(2S,5S)-2,5-dimethylpyrrolidine

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and mixture of cis and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and mixture of cis and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2

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

Procedure: The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an 8 mL vial equipped with a stir bar was placed 5-(3′Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456, 100 mg, 0.289 mmol), (2S,5S)-2,5-dimethyl-pyrrolidine (176 mg, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (367 uL, 2.60 mmol). The mixture was heated to 160° C. for 3 hours and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 5% acetone/dichloromethane as the eluent to produce 10 mg of P-577 as a pale viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6 Hz, 6H), 1.56-1.61 (m, 4H), 3.72 (s, 3H), 3.75 (s, 2H), 4.07-4.12 (m, 2H), 6.38 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 425.1 (M+1) LC-MS: 92% In an 8 mL vial equipped with a stir bar cooled to room temperature The aqueous portion was extracted with dichloromethane (2×30 mL) washed with brine (15 mL) dried (MgSO4) concentrated The crude material was purified by silica gel column chromatography to produce 10 mg of P-577 as a pale viscous oil

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

Procedure: By a procedure analogous to Example 6, methyl bromoacetate is reacted with trans-2,5-dimethylpyrrolidine (J. Amer. Chem. Soc. 1951, 73, 5230) to give methyl (trans-2,5-dimethylpyrrolidin-1-yl)acetate.