4-bromo-3,5-difluorophenol

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-3,5-difluorophenol (5.0 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5 g) and triphenylphosphine (7.5 g) in THF (50 mL) was added diisopropyl azodicarboxylate (1.9 M in toluene, 14 mL) dropwise at room temperature. The reaction mixture was stirred at 60° C. overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (5.1 g). concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

Procedure: DIAD (2.45 mL, 12.6 mmol) was slowly added to a solution of 2-((1S,2R)-2-(1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (2.45 g, 8.41 mmol), 4-bromo-3,5-difluorophenol (1.93 g, 9.25 mmol), and triphenylphosphine (3.31 g, 12.6 mmol) in DCM (30 mL) that had been cooled to 0° C. The ice bath was removed and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM (20 mL) and washed with a 2 N NaOH solution (30 mL×1). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc:hexanes over 12 CV to afford the title compound. LC/MS (m/z): 482 (M+H)+. The ice bath was removed The reaction mixture was diluted with DCM (20 mL) washed with a 2 N NaOH solution (30 mL×1) The organic phase was dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc

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

Procedure: 2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (1.4 g, 5.05 mmol), 4-bromo-3,5-difluorophenol (1.26 g, 6.06 mmol) and triphenylphosphine (1.98 g, 7.57 mmol) were dissolved in dichloromethane (25 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.53 g, 7.57 mmol) added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with 0.5 N NaOH (50 ml), brine, dried over sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel column chromatography (50 g SNAP, 10˜40% EtOAc in hexane) to afford 1.86 g (79%) of the titled compound. LC/MS (m/z): 469 (M+H)+. Rf was 0.3 @ 30% EtOAc in hexanes (blue spot on CAM stain) The mixture was stirred at RT overnight washed with 0.5 N NaOH (50 ml), brine dried over sodium sulfate the volatiles removed in vacuo The residue was purified by silica gel column chromatography (50 g SNAP, 10˜40% EtOAc in hexane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-3,5-difluorophenol (5.0 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5 g) and triphenylphosphine (7.5 g) in THF (50 mL) was added diisopropyl azodicarboxylate (1.9 M in toluene, 14 mL) dropwise at room temperature. The reaction mixture was stirred at 60° C. overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (5.1 g). concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)