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

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

Procedure: (R)-1-methyl-2-pyrrolidinemethanol (Aldrich Chemical Co.) was dissolved in 8 mL of DMF and stirred under N2, then 240 mg of NaH (80% dispersion in mineral oil) was added. The reaction mixture was stirred fifteen minutes, and 363 mg of 3-chloro-5-trifluoromethylpyridine (2.0 mmol) was added. The reaction mixture was stirred at 50° C. for 16 hours. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2:1 ethyl acetate:hexane to give 336 mg of the title product. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44-2.30 (m, 1H), 2.13-1.73 (m, 4H). The reaction mixture was stirred fifteen minutes The reaction mixture was stirred at 50° C. for 16 hours The volatiles were removed under vacuum the residue was purified by chromatography on silica gel eluting with 2:1 ethyl acetate

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

Procedure: (R)-1-Methyl-2-pyrrolidinemethanol (300 mg, 2.61 mmol) was dissolved in anhydrous THF and cooled to 0° C. with stirring. NaH (80% dispersion in mineral oil, 0.082 g, 2.9 mmol) was added and the mixture was slowly warmed to room temperature with stirring. After 30 minutes a THF solution of 3,6-dichloropyridazine (0.41 g, 2.74 mmol) was added to the mixture via syringe. The reaction was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and then with brine. The organic layer was dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.25 g (42% yield) of the title compound as a cream colored solid. MS (DCI/NH3) m/e 228 (M+H)+. [α]25D =+32° (c=1, MeOH). the mixture was slowly warmed to room temperature with stirring The reaction was stirred for 48 hours The solvent was then evaporated in vacuo the mixture diluted with chloroform washed with saturated NaHCO3 The organic layer was dried over MgSO4 The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3)

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

Procedure: (R)-1-Methyl-2-pyrrolidinemethanol (300 mg, 2.61 mmol) was dissolved in anhydrous THF and cooled to 0° C. with stirring. NaH (80% dispersion in mineral oil, 0.082 g, 2.9 mmol) was added and the mixture was slowly warmed to room temperature with stirring. After 30 minutes a THF solution of 3,6-dichloropyridazine (0.41 g, 2.74 mmol) was added to the mixture via syringe. The reaction was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and then with brine. The organic layer was dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.25 g (42% yield) of the title compound as a cream colored solid. MS (DCI/NH3) m/e 228 (M+H)+. [α]25D =+32° (c=1, MeOH). the mixture was slowly warmed to room temperature with stirring The reaction was stirred for 48 hours The solvent was then evaporated in vacuo the mixture diluted with chloroform washed with saturated NaHCO3 The organic layer was dried over MgSO4 The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3)

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

Procedure: Following the procedures of Example 6, substituting (R)-1-methyl-2-pyrrolidinemethanol (Aldrich) for the (S)-1-methyl-2-pyrrolidinemethanol of Example 6, the title compound was prepared. MS: 210 (M+H)+. NMR (CDCl3) δ: 2.20-2.30 (m, 3H), 2.34-2.43 (m, 1H), 3.03 (s, 3H), 3.20-3.30 (m, 1H), 3.72-3.77 (m, 1H), 3.89-3.91 (m, 1H), 4.27 (dd, 1H, J=6, 11.5 Hz), 4.44 (dd, 1H, J=3, 11.5 Hz), 6.82-6.89 (m, 3H), 7.34-7.42 (m, 1H). Anal. Calcd for C12H17ClFNO.0.25 H2O: C, 57.60; H, 7.05; N, 5.59; Found: C, 57.86; H, 6.76; N, 5.59.

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

Procedure: Following the procedures of Example 6, substituting (R)-1-methyl-2-pyrrolidinemethanol (Aldrich) for the (S)-1-methyl-2-pyrrolidinemethanol of Example 6, the title compound was prepared. MS: 210 (M+H)+. NMR (CDCl3) δ: 2.20-2.30 (m, 3H), 2.34-2.43 (m, 1H), 3.03 (s, 3H), 3.20-3.30 (m, 1H), 3.72-3.77 (m, 1H), 3.89-3.91 (m, 1H), 4.27 (dd, 1H, J=6, 11.5 Hz), 4.44 (dd, 1H, J=3, 11.5 Hz), 6.82-6.89 (m, 3H), 7.34-7.42 (m, 1H). Anal. Calcd for C12H17ClFNO.0.25 H2O: C, 57.60; H, 7.05; N, 5.59; Found: C, 57.86; H, 6.76; N, 5.59.

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

Procedure: Following the procedures of Example 6, substituting (R)-1-methyl-2-pyrrolidinemethanol (Aldrich) for the (S)-1-methyl-2-pyrrolidinemethanol of Example 6, the title compound was prepared. MS: 210 (M+H)+. NMR (CDCl3) δ: 2.20-2.30 (m, 3H), 2.34-2.43 (m, 1H), 3.03 (s, 3H), 3.20-3.30 (m, 1H), 3.72-3.77 (m, 1H), 3.89-3.91 (m, 1H), 4.27 (dd, 1H, J=6, 11.5 Hz), 4.44 (dd, 1H, J=3, 11.5 Hz), 6.82-6.89 (m, 3H), 7.34-7.42 (m, 1H). Anal. Calcd for C12H17ClFNO.0.25 H2O: C, 57.60; H, 7.05; N, 5.59; Found: C, 57.86; H, 6.76; N, 5.59.

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

Procedure: To a solution of 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) (3.9 g, 191 mmol) in acetonitrile (95 ml) is added ((R)-1-methyl-pyrrolidin-2-yl)-methanol (2.2 g, 191 mmol) in acetonitrile (5 ml). The reaction mixture is stirred at room temperature for 3 hours and then the solvent is removed in vacuo. The resulting oil is taken up in acetonitrile and ethyl acetate is then added. The resulting cloudy solution is stirred at room temperature for 30 minutes. There after, the supernatant is decanted off and the solid is dried under vacuum over two days to afford the titled compound. the solvent is removed in vacuo ethyl acetate is then added The resulting cloudy solution is stirred at room temperature for 30 minutes There after, the supernatant is decanted off the solid is dried under vacuum over two days

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

Procedure: (R)-1-methyl-2-pyrrolidinemethanol (Aldrich Chemical Co.) was dissolved in 8 mL of DMF and stirred under N2, then 240 mg of NaH (80% dispersion in mineral oil) was added. The reaction mixture was stirred fifteen minutes, and 363 mg of 3-chloro-5-trifluoromethylpyridine (2.0 mmol) was added. The reaction mixture was stirred at 50° C. for 16 hours. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2:1 ethyl acetate:hexane to give 336 mg of the title product. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44-2.30 (m, 1H), 2.13-1.73 (m, 4H). The reaction mixture was stirred fifteen minutes The reaction mixture was stirred at 50° C. for 16 hours The volatiles were removed under vacuum the residue was purified by chromatography on silica gel eluting with 2:1 ethyl acetate

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

Procedure: (R)-1-methyl-2-pyrrolidinemethanol (Aldrich Chemical Co.) was dissolved in 8 mL of DMF and stirred under N2, then 240 mg of NaH (80% dispersion in mineral oil) was added. The reaction mixture was stirred fifteen minutes, and 363 mg of 3-chloro-5-trifluoromethylpyridine (2.0 mmol) was added. The reaction mixture was stirred at 50° C. for 16 hours. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2:1 ethyl acetate:hexane to give 336 mg of the title product. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44-2.30 (m, 1H), 2.13-1.73 (m, 4H). The reaction mixture was stirred fifteen minutes The reaction mixture was stirred at 50° C. for 16 hours The volatiles were removed under vacuum the residue was purified by chromatography on silica gel eluting with 2:1 ethyl acetate

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

Procedure: (R)-1-Methyl-2-pyrrolidinemethanol (300 mg, 2.61 mmol) was dissolved in anhydrous THF and cooled to 0° C. with stirring. NaH (80% dispersion in mineral oil, 0.082 g, 2.9 mmol) was added and the mixture was slowly warmed to room temperature with stirring. After 30 minutes a THF solution of 3,6-dichloropyridazine (0.41 g, 2.74 mmol) was added to the mixture via syringe. The reaction was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and then with brine. The organic layer was dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.25 g (42% yield) of the title compound as a cream colored solid. MS (DCI/NH3) m/e 228 (M+H)+. [α]25D =+32° (c=1, MeOH). the mixture was slowly warmed to room temperature with stirring The reaction was stirred for 48 hours The solvent was then evaporated in vacuo the mixture diluted with chloroform washed with saturated NaHCO3 The organic layer was dried over MgSO4 The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3)