(2R)-2-methylpyrrolidine;hydrochloride

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

Procedure: In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area % of ethyl acrylate was less than 1% (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification. To the stirred solution was added The reaction mixture was stirred until analysis by GC less than 1% (approximately 2 h) The reaction mixture was filtered the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL) The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry) Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved The organic layer was washed a second time with water concentrated

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

Procedure: A solution of 2-(6-bromo-benzothiazol-2-yl)-ethanol (2.23 g, 8.6 mmol) and triethylamine (2.19 g, 21.6 mmol) in THF (45 mL) was cooled to −20° C., and mesyl chloride (1.58 g, 13.8 mmol) was added at −20 to −10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate (1.79 g, 13 mmol), 2-(R)-methylpyrrolidine hydrochloride (2.1 g, 17.2 mmol) and acetonitrile (40 mL) were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give 6-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (2.48 g, 88.3% yield). 1H NMR (CDCl3, 400 MHz) δ 1.12 (d, 3H, J=7 Hz), 1.41-1.50 (m, 1H), 1.68-1.87 (m, 2H), 1.91-1.99 (m, 1H), 2.24 (q, 1H, J=7 Hz), 2.39-2.48 (m, 1H), 2.56-2.64 (m, 1H), 3.19-3.33 (m, 4H), 7.52 (dd, 1H, J=8, 4 Hz), 7.79 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=4 Hz); 13C NMR (CDCl3, 400 MHz) δ 19.3, 22.1, 33.1, 33.9, 52.5, 53.7, 59.9, 117.9, 123.3, 123.7, 128.9, 136.9, 151.3, 170.4; (DCl/NH3) m/z 325, 327 (M+H)+. the mixture was stirred at 60° C. for 18 hr Solvents were removed the residue was dissolved in 45 mL methylene chloride washed with 10 mL water The aqueous layer was re-extracted with 10 mL methylene chloride The combined methylene chloride was concentrated to oil purified by column chromatography (silica gel, 10:90 MeOH:CHCl3)

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

Procedure: The product from Example 74B, methanesulfonyl chloride, and (2R)-2-methylpyrrolidine hydrochloride are processed as described in Example 62F to provide the title compound.

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

Procedure: The product from Example 74B, methanesulfonyl chloride, and (2R)-2-methylpyrrolidine hydrochloride are processed as described in Example 62F to provide the title compound.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 (0.25 g, 0.9 mmol, 1 eq), 0.15 g of (2R)-2-methylpyrrolidine hydrochloride (1.2 mmol, 1.4 eq) and triethylamine (0.3 ml, 2.2 mmol, 2.4 eq) is stirred under microwave irradiation (120° C., 3.75 h). The mixture is then filtered. Triethylamine (0.2 ml, 1.44 mmol, 1.6 eq) is added to the organic layer, and the mixture is again stirred under microwave irradiation, at 120° C. for another 1.5 h. The solvent is then removed under vacuum and the residue diluted with ethyl acetate. The organic layer is washed with water, with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The residue is purified over silicagel (eluent: dichloromethane/ethanol/ammonia, gradient from 98:2:0.2 to 96:4:0.4) to give 4,4-dimethyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4,5-dihydro-1,3-oxazole 15 (60 mg) as a beige powder. The mixture is then filtered the mixture is again stirred under microwave irradiation, at 120° C. for another 1.5 h The solvent is then removed under vacuum the residue diluted with ethyl acetate The organic layer is washed with water, with a saturated solution of sodium chloride dried over magnesium sulfate concentrated under vacuum The residue is purified over silicagel (eluent: dichloromethane/ethanol/ammonia, gradient from 98:2:0.2 to 96:4:0.4)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 (0.25 g, 0.9 mmol, 1 eq), 0.15 g of (2R)-2-methylpyrrolidine hydrochloride (1.2 mmol, 1.4 eq) and triethylamine (0.3 ml, 2.2 mmol, 2.4 eq) is stirred under microwave irradiation (120° C., 3.75 h). The mixture is then filtered. Triethylamine (0.2 ml, 1.44 mmol, 1.6 eq) is added to the organic layer, and the mixture is again stirred under microwave irradiation, at 120° C. for another 1.5 h. The solvent is then removed under vacuum and the residue diluted with ethyl acetate. The organic layer is washed with water, with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The residue is purified over silicagel (eluent: dichloromethane/ethanol/ammonia, gradient from 98:2:0.2 to 96:4:0.4) to give 4,4-dimethyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4,5-dihydro-1,3-oxazole 15 (60 mg) as a beige powder. The mixture is then filtered the mixture is again stirred under microwave irradiation, at 120° C. for another 1.5 h The solvent is then removed under vacuum the residue diluted with ethyl acetate The organic layer is washed with water, with a saturated solution of sodium chloride dried over magnesium sulfate concentrated under vacuum The residue is purified over silicagel (eluent: dichloromethane/ethanol/ammonia, gradient from 98:2:0.2 to 96:4:0.4)

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

Procedure: In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area % of ethyl acrylate was less than 1% (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification. To the stirred solution was added The reaction mixture was stirred until analysis by GC less than 1% (approximately 2 h) The reaction mixture was filtered the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL) The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry) Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved The organic layer was washed a second time with water concentrated

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

Procedure: In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area % of ethyl acrylate was less than 1% (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification. To the stirred solution was added The reaction mixture was stirred until analysis by GC less than 1% (approximately 2 h) The reaction mixture was filtered the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL) The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry) Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved The organic layer was washed a second time with water concentrated

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

Procedure: A solution of 2-(6-bromo-benzothiazol-2-yl)-ethanol (2.23 g, 8.6 mmol) and triethylamine (2.19 g, 21.6 mmol) in THF (45 mL) was cooled to −20° C., and mesyl chloride (1.58 g, 13.8 mmol) was added at −20 to −10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate (1.79 g, 13 mmol), 2-(R)-methylpyrrolidine hydrochloride (2.1 g, 17.2 mmol) and acetonitrile (40 mL) were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give 6-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (2.48 g, 88.3% yield). 1H NMR (CDCl3, 400 MHz) δ 1.12 (d, 3H, J=7 Hz), 1.41-1.50 (m, 1H), 1.68-1.87 (m, 2H), 1.91-1.99 (m, 1H), 2.24 (q, 1H, J=7 Hz), 2.39-2.48 (m, 1H), 2.56-2.64 (m, 1H), 3.19-3.33 (m, 4H), 7.52 (dd, 1H, J=8, 4 Hz), 7.79 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=4 Hz); 13C NMR(CDCl3, 400 MHz) δ 19.3, 22.1, 33.1, 33.9, 52.5, 53.7, 59.9, 117.9, 123.3, 123.7, 128.9, 136.9, 151.3, 170.4; (DCl/NH3) m/z 325, 327 (M+H)+. the mixture was stirred at 60° C. for 18 hr Solvents were removed the residue was dissolved in 45 mL methylene chloride washed with 10 mL water The aqueous layer was re-extracted with 10 mL methylene chloride The combined methylene chloride was concentrated to oil purified by column chromatography (silica gel, 10:90 MeOH:CHCl3)

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

Procedure: To a round-bottom flask was added phenol (5.0 g, 53.1 mmol), 1-bromo-3-chloropropane (5.52 mL, 55.8 mmol), potassium carbonate (22.0 g, 159 mmol), and acetonitrile (100 mL). The reaction mixture was heated to reflux for 15 h. To this reaction was then added (R)-2-methyl-pyrrolidine hydrochloride (12.9 g, 106 mmol) and sodium iodide (7.96 g, 53.1 mmol) at room temperature. The reaction was continued to reflux for 24 h. After cooled to room temperature, the reaction was filtered through a pad of Celite eluted with CH2Cl2 (100 mL). The filtrate was concentrated. Purification by column chromatography (5% MeOH in CH2Cl2) to give 9.02 g (77%) of (R)-2-methyl-1-(3-phenoxy-propyl)-pyrrolidine. The reaction mixture was heated to reflux for 15 h at room temperature to reflux for 24 h the reaction was filtered through a pad of Celite eluted with CH2Cl2 (100 mL) The filtrate was concentrated Purification by column chromatography (5% MeOH in CH2Cl2)

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

Procedure: The product from Example 74B, methanesulfonyl chloride, and (2R)-2-methylpyrrolidine hydrochloride are processed as described in Example 62F to provide the title compound.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2R)-2-Methylpyrrolidine hydrochloride 5 (973 mg, 8.0 mmol) and 37% aqueous solution of formaldehyde (0.57 mL, 7.0 mmol) were combined in EtOH (20 mL) and heated in a sealed tube at 85° C. for 1 hour. The mixture was allowed to cool to room temperature, treated with the products from Example 61C (500 mg, 2.0 mmol), and heated at 85° C. overnight. The mixture was allowed to cool to room and concentrated to dryness under vacuum. The residue was partitioned between IPAc (50 mL) and 20% brine (40 mL). The organic layer was separated, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with heptane:acetone:CH2Cl2:Et3N (60:40:3:1) to provide the title compounds. MS 343 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.72 (s, 1H), 8.16 (m, 2H), 8.06 (m, 2H), 7.85 (m, 2H), 7.70 (m, 4H), 3.17 (m, 8H), 2.52 (m, 2H), 2.31 (m, 2H), 2.17 (m, 2H), 1.83 (m, 2H), 1.65 (m, 4H), 1.32 (m, 2H). 13C NMR (400 MHz, CDCl3) δ 156.63, 156.41, 146.45, 145.16, 143.73, 143.70, 141.75, 141.53, 140.81, 140.60, 139.89, 139.04, 132.38, 129.66, 129.36, 128.42, 127.68, 127.65, 127.55, 137.13, 126.86, 118.29, 111.48, 111.40, 59.87, 53.93, 52.89, 35.83, 32.90, 21.98, 19.25. to cool to room temperature heated at 85° C. overnight to cool to room concentrated to dryness under vacuum The residue was partitioned between IPAc (50 mL) and 20% brine (40 mL) The organic layer was separated dried with Na2SO4 filtered the filtrate was concentrated under vacuum The residue was purified by silica gel column chromatography eluting with heptane:acetone:CH2Cl2:Et3N (60:40:3:1)