2-(3-fluorophenyl)acetonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CHART B, Preparation of the amine used in Chart B, Step B-2. A stirred suspension of freshly washed and dried sodium hydride (50% by wt, 9.59 g, 200 mmol) in dry dimethyl sulfoxide (75 mL) under N2 is cooled to 0° C. A mixture of 3-fluorophenylacetonitrile (8.6 mL, 74.0 mmol) and 1,3-dibromopropane (8.3 mL, 81.4 mmol) in ether (40 mL) is then added dropwise over 35 minutes, via cannula. The resulting orange-red mixture is allowed to stir at 20°-25° C. overnight. The thick reaction mixture is cooled to 0° C. and treated with isopropanol (4 mL). After stirring for 15 minutes, water (64 mL) is added in 10 mL increments and the phases are separated. The aqueous layer is extracted with ether (4×100 mL). The combined organics are washed with water (3×100mL), brine (1×100 mL), dried (MgSO4), filtered and concentrated. The product is distilled at 95° C. (1.0 torr) to afford 7.41 g of 1-(3-fluorophenyl)cyclobutanecarbonitrile. 1H NMR (CDCl3) δ7.39 (m, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 7.05 (m, 1 H), 2.81 (m, 2 H), 2.60 (m, 4 H), 2.50 (m, 1 H), 2.12 (m, 1 H); 13C NMR (CDCl3) δ164.6, 161.3, 142.2, 130.6, 130.5, 123.8, 121.37, 121.32, 115.0, 114.7, 113.0, 112.7, 77.2, 40.9, 39.9, 34.6, 17.0. A stirred suspension of freshly washed is then added dropwise over 35 minutes, via cannula After stirring for 15 minutes the phases are separated The aqueous layer is extracted with ether (4×100 mL) The combined organics are washed with water (3×100mL), brine (1×100 mL) dried (MgSO4) filtered concentrated The product is distilled at 95° C. (1.0 torr)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CHART B, Preparation of the amine used in Chart B, Step B-2. A stirred suspension of freshly washed and dried sodium hydride (50% by wt, 9.59 g, 200 mmol) in dry dimethyl sulfoxide (75 mL) under N2 is cooled to 0° C. A mixture of 3-fluorophenylacetonitrile (8.6 mL, 74.0 mmol) and 1,3-dibromopropane (8.3 mL, 81.4 mmol) in ether (40 mL) is then added dropwise over 35 minutes, via cannula. The resulting orange-red mixture is allowed to stir at 20°-25° C. overnight. The thick reaction mixture is cooled to 0° C. and treated with isopropanol (4 mL). After stirring for 15 minutes, water (64 mL) is added in 10 mL increments and the phases are separated. The aqueous layer is extracted with ether (4×100 mL). The combined organics are washed with water (3×100mL), brine (1×100 mL), dried (MgSO4), filtered and concentrated. The product is distilled at 95° C. (1.0 torr) to afford 7.41 g of 1-(3-fluorophenyl)cyclobutanecarbonitrile. 1H NMR (CDCl3) δ7.39 (m, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 7.05 (m, 1 H), 2.81 (m, 2 H), 2.60 (m, 4 H), 2.50 (m, 1 H), 2.12 (m, 1 H); 13C NMR (CDCl3) δ164.6, 161.3, 142.2, 130.6, 130.5, 123.8, 121.37, 121.32, 115.0, 114.7, 113.0, 112.7, 77.2, 40.9, 39.9, 34.6, 17.0. A stirred suspension of freshly washed is then added dropwise over 35 minutes, via cannula After stirring for 15 minutes the phases are separated The aqueous layer is extracted with ether (4×100 mL) The combined organics are washed with water (3×100mL), brine (1×100 mL) dried (MgSO4) filtered concentrated The product is distilled at 95° C. (1.0 torr)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6 mmol) and 3-fluoro-benzeneacetonitrile (CAS 501-00-8) (4.35 g, 29.6 mmol) in absolute EtOH, 30 mL, was added NaOMe (0.1 equiv), then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with cold EtOH and gave (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile as a white solid (6.20 g, 78%). NaBH4 (1.8 g, 47 mmol) was added slowly to a solution of (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile (6.17 g, 23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70° C. for 16 h. The solution was cooled to room temperature and quenched with water. The reaction mixture was diluted with 100 mL water and acidified with 6M HCl (aq.). After extraction with ether (3×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated and gave 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile as a white solid (6 g, 96%). DIBAL-H (1.0 M in toluene, 14 mL, 14 mmol) was added dropwise to a solution of 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile (2.93 g, 11.72 mmol) in Toluene (40 mL) at −78° C. under argon. The mixture was stirred at −78° C. to −20° C. for 3 h and then quenched by slow addition of saturated NH4Cl solution (2 mL) followed by Celite (2 g) at −20° C. The mixture was diluted with Et2O (50 mL), warmed slowly to room temperature, and stirred till all aluminum precipitated. The solid was filtered and washed with ether (3×50 mL), the combined organic layers were dried over MgSO4, filtered, concentrated and gave Intermediate 5 (2.34 g, 74%). The reaction mixture was cooled to 0° C. filtered The precipitate was washed with cold EtOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6 mmol) and 3-fluoro-benzeneacetonitrile (CAS 501-00-8) (4.35 g, 29.6 mmol) in absolute EtOH, 30 mL, was added NaOMe (0.1 equiv), then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with cold EtOH and gave (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile as a white solid (6.20 g, 78%). NaBH4 (1.8 g, 47 mmol) was added slowly to a solution of (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile (6.17 g, 23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70° C. for 16 h. The solution was cooled to room temperature and quenched with water. The reaction mixture was diluted with 100 mL water and acidified with 6M HCl (aq.). After extraction with ether (3×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated and gave 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile as a white solid (6 g, 96%). DIBAL-H (1.0 M in toluene, 14 mL, 14 mmol) was added dropwise to a solution of 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile (2.93 g, 11.72 mmol) in Toluene (40 mL) at −78° C. under argon. The mixture was stirred at −78° C. to −20° C. for 3 h and then quenched by slow addition of saturated NH4Cl solution (2 mL) followed by Celite (2 g) at −20° C. The mixture was diluted with Et2O (50 mL), warmed slowly to room temperature, and stirred till all aluminum precipitated. The solid was filtered and washed with ether (3×50 mL), the combined organic layers were dried over MgSO4, filtered, concentrated and gave Intermediate 5 (2.34 g, 74%). The reaction mixture was cooled to 0° C. filtered The precipitate was washed with cold EtOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CHART B, Preparation of the amine used in Chart B, Step B-2. A stirred suspension of freshly washed and dried sodium hydride (50% by wt, 9.59 g, 200 mmol) in dry dimethyl sulfoxide (75 mL) under N2 is cooled to 0° C. A mixture of 3-fluorophenylacetonitrile (8.6 mL, 74.0 mmol) and 1,3-dibromopropane (8.3 mL, 81.4 mmol) in ether (40 mL) is then added dropwise over 35 minutes, via cannula. The resulting orange-red mixture is allowed to stir at 20°-25° C. overnight. The thick reaction mixture is cooled to 0° C. and treated with isopropanol (4 mL). After stirring for 15 minutes, water (64 mL) is added in 10 mL increments and the phases are separated. The aqueous layer is extracted with ether (4×100 mL). The combined organics are washed with water (3×100mL), brine (1×100 mL), dried (MgSO4), filtered and concentrated. The product is distilled at 95° C. (1.0 torr) to afford 7.41 g of 1-(3-fluorophenyl)cyclobutanecarbonitrile. 1H NMR (CDCl3) δ7.39 (m, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 7.05 (m, 1 H), 2.81 (m, 2 H), 2.60 (m, 4 H), 2.50 (m, 1 H), 2.12 (m, 1 H); 13C NMR (CDCl3) δ164.6, 161.3, 142.2, 130.6, 130.5, 123.8, 121.37, 121.32, 115.0, 114.7, 113.0, 112.7, 77.2, 40.9, 39.9, 34.6, 17.0. A stirred suspension of freshly washed is then added dropwise over 35 minutes, via cannula After stirring for 15 minutes the phases are separated The aqueous layer is extracted with ether (4×100 mL) The combined organics are washed with water (3×100mL), brine (1×100 mL) dried (MgSO4) filtered concentrated The product is distilled at 95° C. (1.0 torr)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound, light yellow solid (85 mg, 65%), MS (ISP) m/z=392.2 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound, light yellow solid (46 mg, 35%), MS (ISP) m/z=390.2 [(M+H)+], mp 184° C., was prepared in accordance with the general method of example 1 from 1-(4-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate H) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound, light green solid (81 mg, 62%), MS (ISP) m/z=386.2 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.