4-bromo-2-fluoro-6-methoxybenzonitrile

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (2, 5.22 g, 22.7 mmol), phenylboronic acid (4.15 g, 34 mmol) and 2 M Na2CO3 (23 mL) in toluene (100 mL) was purged with N2 for 10 min. Pd(PPh4)3 (2.62 g, 27.7 mmol) and EtOH (5 drops) were added. The mixture was then heated under N2 in a sealed tube at 80° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (5.05 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.50-7.23 (m, 3H), 7.01-6.99 (m, 1H), 6.93 (s, 1H), 3.95 (s, 3H). was purged with N2 for 10 min The mixture was cooled to room temperature filtered through celite, concentrated purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (2, 5.22 g, 22.7 mmol), phenylboronic acid (4.15 g, 34 mmol) and 2 M Na2CO3 (23 mL) in toluene (100 mL) was purged with N2 for 10 min. Pd(PPh4)3 (2.62 g, 27.7 mmol) and EtOH (5 drops) were added. The mixture was then heated under N2 in a sealed tube at 80° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (5.05 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.50-7.23 (m, 3H), 7.01-6.99 (m, 1H), 6.93 (s, 1H), 3.95 (s, 3H). was purged with N2 for 10 min The mixture was cooled to room temperature filtered through celite, concentrated purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

Procedure: To a solution of 4-bromo-2,6-difluorobenzonitrile (1, 15.0 g, 69 mmol) in THF (100 mL) at 0° C. was slowly added sodium methoxide (25% wt in methanol, 14.9 g, 69 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between dichloromethane (500 mL) and water (250 mL). The organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (15.2 g, 99%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.01-6.99 (m, 1H), 6.94 (s, 1H), 3.96 (s, 1H). at 0° C. The mixture was concentrated partitioned between dichloromethane (500 mL) and water (250 mL) The organic extracts were dried (MgSO4) filtered concentrated The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

Procedure: To a solution of 4-bromo-2,6-difluoro-benzonitrile (15.0 g, 68.8 mmol) in tetrahydrofuran (150 ml) is added sodium methoxide (4.5 g, 82.6 mmol) at room temperature and the mixture is stirred for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) to obtain 4-bromo-2-fluoro-6-methoxy-benzonitrile (8.5 g, 36.9 mmol, 53%). The reaction mixture is concentrated under reduced pressure the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (2, 5.22 g, 22.7 mmol), phenylboronic acid (4.15 g, 34 mmol) and 2 M Na2CO3 (23 mL) in toluene (100 mL) was purged with N2 for 10 min. Pd(PPh4)3 (2.62 g, 27.7 mmol) and EtOH (5 drops) were added. The mixture was then heated under N2 in a sealed tube at 80° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (5.05 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.50-7.23 (m, 3H), 7.01-6.99 (m, 1H), 6.93 (s, 1H), 3.95 (s, 3H). was purged with N2 for 10 min The mixture was cooled to room temperature filtered through celite, concentrated purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

Procedure: To a solution of 4-bromo-2,6-difluorobenzonitrile (1, 15.0 g, 69 mmol) in THF (100 mL) at 0° C. was slowly added sodium methoxide (25% wt in methanol, 14.9 g, 69 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between dichloromethane (500 mL) and water (250 mL). The organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (15.2 g, 99%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.01-6.99 (m, 1H), 6.94 (s, 1H), 3.96 (s, 1H). at 0° C. The mixture was concentrated partitioned between dichloromethane (500 mL) and water (250 mL) The organic extracts were dried (MgSO4) filtered concentrated The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

Procedure: To methanol (0.28 mL, 6.9 mmol) and 4-bromo-2,6-difluorobenzonitrile (1500 mg, 6.88 mmol) in THF (34 mL) was added NaHMDS (6.88 mL, 1.0 M in THF, 6.88 mmol) at 0° C. The reaction mixture was stirred at rt overnight, and diluted with brine, extracted with EtOAc. The organic layer was dried, and evaporated. The crude product was purified by column chromatography (0-30% EtOAc/Hex) to give 4-bromo-2-fluoro-6-methoxybenzonitrile. extracted with EtOAc The organic layer was dried evaporated The crude product was purified by column chromatography (0-30% EtOAc/Hex)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (2, 5.22 g, 22.7 mmol), phenylboronic acid (4.15 g, 34 mmol) and 2 M Na2CO3 (23 mL) in toluene (100 mL) was purged with N2 for 10 min. Pd(PPh4)3 (2.62 g, 27.7 mmol) and EtOH (5 drops) were added. The mixture was then heated under N2 in a sealed tube at 80° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (5.05 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.50-7.23 (m, 3H), 7.01-6.99 (m, 1H), 6.93 (s, 1H), 3.95 (s, 3H). was purged with N2 for 10 min The mixture was cooled to room temperature filtered through celite, concentrated purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

Procedure: To a solution of 4-bromo-2,6-difluorobenzonitrile (1, 15.0 g, 69 mmol) in THF (100 mL) at 0° C. was slowly added sodium methoxide (25% wt in methanol, 14.9 g, 69 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between dichloromethane (500 mL) and water (250 mL). The organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (15.2 g, 99%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.01-6.99 (m, 1H), 6.94 (s, 1H), 3.96 (s, 1H). at 0° C. The mixture was concentrated partitioned between dichloromethane (500 mL) and water (250 mL) The organic extracts were dried (MgSO4) filtered concentrated The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

Procedure: To a solution of 4-bromo-2,6-difluoro-benzonitrile (15.0 g, 68.8 mmol) in tetrahydrofuran (150 ml) is added sodium methoxide (4.5 g, 82.6 mmol) at room temperature and the mixture is stirred for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) to obtain 4-bromo-2-fluoro-6-methoxy-benzonitrile (8.5 g, 36.9 mmol, 53%). The reaction mixture is concentrated under reduced pressure the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane)