR, IR, HRMS, Mass Spec, State