3-bromo-2-fluorobenzonitrile

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

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.81 g, 11.00 mmol) in a mixture of DME (30 mL), ethanol (15 mL), and water (15 mL) was added Na2CO3 (4.24 g, 40.0 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.500 mmol) was added followed by degassing with nitrogen for 10 minutes. The tube was then sealed and heated to 90° C. for 14 hours. The vessel was cooled to room temperature and diluted with EtOAc and water. The mixture was further diluted with brine and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the crude product as a brown oil. The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes) to give the title compound (2.18 g, 8.69 mmol, 87% yield) as a pale yellow solid. ESI MS (M+H)+=249.1. This suspension was degassed with a stream of N2 for 10 minutes by degassing with nitrogen for 10 minutes The tube was then sealed The vessel was cooled to room temperature diluted with EtOAc and water The mixture was further diluted with brine extracted three times with EtOAc The combined organics were dried over MgSO4 filtered concentrated to give the crude product as a brown oil The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes)

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

Procedure: A reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (1.040 g, 0.900 mmol), 3-bromo-2-fluorobenzonitrile (3.6 g, 18.00 mmol), sodium carbonate (7.63 g, 72.0 mmol), and 4-methylpyridin-3-ylboronic acid (2.59 g, 18.90 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (67.2 mL), EtOH (33.6 mL), and water (33.6 mL) were added sequentially. The resultant mixture was heated at 90° C. overnight. After 17 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (120 g column, 85 mL/min, 0-70% EtOAc in hexanes over 25 min, tr=15 min) gave the title compound (2.80 g, 13.19 mmol, 73.3% yield) as a purple residue. ESI MS (M+H)+=213.1. HPLC Peak tr=1.01 minutes. Purity >99%. HPLC Conditions: C. After 17 hr to cool to room temperature The reaction was quenched with water The reaction mixture was diluted with EtOAc The layers were separated the aqueous phase was extracted with EtOAc (3×) dried over Na2SO4 filtered concentrated to afford a brown residue to be chromatographed Purification of the crude material by silica gel chromatography an ISCO machine (120 g column, 85 mL/min, 0-70% EtOAc in hexanes over 25 min, tr=15 min)

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

Procedure: A mixture of 3-bromo-2-fluoro-benzonitrile (40.0 g, 0.200 mol) and tetrahydrofuran (200 mL) was chilled to 0° C. and stirred for 5 min. A solution of potassium tert-butoxide (130 mL, 0.210 mol) was added dropwise at 0° C. and the reaction was allowed to warm to RT with stirring over 90 min. The reaction was quenched with water (200 mL) and 2 M Na2CO3 (100 mL) and extracted with EtOAc (3×200 mL). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to provide the title compound as a light yellow oil. to warm to RT with stirring over 90 min The reaction was quenched with water (200 mL) and 2 M Na2CO3 (100 mL) extracted with EtOAc (3×200 mL) The organic layer was dried over Na2SO4 the solvent was removed by rotary evaporation

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

Procedure: To a flask containing sodium hydride (1.44 g, 60.0 mmol) suspended in DMF (60 mL, 800 mmol) at 0° C. was added benzyl alcohol (6.21 mL, 60.0 mmol) over 5 min. The reaction mixture was stirred at 0° C. for 30 min and then 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred at 80° C. for 2 h, cooled to room temperature, and extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was suspended with ethyl acetate:hexanes (1:3; 50 mL). The resulting suspension was stirred vigorously for 1 h, filtered, and dried. The mother liquor was concentrated and recrystallized. The crystals were combined and dried under vacuum to give the title compound (10.3 g). The reaction mixture was warmed to room temperature stirred at 80° C. for 2 h cooled to room temperature extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL) collected dried over anhydrous sodium sulfate filtered concentrated The resulting suspension was stirred vigorously for 1 h filtered dried The mother liquor was concentrated recrystallized dried under vacuum

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

Procedure: To a flask containing sodium hydride (1.44 g, 60.0 mmol) suspended in DMF (60 mL, 800 mmol) at 0° C. was added benzyl alcohol (6.21 mL, 60.0 mmol) over 5 min. The reaction mixture was stirred at 0° C. for 30 min and then 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred at 80° C. for 2 h, cooled to room temperature, and extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was suspended with ethyl acetate:hexanes (1:3; 50 mL). The resulting suspension was stirred vigorously for 1 h, filtered, and dried. The mother liquor was concentrated and recrystallized. The crystals were combined and dried under vacuum to give the title compound (10.3 g). The reaction mixture was warmed to room temperature stirred at 80° C. for 2 h cooled to room temperature extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL) collected dried over anhydrous sodium sulfate filtered concentrated The resulting suspension was stirred vigorously for 1 h filtered dried The mother liquor was concentrated recrystallized dried under vacuum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.81 g, 11.00 mmol) in a mixture of DME (30 mL), ethanol (15 mL), and water (15 mL) was added Na2CO3 (4.24 g, 40.0 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.500 mmol) was added followed by degassing with nitrogen for 10 minutes. The tube was then sealed and heated to 90° C. for 14 hours. The vessel was cooled to room temperature and diluted with EtOAc and water. The mixture was further diluted with brine and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the crude product as a brown oil. The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes) to give the title compound (2.18 g, 8.69 mmol, 87% yield) as a pale yellow solid. ESI MS (M+H)+=249.1. This suspension was degassed with a stream of N2 for 10 minutes by degassing with nitrogen for 10 minutes The tube was then sealed The vessel was cooled to room temperature diluted with EtOAc and water The mixture was further diluted with brine extracted three times with EtOAc The combined organics were dried over MgSO4 filtered concentrated to give the crude product as a brown oil The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.81 g, 11.00 mmol) in a mixture of DME (30 mL), ethanol (15 mL), and water (15 mL) was added Na2CO3 (4.24 g, 40.0 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.500 mmol) was added followed by degassing with nitrogen for 10 minutes. The tube was then sealed and heated to 90° C. for 14 hours. The vessel was cooled to room temperature and diluted with EtOAc and water. The mixture was further diluted with brine and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the crude product as a brown oil. The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes) to give the title compound (2.18 g, 8.69 mmol, 87% yield) as a pale yellow solid. ESI MS (M+H)+=249.1. This suspension was degassed with a stream of N2 for 10 minutes by degassing with nitrogen for 10 minutes The tube was then sealed The vessel was cooled to room temperature diluted with EtOAc and water The mixture was further diluted with brine extracted three times with EtOAc The combined organics were dried over MgSO4 filtered concentrated to give the crude product as a brown oil The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes)

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

Procedure: A reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (1.040 g, 0.900 mmol), 3-bromo-2-fluorobenzonitrile (3.6 g, 18.00 mmol), sodium carbonate (7.63 g, 72.0 mmol), and 4-methylpyridin-3-ylboronic acid (2.59 g, 18.90 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (67.2 mL), EtOH (33.6 mL), and water (33.6 mL) were added sequentially. The resultant mixture was heated at 90° C. overnight. After 17 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (120 g column, 85 mL/min, 0-70% EtOAc in hexanes over 25 min, tr=15 min) gave the title compound (2.80 g, 13.19 mmol, 73.3% yield) as a purple residue. ESI MS (M+H)+=213.1. HPLC Peak tr=1.01 minutes. Purity >99%. HPLC Conditions: C. After 17 hr to cool to room temperature The reaction was quenched with water The reaction mixture was diluted with EtOAc The layers were separated the aqueous phase was extracted with EtOAc (3×) dried over Na2SO4 filtered concentrated to afford a brown residue to be chromatographed Purification of the crude material by silica gel chromatography an ISCO machine (120 g column, 85 mL/min, 0-70% EtOAc in hexanes over 25 min, tr=15 min)

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

Procedure: A mixture of 3-bromo-2-fluoro-benzonitrile (40.0 g, 0.200 mol) and tetrahydrofuran (200 mL) was chilled to 0° C. and stirred for 5 min. A solution of potassium tert-butoxide (130 mL, 0.210 mol) was added dropwise at 0° C. and the reaction was allowed to warm to RT with stirring over 90 min. The reaction was quenched with water (200 mL) and 2 M Na2CO3 (100 mL) and extracted with EtOAc (3×200 mL). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to provide the title compound as a light yellow oil. to warm to RT with stirring over 90 min The reaction was quenched with water (200 mL) and 2 M Na2CO3 (100 mL) extracted with EtOAc (3×200 mL) The organic layer was dried over Na2SO4 the solvent was removed by rotary evaporation

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

Procedure: To a flask containing sodium hydride (1.44 g, 60.0 mmol) suspended in DMF (60 mL, 800 mmol) at 0° C. was added benzyl alcohol (6.21 mL, 60.0 mmol) over 5 min. The reaction mixture was stirred at 0° C. for 30 min and then 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred at 80° C. for 2 h, cooled to room temperature, and extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was suspended with ethyl acetate:hexanes (1:3; 50 mL). The resulting suspension was stirred vigorously for 1 h, filtered, and dried. The mother liquor was concentrated and recrystallized. The crystals were combined and dried under vacuum to give the title compound (10.3 g). The reaction mixture was warmed to room temperature stirred at 80° C. for 2 h cooled to room temperature extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL) collected dried over anhydrous sodium sulfate filtered concentrated The resulting suspension was stirred vigorously for 1 h filtered dried The mother liquor was concentrated recrystallized dried under vacuum