2-bromo-3-fluorobenzonitrile

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

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and (1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction was then cooled to 23° C. filtered and the solids were rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30% ethyl acatate/hexanes) afforded 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%). the reaction purged with bubbling N2 for 5 minutes purged with bubbling for 5 minutes in a sealed vessel heated to reflux for 2 h filtered the solids were rinsed with EtOAc the layers separated dried concentrated under reduced pressure

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and (1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction was then cooled to 23° C. filtered and the solids were rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30% ethyl acatate/hexanes) afforded 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%). the reaction purged with bubbling N2 for 5 minutes purged with bubbling for 5 minutes in a sealed vessel heated to reflux for 2 h filtered the solids were rinsed with EtOAc the layers separated dried concentrated under reduced pressure

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

Procedure: 2-Amino-3-fluorobenzonitrile (9.8 g, 71.9 mmol) was dissolved in hot 1,4-dioxane (10 mL), 48% hydrobromic acid (100 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (5.71 g, 82.7 mmol) in water (10 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (31.0 g, 216 mmol) in 48% hydrobromic acid (25 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (600 mL) and extracted with ethyl acetate (2×200 mL). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-3-fluorobenzonitrile (7.05 g, 49%) as a pale brown solid: δH (360 MHz, CDCl3) 7.62-7.68 (1H, m), 7.74-7.85 (1H, ddd, J 9, 9 and 1), 7.74-7.85 (1H, ddd, J 8, 1 and 1). then poured onto The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min The mixture was cooled to ambient temperature extracted with ethyl acetate (2×200 mL) The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (250 mL) dried over anhydrous magnesium sulfate filtered evaporated to give an orange oil Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%)

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

Procedure: 2-Amino-3-fluorobenzonitrile (9.8 g, 71.9 mmol) was dissolved in hot 1,4-dioxane (10 mL), 48% hydrobromic acid (100 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (5.71 g, 82.7 mmol) in water (10 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (31.0 g, 216 mmol) in 48% hydrobromic acid (25 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (600 mL) and extracted with ethyl acetate (2×200 mL). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-3-fluorobenzonitrile (7.05 g, 49%) as a pale brown solid: δH (360 MHz, CDCl3) 7.62-7.68 (1H, m), 7.74-7.85 (1H, ddd, J 9, 9 and 1), 7.74-7.85 (1H, ddd, J 8, 1 and 1). then poured onto The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min The mixture was cooled to ambient temperature extracted with ethyl acetate (2×200 mL) The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (250 mL) dried over anhydrous magnesium sulfate filtered evaporated to give an orange oil Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%)

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

Procedure: 2-{7-[4-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-3-yl}propan-2-ol was coupled to 2-bromo-3-fluorobenzonitrile (from Example 2, step a) under the conditions described in Example 1, step e. The residue was purified by flash column chromatography (silica gel, 3% isopropyl alcohol in dichloromethane) to give the title compound in 40% yield: 1H NMR (400 MHz, CDCl3) δ 1.69 (6H, s), 3.53 (1H, s), 3.96 (3H, s), 6.96 (1H, d, J 10.3), 7.43–7.62 (3H, m), 8.11 (1H, d, J 7.9), 8.34 (1H, s), 8.71(1H, s); MS (ES+) m/z 422 [M+H]+ The residue was purified by flash column chromatography (silica gel, 3% isopropyl alcohol in dichloromethane)

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

Procedure: To a solution of 2-amino-3-fluorobenzonitrile (17.07 g, 0.125 mol) in 1,4-dioxane (20 ml) was added 48% aqueous hydrobromic acid (200 ml) and the solution was cooled to 0° C. before adding dropwise a solution of sodium nitrite (9.95 g, 0.144 mol) in water (22 ml) over 35 min so that the temperature did not rise above 3° C. The resulting mixture was stirred at 2–3° C. for 2 h then poured onto a cooled (5° C.) solution of copper(I) bromide (26.98 g, 0.188 mol) in 48% hydrobromic acid (100 ml). The mixture was stirred for 10 min then heated to 50° C. over 1 h. The mixture was cooled to ambient temperature, diluted with water (1 l) and extracted with diethyl ether (2×500 ml). The combined organic extracts were washed with 1 M aqueous Na2SO3 (500 ml), then saturated aqueous NH4Cl (200 ml), dried (MgSO4), and evaporated to give a brown oil/solid. Purification by chromatography (silica gel, 10% EtOAc/isohexane) and trituration of a mixed fraction with isohexane afforded 13.22 g (53%) of 2-bromo-3-fluorobenzonitrile as a pale yellow solid: 1H NMR (360 MHz, CDCl3) δ 7.62–7.68 (1H, m), 7.74–7.85 (1H, ddd, J 9, 9, 1), 7.74–7.85 (1H, ddd, J 8, 1, 1). did not rise above 3° C then poured onto The mixture was stirred for 10 min then heated to 50° C. over 1 h The mixture was cooled to ambient temperature extracted with diethyl ether (2×500 ml) The combined organic extracts were washed with 1 M aqueous Na2SO3 (500 ml) saturated aqueous NH4Cl (200 ml), dried (MgSO4) evaporated to give a brown oil/solid Purification by chromatography (silica gel, 10% EtOAc/isohexane) and trituration of a mixed fraction with isohexane

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

Procedure: 2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 4 to give 6,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: 1H NMR (360 MHz, CDCl3) δ 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).

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

Procedure: 2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 4 to give 6,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: 1H NMR (360 MHz, CDCl3) δ 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and (1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction was then cooled to 23° C. filtered and the solids were rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30% ethyl acatate/hexanes) afforded 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%). the reaction purged with bubbling N2 for 5 minutes purged with bubbling for 5 minutes in a sealed vessel heated to reflux for 2 h filtered the solids were rinsed with EtOAc the layers separated dried concentrated under reduced pressure

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

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

Procedure: 2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 51 to give 6,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (400 MHz, CDCl3) 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).