2,3-difluorobenzonitrile

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

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

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

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl alcohol (5.51 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (2.128 g of a 60% dispersion in mineral oil) and 2,3-difluorobenzonitrile (7.4 g) in THF (100 mL) with external ice bath cooling to maintain temperature around 25° C. After addition was complete, the reaction mixture was stirred at room temperature for 24 h, quenched with water (200 mL) and extracted into ethyl acetate (3×120 mL), combined organics were dried (MgSO4) and evaporated. The residual oil was purified (SiO2 chromatography eluting with 20% ether in isohexane) to give the subtitle compound as an oil (9.70 g). cooling After addition quenched with water (200 mL) extracted into ethyl acetate (3×120 mL) combined organics were dried (MgSO4) evaporated The residual oil was purified (SiO2 chromatography eluting with 20% ether in isohexane)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 mL) pre-saturated with ammonia gas was heated at 140° C. in an autoclave for 8 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was dissolved in water (400 mL) and extracted with diethyl ether (2×300 mL). The combined organics were washed with water (300 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. Trituration with isohexane (150 mL) afforded 2-amino-3-fluorobenzonitrile (9.8 g, 50%) as an off-white solid: δH (360 MHz, CDCl3) 4.47 (2H, s), 6.65-6.71 (1H, m), 7.14-7.20 (2H, m). to cool to ambient temperature evaporated to dryness The residue was dissolved in water (400 mL) extracted with diethyl ether (2×300 mL) The combined organics were washed with water (300 mL) and brine (250 mL) dried over anhydrous magnesium sulfate filtered evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of NaN3 (1.17 g, 1.8 mmol) and difluorobenzonitrile (0.5 g, 3.6 mmol) in DMA (60 mL) was heated at 100° C. for 30 minutes. The mixture was next diluted with water (300 mL) and ether (300 mL). The organic layer was washed three times with water and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography using ether:hexane (1:5) as eluent to give the desired product (1q) as white crystals (0.3 g, 53% isolated yield). 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.27-7.18 (m, 1H). The organic layer was washed three times with water and brine The organic layer was dried (MgSO4) concentrated The crude product was purified by flash column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of NaN3 (1.17 g, 1.8 mmol) and difluorobenzonitrile (0.5 g, 3.6 mmol) in DMA (60 mL) was heated at 100° C. for 30 minutes. The mixture was next diluted with water (300 mL) and ether (300 mL). The organic layer was washed three times with water and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography using ether:hexane (1:5) as eluent to give the desired product (1q) as white crystals (0.3 g, 53% isolated yield). 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.27-7.18 (m, 1H). The organic layer was washed three times with water and brine The organic layer was dried (MgSO4) concentrated The crude product was purified by flash column chromatography

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 ml) pre-saturated with ammonia gas was heated at 140° C. in an autoclave for 8 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was dissolved in water (400 ml) and extracted with diethyl ether (2×300 ml). The combined organics were washed with water (300 ml) and brine (250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Trituration with isohexane (150 ml) afforded 2-amino-3-fluorobenzonitrile (9.8 g, 50%) as an off-white solid: 1H NMR (360 MHz, CDCl3) δ 4.47 (2H, s), 6.65–6.71 (1H, m), 7.14–7.20 (2H, m). to cool to ambient temperature evaporated to dryness The residue was dissolved in water (400 ml) extracted with diethyl ether (2×300 ml) The combined organics were washed with water (300 ml) and brine (250 ml) dried over anhydrous magnesium sulfate filtered evaporated

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-5-methylisoindolin-1-one (0.05 g) in DMF (1.00 mL) were added potassium carbonate (0.07 g) and 2,3-difluorobenzonitrile (0.05 g), and the mixture was stirred overnight at 150° C. under argon atmosphere. The reaction mixture was diluted with water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then HPLC (water/methanol) to give the title compound (7.80 mg). the mixture was partitioned The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-5-methylisoindolin-1-one (0.05 g) in DMF (1.00 mL) were added potassium carbonate (0.07 g) and 2,3-difluorobenzonitrile (0.05 g), and the mixture was stirred overnight at 150° C. under argon atmosphere. The reaction mixture was diluted with water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then HPLC (water/methanol) to give the title compound (7.80 mg). the mixture was partitioned The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 ml) pre-saturated with ammonia gas was heated at 140° C. in an autoclave for 8 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was dissolved in water (400 ml) and extracted with diethyl ether (2×300 ml). The combined organics were washed with water (300 ml) and brine (250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Trituration with isohexane (150 ml) afforded 2-amino-3-fluorobenzonitrile (9.8 g, 50%) as an off-white solid: 1H NMR (360 MHz, CDCl3) δ 4.47 (2H, s), 6.65-6.71 (1H, m), 7.14-7.20 (2H, m). to cool to ambient temperature evaporated to dryness The residue was dissolved in water (400 ml) extracted with diethyl ether (2×300 ml) The combined organics were washed with water (300 ml) and brine (250 ml) dried over anhydrous magnesium sulfate filtered evaporated