1-[(3-bromophenyl)methyl]-4,4-difluoropiperidine

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at −78° C. for 20 min, then allowed to warm to RT over 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z 442 [MH+]. The mixture was stirred at −78° C. for 20 min to warm to RT over 20 min The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL) The combined organic extracts were washed with brine (20 mL) dried (Na2SO4) The solvent was evaporated the residue purified by FCC eluting with 0-100% EtOAc in pentane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at −78° C. for 20 min, then allowed to warm to RT over 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z 442 [MH+]. The mixture was stirred at −78° C. for 20 min to warm to RT over 20 min The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL) The combined organic extracts were washed with brine (20 mL) dried (Na2SO4) The solvent was evaporated the residue purified by FCC eluting with 0-100% EtOAc in pentane

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

Procedure: A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4-difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol), and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) was stirred at RT for 16 h. The mixture was filtered and evaporated, and the residue partitioned between water (30 mL) and EtOAc (3×30 mL). The combined organic extracts were washed with water (2×50 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as a colourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290/292 [MH+]. The mixture was filtered evaporated the residue partitioned between water (30 mL) and EtOAc (3×30 mL) The combined organic extracts were washed with water (2×50 mL) dried (Na2SO4) The solvent was evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at −78° C. for 20 min, then allowed to warm to RT over 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z 442 [MH+]. The mixture was stirred at −78° C. for 20 min to warm to RT over 20 min The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL) The combined organic extracts were washed with brine (20 mL) dried (Na2SO4) The solvent was evaporated the residue purified by FCC eluting with 0-100% EtOAc in pentane

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

Procedure: A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4-difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol), and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) was stirred at RT for 16 h. The mixture was filtered and evaporated, and the residue partitioned between water (30 mL) and EtOAc (3×30 mL). The combined organic extracts were washed with water (2×50 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as a colourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290/292 [MH+]. The mixture was filtered evaporated the residue partitioned between water (30 mL) and EtOAc (3×30 mL) The combined organic extracts were washed with water (2×50 mL) dried (Na2SO4) The solvent was evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at −78° C. for 20 min, then allowed to warm to RT over 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z 442 [MH+]. The mixture was stirred at −78° C. for 20 min to warm to RT over 20 min The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL) The combined organic extracts were washed with brine (20 mL) dried (Na2SO4) The solvent was evaporated the residue purified by FCC eluting with 0-100% EtOAc in pentane

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

Procedure: A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4-difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol), and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) was stirred at RT for 16 h. The mixture was filtered and evaporated, and the residue partitioned between water (30 mL) and EtOAc (3×30 mL). The combined organic extracts were washed with water (2×50 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as a colourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290/292 [MH+]. The mixture was filtered evaporated the residue partitioned between water (30 mL) and EtOAc (3×30 mL) The combined organic extracts were washed with water (2×50 mL) dried (Na2SO4) The solvent was evaporated