(2S)-2-(trifluoromethyl)pyrrolidine

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

Procedure: A flask was charged with 5-bromo-2-chloropyrimidine (36.62 g, 189 mmol), (S)-2-(trifluoromethyl)pyrrolidine (34.2 g, 246 mmol), potassium carbonate (39.2 g, 284 mmol)) and t-amyl alcohol (189 mL). The reaction mixture was stirred at 85° C. for 72 hours. The reaction mixture was then filtered over Celite®, washed with CH2Cl2 (2×) and concentrated in vacuo. The crude residue was redissolved in CH2Cl2 and washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give crystalline solids. The solids were washed with cold water (3×) and triturated with toluene to give the title product as pale orange crystals, 43.4 g (147 mmol, 77%); 1H NMR (300 MHz, DMSO-d6)_8.58 (s, 2H), 5.06-4.83 (m, 1H), 3.71-3.44 (m, 2H), 10 2.30-1.89 (m, 4H); m/z found [M+H]+=295.99. The reaction mixture was then filtered over Celite® washed with CH2Cl2 (2×) concentrated in vacuo The crude residue was redissolved in CH2Cl2 washed with water and brine The combined organic layers were dried over MgSO4 filtered concentrated in vacuo to give crystalline solids The solids were washed with cold water (3×) triturated with toluene

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

Procedure: A flask was charged with 5-bromo-2-chloropyrimidine (36.62 g, 189 mmol), (S)-2-(trifluoromethyl)pyrrolidine (34.2 g, 246 mmol), potassium carbonate (39.2 g, 284 mmol)) and t-amyl alcohol (189 mL). The reaction mixture was stirred at 85° C. for 72 hours. The reaction mixture was then filtered over Celite®, washed with CH2Cl2 (2×) and concentrated in vacuo. The crude residue was redissolved in CH2Cl2 and washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give crystalline solids. The solids were washed with cold water (3×) and triturated with toluene to give the title product as pale orange crystals, 43.4 g (147 mmol, 77%); 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 2H), 5.06-4.83 (m, 1H), 3.71-3.44 (m, 2H), 2.30-1.89 (m, 4H); m/z found [M+H]+=295.99. The reaction mixture was then filtered over Celite® washed with CH2Cl2 (2×) concentrated in vacuo The crude residue was redissolved in CH2Cl2 washed with water and brine The combined organic layers were dried over MgSO4 filtered concentrated in vacuo to give crystalline solids The solids were washed with cold water (3×) triturated with toluene

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

Procedure: A flask was charged with 5-bromo-2-chloropyrimidine (36.62 g, 189 mmol), (S)-2-(trifluoromethyl)pyrrolidine (34.2 g, 246 mmol), potassium carbonate (39.2 g, 284 mmol)) and t-amyl alcohol (189 mL). The reaction mixture was stirred at 85° C. for 72 hours. The reaction mixture was then filtered over Celite®, washed with CH2Cl2 (2×) and concentrated in vacuo. The crude residue was redissolved in CH2Cl2 and washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give crystalline solids. The solids were washed with cold water (3×) and triturated with toluene to give the title product as pale orange crystals, 43.4 g (147 mmol, 77%); 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 2H), 5.06-4.83 (m, 1H), 3.71-3.44 (m, 2H), 2.30-1.89 (m, 4H); m/z found [M+H]+=295.99. The reaction mixture was then filtered over Celite® washed with CH2Cl2 (2×) concentrated in vacuo The crude residue was redissolved in CH2Cl2 washed with water and brine The combined organic layers were dried over MgSO4 filtered concentrated in vacuo to give crystalline solids The solids were washed with cold water (3×) triturated with toluene

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

Procedure: B16 was prepared following the general procedure reported for B10 using A1 and (S)-2-(trifluoromethyl)pyrrolidine. The title compound (B16) was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and MeOH (0.1% TFA) as eluents. Yield: 58.7 mg (15%), colorless amorphous solid. MS (ES) C15H17F3N6O2S requires: 402. found: 403 (M+H)+. B16 was prepared The title compound (B16) was purified by reverse phase RP-HPLC (column: C18)

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

Procedure: To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DCM (3.0 mL) and MeOH (1.5 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 drops). After 6 h of stirring at room temperature, sodium borohydride (43 mg, 1.12 mmol) was added and the reaction was stirred overnight at room temperature. The reaction mixture was purified by Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%). the reaction was stirred overnight at room temperature The reaction mixture was purified by Gilson Preparatory HPLC

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

Procedure: To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DCM (3.0 mL) and MeOH (1.5 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 drops). After 6 h of stirring at room temperature, sodium borohydride (43 mg, 1.12 mmol) was added and the reaction was stirred overnight at room temperature. The reaction mixture was purified by Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%). the reaction was stirred overnight at room temperature The reaction mixture was purified by Gilson Preparatory HPLC

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

Procedure: To a mixture of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (100 mg, 0.455 mmol, Intermediate 10) and polymer supported N-methylmorpholine (4 mmol/g, 171 mg, 0.683 mmol) in acetonitrile (3 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.683 mmol). The reaction mixture was heated at 120° C. for 20 min in a microwave reactor and at 140° C. for 20 min and at 150° C. for 30 min and finally at 160° C. for 30 min in the microwave reactor.

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

Procedure: To a mixture of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (100 mg, 0.455 mmol, Intermediate 10) and polymer supported N-methylmorpholine (4 mmol/g, 171 mg, 0.683 mmol) in acetonitrile (3 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.683 mmol). The reaction mixture was heated at 120° C. for 20 min in a microwave reactor and at 140° C. for 20 min and at 150° C. for 30 min and finally at 160° C. for 30 min in the microwave reactor.

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

Procedure: (2S)-2-(Trifluoromethyl)pyrrolidine (858 mg, 6.17 mmol) was dissolved in THF (10 mL) in a 250 mL RB flask. The mixture was cooled in an ice bath. Then molecular sieves were added and let stir for 5 minutes. LiHMDS (6.78 mL, 6.78 mmol) was added slowly followed by addition of 4,6-dichloro-2-(methylthio)pyrimidine (1.444 g, 7.40 mmol), and the reaction was stirred at 0° C. for an additional 10 minutes. Then water (10 mL) was added followed by dropwise addition of 6N HCl until pH was acidic. The mixture was then extracted with EtOAc (3×30 mL) and the organic was combined, washed with saturated NaCl, filtered and concentrated. The crude oil was purified on Biotage 25 g SNAP column with a gradient of 0 to 35% EtOAc in Hexane over 25 minutes to afford the title compound (1.42 g) as a clear oil. LC-MS (ES) m/z=298 [M+H]+. The mixture was cooled in an ice bath Then molecular sieves were added the reaction was stirred at 0° C. for an additional 10 minutes The mixture was then extracted with EtOAc (3×30 mL) washed with saturated NaCl filtered concentrated The crude oil was purified on Biotage 25 g SNAP column with a gradient of 0 to 35% EtOAc in Hexane over 25 minutes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 350 mg, 0.79 mmol), (S)-2-(trifluoromethyl)pyrrolidine (purchased from Sigma Aldrich) (219 mg, 1.57 mmol), potassium fluoride (229 mg, 3.93 mmol), DMSO (2.4 mL), and N,N-diisopropylethylamine (0.69 mL, 3.93 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C25H26ClF3N6 [M+H]+ 503. found 503. The vial was sealed The reaction mixture was cooled to room temperature washed with water The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient)

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

Procedure: To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DCM (3.0 mL) and MeOH (1.5 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 drops). After 6 h of stirring at room temperature, sodium borohydride (43 mg, 1.12 mmol) was added and the reaction was stirred overnight at room temperature. The reaction mixture was purified by Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%). the reaction was stirred overnight at room temperature The reaction mixture was purified by Gilson Preparatory HPLC

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 350 mg, 0.79 mmol), (S)-2-(trifluoromethyl)pyrrolidine (purchased from Sigma Aldrich) (219 mg, 1.57 mmol), potassium fluoride (229 mg, 3.93 mmol), DMSO (2.4 mL), and N,N-diisopropylethylamine (0.69 mL, 3.93 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C25H26ClF3N6 [M+H]+ 503. found 503. The vial was sealed The reaction mixture was cooled to room temperature washed with water The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient)