3,5-difluoro-4-(hydroxymethyl)benzonitrile

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

Procedure: A mixture of (4-bromo-2,6-difluorophenyl)methanol (1.12 g, 5.0 mmol), Pd(PPh3)4 (323 mg, 0.28 mmol) and zinc cyanide (587 mg, 5.0 mmol) was prepared in DMF (7 mL) under nitrogen atmosphere and heated at 90° C. for 18 hours. The mixture was diluted with DCM and water. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.28-7.21 (2H, m), 4.83 (2H, d, J=6.7 Hz), 1.95 (1H, t, J=6.7 Hz). the solvent evaporated in vacuo The residue was purified by flash chromatography (silica, iso-hexane/EtOAc)

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

Procedure: A mixture of (4-bromo-2,6-difluorophenyl)methanol (1.12 g, 5.0 mmol), Pd(PPh3)4 (323 mg, 0.28 mmol) and zinc cyanide (587 mg, 5.0 mmol) was prepared in DMF (7 mL) under nitrogen atmosphere and heated at 90° C. for 18 hours. The mixture was diluted with DCM and water. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.28-7.21 (2H, m), 4.83 (2H, d, J=6.7 Hz), 1.95 (1H, t, J=6.7 Hz). the solvent evaporated in vacuo The residue was purified by flash chromatography (silica, iso-hexane/EtOAc)

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

Procedure: To a solution of 3,5-difluoro-4-(hydroxymethyl)benzonitrile (all material from above reaction) in DCM at 0° C. was added PBr3 (283 μL, 3 mmol). After stirring 1 h at 0° C., the reaction mixture was quenched with water and then extracted with DCM. The combined extracts were washed with satd NaHCO3, dried over Na2SO4 and concentrated to yield 4-(bromomethyl)-3,5-difluorobenzonitrile (0.88 g, 63%, combined yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 1H), 4.51 (d, J=10.1, 1H); GC-MS (ES) m/z 231 (M). the reaction mixture was quenched with water extracted with DCM The combined extracts were washed with satd NaHCO3 dried over Na2SO4 concentrated

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

Procedure: To a solution of 3,5-difluoro-4-formylbenzonitrile (1.0 g, 6.0 mmol) in EtOH (15 mL) at 0° C. was added NaBH4 (113 mg, 0.5 equiv). After stirring 2 h at 0° C., the reaction mixture was quenched with water and concentrated under reduced pressure. The crude residue was dissolved in DCM, washed with brine, dried over Na2SO4 and concentrated to give 3,5-difluoro-4-(hydroxymethyl)benzonitrile as a solid. All material was used in the next step. 1H NMR (400 MHz, CDCl3) δ 7.29-7.15 (m, 2H), 4.82 (d, J=6.2, 2H), 2.02 (dd, J=12.0, 5.6, 1H); GC-MS (ES) m/z 169 (M). the reaction mixture was quenched with water concentrated under reduced pressure The crude residue was dissolved in DCM washed with brine dried over Na2SO4 concentrated