[(2S)-1-methylpyrrolidin-2-yl]methanol

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

Procedure: A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31). the reaction heated to reflux for 6.5 h The solvent was evaporated the mixture extracted with ether extracted with EtOAc The extracts were washed with water dried the solvent evaporated to give a liquid The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31)

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

Procedure: A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31). the reaction heated to reflux for 6.5 h The solvent was evaporated the mixture extracted with ether extracted with EtOAc The extracts were washed with water dried the solvent evaporated to give a liquid The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31)

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

Procedure: A solution of (S)-1-methyl-2-pyrrolidinemethanol (1.15 g) in THF (45 mL) was treated with potassium tert-butoxide (1.2 g). After 10 min, chloropyrazine was added and the reaction stirred for 1.5 h. The reaction was quenched with 5 N HCl (4 mL) and the solvent evaporated. The residue was suspended in water and extracted with ether. The aqueous fraction was made basic and extracted with CHCl3. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 20%-EtOH-2%--NH4OH--CHCl3 to give (S)-2-(1-methyl-2-pyrrolidinylmethoxy)pyrazine (1.1). The HCl salt crystallized from EtOAc as a white solid, m.p. 121-122° C. (Compound 28) The reaction was quenched with 5 N HCl (4 mL) the solvent evaporated extracted with ether extracted with CHCl3 The extracts were dried the solvent evaporated the residue purified by radial chromatography eluting with 20%-EtOH-2%

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

Procedure: To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (5.5 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 12.0 g (100%) of the title compound. LCMS (APCI+) m/z 285 (M+H)+. the reaction mixture was quenched with saturated NaHCO3 (30 mL) The aqueous layer was extracted with ethyl acetate (3×30 mL) The combined organic layers were washed with brine (50 mL) dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: A solution of (S)-(1-methylpyrrolidin-2-yl)methanol (109 mg, 0.94 mmol) in THF (5 mL) was treated with 1 M solution of potassium t-butoxide (0.95 mL, 0.944 mmol) and stirred for 15 min. A solution of Example 9B (190 mg, 0.47 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo, partitioned between EtOAc and brine, dried (MgSO4), filtered, and concentrated. The residue was purified using an Analogix® Intelliflash280™ (SiO2, 0-15% methanol in dichloromethane) to afford the title compound (175 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.17-1.42 (m, 11H), 1.49-1.83 (m, 5H), 1.82-2.03 (m, 1H), 2.17 (q, J=8.7 Hz, 1H), 2.32 (s, 3H), 2.54-2.67 (m, 1H), 2.83-3.01 (m, 1H), 3.92-4.10 (m, 2H), 4.14 (t, J=7.3 Hz, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.72 (dd, J=9.0, 2.2 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H). MS (DCI/NH3) m/z 498 (M+H)+. Anal. calcd for C25H34F3N3O2S: C, 60.34; H, 6.99; N, 8.44. Found: C, 60.27; H, 7.09; N, 8.40. stirred for 6 hours The reaction mixture was quenched with saturated NH4Cl solution concentrated in vacuo partitioned between EtOAc and brine dried (MgSO4) filtered concentrated The residue was purified

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

Procedure: A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31). the reaction heated to reflux for 6.5 h The solvent was evaporated the mixture extracted with ether extracted with EtOAc The extracts were washed with water dried the solvent evaporated to give a liquid The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31)

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

Procedure: A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31). the reaction heated to reflux for 6.5 h The solvent was evaporated the mixture extracted with ether extracted with EtOAc The extracts were washed with water dried the solvent evaporated to give a liquid The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31)

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

Procedure: A mixture pyridine-triflate intermediate (see Example 1) (10 mg) and N-methyl-L-prolinol (40 mg) in dioxane was heated under Ar at 90° C. for 3 h. The mixture was cooled to room temperature, and Na2CO3 (2 M, 0.2 mL) was added. The mixture was heated at 100° C. under Ar for 10 h, cooled to room temperature and diluted with water (1 mL). The mixture was extracted with EtOAc, dried with Na2SO4 and concentrated. The residue was purified by preparative silica gel chromatography to give 6 mg of the title compound as a white solid. The mixture was heated at 100° C. under Ar for 10 h cooled to room temperature The mixture was extracted with EtOAc dried with Na2SO4 concentrated The residue was purified by preparative silica gel chromatography

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

Procedure: NaH (0.19 g, 5.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL) at 0° C. and (S)—N-methylpyrrolidine-2-methanol (0.47 mL, 4.80 mmol) was added. The suspension was stirred at 0° C. for 30 min and added to a solution of Intermediate 2 (1.33 g, 4.00 mmol) in THF (10 mL) and the reaction mixture was stirred at room temperature. An additional such portion of NaH and N-methylpyrrolidine methanol in THF was added after 8 h. After 18 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5%, 10%, and 20% MeOH in DCM (200 mL)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 60% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid]). The residue was de-salted using K2CO3 in DCM to give [(2S)-1-methylpyrrolidin-2-yl]methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (52.1 mg, 4.2%) as a colourless gum. the reaction mixture was stirred at room temperature After 18 h the reaction mixture was quenched with water (10 mL) the solvents were removed in vacuo The residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5%, 10%, and 20% MeOH in DCM (200 mL)) phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 60% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid])

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

Procedure: A mixture of N-methyl prolinol (0.226 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (3 mL). The gum which separated was collected (by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH-CHCl3) to afford the title compound E25 as a semi-solid (0.06 g, 20%). HPLC: Symmetry shield RP18 (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 3.0); solvent B=CH3CN], Gradient elution program: T/%B=0/35, 10/35, 40/80, 50/80, 55/35, 60/35; 270 nm, Rt 15.51 min, 99.55% purity; MS (CI): m/z 461 (M+H, 100). was heated to reflux for 2 hours The mixture was heated to reflux for 6 hours concentrated under vacuum diluted with water (3 mL) The gum which separated was collected ( by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH-CHCl3)

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

Procedure: A mixture of N-methyl prolinol (0.226 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (3 mL). The gum which separated was collected (by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH—CHCl3) to afford the title compound E25 as a semi-solid (0.06 g, 20%). HPLC: Symmetry shield RP18 (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 3.0); solvent B=CH3CN], Gradient elution program: T/% B=0/35, 10/35, 40/80, 50/80, 55/35, 60/35; 270 nm, Rt 15.51 min, 99.55% purity; MS (CI): m/z 461 (M+H, 100). was heated to reflux for 2 hours The mixture was heated to reflux for 6 hours concentrated under vacuum diluted with water (3 mL) The gum which separated was collected ( by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH—CHCl3)

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

Procedure: A mixture of N-methyl prolinol (0.226 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (3 mL). The gum which separated was collected (by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH—CHCl3) to afford the title compound E25 as a semi-solid (0.06 g, 20%). HPLC: Symmetry shield RP18 (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 3.0); solvent B=CH3CN], Gradient elution program: T/% B=0/35, 10/35, 40/80, 50/80, 55/35, 60/35; 270 nm, Rt 15.51 min, 99.55% purity; MS (CI): m/z 461 (M+H, 100). was heated to reflux for 2 hours The mixture was heated to reflux for 6 hours concentrated under vacuum diluted with water (3 mL) The gum which separated was collected ( by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH—CHCl3)