(2R)-pyrrolidine-2-carboxamide

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

Procedure: Compound 75 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (R)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.5 [M+H]+.

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

Procedure: Compound 75 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (R)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.5 [M+H]+.

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

Procedure: To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2×50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(1-pyrrolidinylmethyl) pyrrolidine. The mixture is refluxed for 2 hrs then cooled quenched with 2 ml of 2.5N sodium hydroxide The mixture is filtered through a pad of sodium sulfate the filter cake washed with 2×50 ml of ether The combined filtrates are concentrated in vacuo

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

Procedure: B23 was obtained as a white powder by following the procedure reported for B4 using A1 and (R)-proline amide; yield: 65 mg (19%). MS (ES) C15H19N7O3S requires: 377. found: 378 (M+H)+. B23 was obtained as a white powder

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

Procedure: B23 was obtained as a white powder by following the procedure reported for B4 using A1 and (R)-proline amide; yield: 65 mg (19%). MS (ES) C15H19N7O3S requires: 377. found: 378 (M+H)+. B23 was obtained as a white powder

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

Procedure: To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-prolinamide (114 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 1.0 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.4 mg of the title compound. The mixture was reacted overnight It was then purified by Gilson Preparatory HPLC

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

Procedure: To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-prolinamide (114 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 1.0 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.4 mg of the title compound. The mixture was reacted overnight It was then purified by Gilson Preparatory HPLC

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

Procedure: Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-prolinamide.

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

Procedure: To 10 ml of methylene chloride, 55.6 mg of a pentamethylcyclopentadienyl iridium(III) chloride dimer ([Cp*IrCl2]2), 16.7 mg of (R)-prolinamide and 15.6 mg of triethylamine were added, and the mixture was stirred under argon atmosphere at room temperature for about 30 minutes to give a catalyst-containing mixture. In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and a 1/10 amount of the catalyst-containing mixture (equivalent to 0.1 mol % as an iridium chloride dimer) was added. After cooling to −10° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was stirred at the same temperature for 2 days to give 2-methyl-1,2,3,4-tetrahydroquinoline (degree of conversion: 67.4%). The R-enantiomer was in excess and the optical purity was 85.4% ee. to give a catalyst-containing mixture After cooling to −10° C. the mixture was stirred at the same temperature for 2 days

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

Procedure: To 10 ml of methylene chloride, 55.6 mg of a pentamethylcyclopentadienyl iridium(III) chloride dimer ([Cp*IrCl2]2), 16.7 mg of (R)-prolinamide and 15.6 mg of triethylamine were added, and the mixture was stirred under argon atmosphere at room temperature for about 30 minutes to give a catalyst-containing mixture. In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and a 1/10 amount of the catalyst-containing mixture (equivalent to 0.1 mol % as an iridium chloride dimer) was added. After cooling to −10° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was stirred at the same temperature for 2 days to give 2-methyl-1,2,3,4-tetrahydroquinoline (degree of conversion: 67.4%). The R-enantiomer was in excess and the optical purity was 85.4% ee. to give a catalyst-containing mixture After cooling to −10° C. the mixture was stirred at the same temperature for 2 days

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

Procedure: Compound 75 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (R)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.5 [M+H]+.

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

Procedure: To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2×50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(1-pyrrolidinylmethyl) pyrrolidine. The mixture is refluxed for 2 hrs then cooled quenched with 2 ml of 2.5N sodium hydroxide The mixture is filtered through a pad of sodium sulfate the filter cake washed with 2×50 ml of ether The combined filtrates are concentrated in vacuo