4-fluoro-2-phenylmethoxybenzonitrile

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

Procedure: A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H, d, J=5.2 Hz). The catalyst was removed by filtration through Celite the filtrate was concentrated The crude product was triturated with ether the resulting solid collected by filtration

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

Procedure: Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59–7.55 (1H, m), 7.45–7.34 (5H, m), 6.75–6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2; found: 228.0. After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml) The organic layer was dried (Na2SO4) filtered concentrated to give a white slurry which was triturated with hexanes filtered

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

Procedure: A solution of 2-(benzyloxy)-4-fluorobenzonitrile (4.8 g, 21 mmol), in ethanol (80 mL) was treated with hydrazine monohydrate (2.6 g, 2.5 mL, 53 mmol) and heated to reflux for 3 days. The mixture was cooled to room temperature and concentrated. Water was added and the residue was extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and condensed to give 2-(benzyloxy)-4-hydrazinylbenzonitrile (3.8 g, 15.8 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 2H), 5.16 (s, 2H), 6.36 (dd, J=8.73, 1.75 Hz, 1H), 6.61 (d, J=1.61 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 7.32-7.51 (m, 5H), 7.78 (s, 1H). ES-MS m/z 240 (M+H) heated to reflux for 3 days concentrated Water was added the residue was extracted three times with ethyl acetate dried over magnesium sulfate filtered condensed

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

Procedure: A solution of 2-(benzyloxy)-4-fluorobenzonitrile (4.8 g, 21 mmol), in ethanol (80 mL) was treated with hydrazine monohydrate (2.6 g, 2.5 mL, 53 mmol) and heated to reflux for 3 days. The mixture was cooled to room temperature and concentrated. Water was added and the residue was extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and condensed to give 2-(benzyloxy)-4-hydrazinylbenzonitrile (3.8 g, 15.8 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 2H), 5.16 (s, 2H), 6.36 (dd, J=8.73, 1.75 Hz, 1H), 6.61 (d, J=1.61 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 7.32-7.51 (m, 5H), 7.78 (s, 1H). ES-MS m/z 240 (M+H) heated to reflux for 3 days concentrated Water was added the residue was extracted three times with ethyl acetate dried over magnesium sulfate filtered condensed

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

Procedure: Benzyl alcohol (3.25 g, 30 mmol) was slowly added to a stirred suspension of sodium hydride (1.15 g, 28.7 mmol) in toluene (50 mL) at room temperature. The mixture was stirred for 30 minutes and then 2,4-difluorobenzonitrile was added all at once and stirring continued overnight. The mixture was quenched with water, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and condensed. The crude product was dissolved in hot ethyl acetate and triturated with hexanes to give 2-(benzyloxy)-4-fluorobenzonitrile (5.4 g, 23.8 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (s, 2H), 6.99 (td, J=8.46, 2.42 Hz, 1H), 7.29-7.51 (m, 6H), 7.86 (dd, J=8.59, 6.44 Hz, 1H). stirring continued overnight The mixture was quenched with water extracted three times with ethyl acetate washed with brine dried over magnesium sulfate filtered condensed triturated with hexanes

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

Procedure: A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H, d, J=5.2 Hz). The catalyst was removed by filtration through Celite the filtrate was concentrated The crude product was triturated with ether the resulting solid collected by filtration

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

Procedure: Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59–7.55 (1H, m), 7.45–7.34 (5H, m), 6.75–6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2; found: 228.0. After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml) The organic layer was dried (Na2SO4) filtered concentrated to give a white slurry which was triturated with hexanes filtered

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

Procedure: A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1 H, s), 8.18 (3 H, s), 7.36 (1 H, t, J=7.3 Hz), 6.79 (1 H, dd, J=10.8, 2.6 Hz), 6.66 (1 H, dt, J=8.5, 2.3 Hz), 3.90 (2 H, d, J=5.2 Hz). The catalyst was removed by filtration through Celite the filtrate was concentrated The crude product was triturated with ether the resulting solid collected by filtration

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

Procedure: Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59-7.55 (1H, m), 7.45-7.34 (5H, m), 6.75-6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2; found: 228.0. After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml) The organic layer was dried (Na2SO4) filtered concentrated to give a white slurry which was triturated with hexanes filtered

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

Procedure: A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H, d, J=5.2 Hz). The catalyst was removed by filtration through Celite the filtrate was concentrated The crude product was triturated with ether the resulting solid collected by filtration

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

Procedure: Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 1100 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59-7.55 (1H, m), 7.45-7.34 (5H, m), 6.75-6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2; found: 228.0. After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml) The organic layer was dried (Na2SO4) filtered concentrated to give a white slurry which was triturated with hexanes filtered

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

Procedure: A solution 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite®, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1 H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2 H, d, J=5.2 Hz). The catalyst was removed by filtration through Celite® the filtrate was concentrated The crude product was triturated with ether the resulting solid collected by filtration