(2S)-2-methylpyrrolidine

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (52 g, 0.15 mol, 1.0 eq) prepared in accordance of the procedures set forth in Intermediate (i), (2S)-2-methyl pyrrolidine (25.2 g, 0.3 mol, 2.0 eq), anhydrous CH3CN (500 ml), and dry K2CO3 powder (50 g, 36 mmol, 2.4 eq) were added to a 2L round-bottom flask equipped with a mechanical stirrer and a reflux condenser. The resulting suspension was stirred at 75° C. for 20 h. The heating block was set at 88° C. LC/MS showed a trivial amount of starting material at m/z 363. The reaction mixture was concentrated in vacuo. The residue was partitioned between 200 ml of water and 400 ml of DCM. The aqueous layer was washed with 50 ml of DCM twice. The organic extracts were combined and washed with 150 ml of saturated NaHCO3 solution, 150 ml of brine, and dried over K2CO3. The crude was purified by silica gel column, eluted with 5-10% MeOH in DCM. The product still had weak UV absorptions at 254 nm and 280 nm. A pale yellow oil was obtained, yield: 24.5 g (64%). equipped with a mechanical stirrer and a reflux condenser was set at 88° C The reaction mixture was concentrated in vacuo The residue was partitioned between 200 ml of water and 400 ml of DCM The aqueous layer was washed with 50 ml of DCM twice washed with 150 ml of saturated NaHCO3 solution, 150 ml of brine dried over K2CO3 The crude was purified by silica gel column eluted with 5-10% MeOH in DCM A pale yellow oil was obtained

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

Procedure: 6-(Methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.093 g, 0.140 mmol) was dissolved in dichloromethane (1.4 mL) and acetic acid (0.012 mL, 0.210 mmol). (S)-2-Methylpyrrolidine (0.036 g, 0.420 mmol) was added followed by sodium triacetoxyborohydride (59.4 mg, 0.280 mmol). The mixture was stirred at room temperature for 2 d. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA) to afford 3-({4-[(2R)-2-methyl-1-pyrrolidinyl]-1-piperidinyl}methyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.035 g, 32% yield). MS (m/z) 733.3 (M+H+). The solvent was removed under reduced pressure the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA)

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

Procedure: 6-(Methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.093 g, 0.140 mmol) was dissolved in dichloromethane (1.4 mL) and acetic acid (0.012 mL, 0.210 mmol). (S)-2-Methylpyrrolidine (0.036 g, 0.420 mmol) was added followed by sodium triacetoxyborohydride (59.4 mg, 0.280 mmol). The mixture was stirred at room temperature for 2 d. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA) to afford 3-({4-[(2R)-2-methyl-1-pyrrolidinyl]-1-piperidinyl}methyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.035 g, 32% yield). MS (m/z) 733.3 (M+H+). The solvent was removed under reduced pressure the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA)

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

Procedure: Solid 5-bromo-2-chloropyrimidine (27.5 g, 142 mmol) was added in three portions to a 500 mL flask containing (S)-2-methylpyrrolidine (20.24 ml, 213 mmol) stirred at room temperature. After 1 hr the resulting solids were dissolved in warm DCM, washed with water, brine, dried over MgSO4 and concentrated onto silica in vacuo. Column purified by silica gel chromatography to afford white crystalline solids (30.7 g, 89%), ESI-MS (EI+, m/z): 241.02, 1H NMR (Chloroform-d) δ: 8.31 (d, J=5.0 Hz, 2H), 4.33-4.14 (m, 1H), 3.61 (tt, J=7.6, 3.0 Hz, 1H), 3.56-3.41 (m, 1H), 2.23-1.88 (m, 3H), 1.88-1.63 (m, 1H), 1.25 (t, J=5.5 Hz, 3H) washed with water, brine dried over MgSO4 concentrated onto silica in vacuo Column purified by silica gel chromatography

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

Procedure: Methanesulfonic acid 4-(4-benzyloxycarbonylamino-3-fluoro-phenyl)-cyclohex-3-enyl ester (200 mg, 0.47 mmol, 1 equiv.) was dissolved in 5 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (159 mg, 1.88 mmol, 4 equiv.) and K2CO3 (285 mg, 2.07 mmol, 4.4 equiv.). The suspension was de-aerated by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. externally with stirring under nitrogen for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction is complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (10 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product. The crude product was purified on a silica gel column, eluted with DCM, followed by 5% MeOH in DCM and 5% of 7N NH3-MeOH in DCM. The combined fractions containing the product were concentrated to yield the title compound. This solution was transferred into a flask heated on an oil bath set at 80° C. Acetonitrile was removed in vacuo The two layers were separated the aqueous layer was extracted with DCM (2×10 mL) The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) dried (K2CO3) The solution was filtered The filtrate was concentrated in vacuo to obtain a crude product The crude product was purified on a silica gel column eluted with DCM The combined fractions containing the product were concentrated

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

Procedure: The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with (S)-2-methyl-pyrrolidine (101.2 mg, 1.19 mmol) to obtain 67 mg (88% yield) of the compound.

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

Procedure: The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (S)-2-methylpyrrolidine.

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

Procedure: Methanesulfonic acid (S)-3-(4-benzyloxycarbonylamino-phenyl)cyclopentyl ester (Intermediate 12) (510 mg, 1.31 mmol, 1 equiv.) was dissolved in 8 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (445 mg, 5.24 mmol, 4 equiv.) and K2CO3 (800 mg, 5.76 mmol, 4.4 equiv.). The suspension was de-gassed by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. under nitrogen with stirring for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction was complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (20 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL), and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product which was purified on a silica gel column eluting with 5% 7N ammonia methanolic solution in DCM to afford 410 mg (84%) of the title compound. This solution was transferred into a flask The suspension was de-gassed by vacuum/nitrogen exchange 3 times heated on an oil bath set at 80° C. under nitrogen Acetonitrile was removed in vacuo The two layers were separated the aqueous layer was extracted with DCM (2×10 mL) The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) dried (K2CO3) The solution was filtered The filtrate was concentrated in vacuo to obtain a crude product which was purified on a silica gel column eluting with 5% 7N ammonia methanolic solution in DCM

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 1 h at 50° C., then (S)-2-methylpyrrolidine (2.385 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. Solvents were evaporated, the residue was dissolved in dichloromethane and washed against saturated aqueous sodium hydrogencarbonate to give 7.8 g (100%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 2): Rt=1.06 min; m/z=307.19 (M+H+). the mixture was stirred at 25° C. overnight Solvents were evaporated the residue was dissolved in dichloromethane washed against saturated aqueous sodium hydrogencarbonate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 1 h at 50° C., then (S)-2-methylpyrrolidine (2.385 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. Solvents were evaporated, the residue was dissolved in dichloromethane and washed against saturated aqueous sodium hydrogencarbonate to give 7.8 g (100%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 2): Rt=1.06 min; m/z=307.19 (M+H+). the mixture was stirred at 25° C. overnight Solvents were evaporated the residue was dissolved in dichloromethane washed against saturated aqueous sodium hydrogencarbonate

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An (S)-2-methylpyrrolidine (0.5 ml) solution of the N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg) synthesized in (Example 3.15) <Step 6> was stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (20 ml) was added to the reaction solution, and the mixed solution was successively washed with water (15 ml) twice and with a saturated saline (10 ml) once, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=40:60), so as to obtain the title compound (13 mg) in the form of a light yellow solid. the mixed solution was successively washed with water (15 ml) twice with a saturated saline (10 ml) once, and was then dried over anhydrous sodium sulfate The solvent was distilled away under reduced pressure the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=40:60)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An (S)-2-methylpyrrolidine (0.5 ml) solution of the N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg) synthesized in (Example 3.15) <Step 6> was stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (20 ml) was added to the reaction solution, and the mixed solution was successively washed with water (15 ml) twice and with a saturated saline (10 ml) once, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=40:60), so as to obtain the title compound (13 mg) in the form of a light yellow solid. the mixed solution was successively washed with water (15 ml) twice with a saturated saline (10 ml) once, and was then dried over anhydrous sodium sulfate The solvent was distilled away under reduced pressure the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=40:60)