tert-butyl N-[[(3S)-pyrrolidin-3-yl]methyl]carbamate

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl (1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6) tR=2.7 min, m/z=559.0/561.0 [M+H]+, m/z=581.0 [M+Na]+.

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl (1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: 6-tert-butyl-3,8-dibromoquinoline (180) is prepared from 2-bromo-4-tert-butyl naphthalene using acrolein and bromine in accord with the procedure in step 2 of example 7. Introduction of 1-pyrrolidin-3-ylmethyl methansulfonamide moiety can be carried out with (S)-1-pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester in accord with the procedures in steps 1 to 3 of example 19. Introduction of the pyridine ring is carried out by a Suzuki condensation of the bromoquinoline intermediate with 115 in accord with the procedure in step 2 of example 24 and subsequent demethylation of the methyl pyridinyl ether in accord with the procedure in step 6 of example 22 to afford I-60. to afford I-60

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

Procedure: 6-tert-butyl-3,8-dibromoquinoline (180) is prepared from 2-bromo-4-tert-butyl naphthalene using acrolein and bromine in accord with the procedure in step 2 of example 7. Introduction of 1-pyrrolidin-3-ylmethyl methansulfonamide moiety can be carried out with (S)-1-pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester in accord with the procedures in steps 1 to 3 of example 19. Introduction of the pyridine ring is carried out by a Suzuki condensation of the bromoquinoline intermediate with 115 in accord with the procedure in step 2 of example 24 and subsequent demethylation of the methyl pyridinyl ether in accord with the procedure in step 6 of example 22 to afford I-60. to afford I-60

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL) The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl(1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL) The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl(1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25 CV) to give (R)-tert-butyl (1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl (1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6) tR=2.7 min, m/z=559.0/561.0 [M+H]+, m/z=581.0 [M+Na]+.

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

Procedure: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg, 0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube under nitrogen at 160° C. for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-85% CH3CN/water, 25CV) to give (R)-tert-butyl (1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate (245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+, Retention time=3.66 minutes. extracted with EtOAc (3×20 mL) The combined organic layer was dried over MgSO4 filtered the filtrate was concentrated to an oil purified by reverse phase chromatography (Biotage SP4

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

Procedure: 6-tert-butyl-3,8-dibromoquinoline (180) is prepared from 2-bromo-4-tert-butyl naphthalene using acrolein and bromine in accord with the procedure in step 2 of example 7. Introduction of 1-pyrrolidin-3-ylmethyl methansulfonamide moiety can be carried out with (S)-1-pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester in accord with the procedures in steps 1 to 3 of example 19. Introduction of the pyridine ring is carried out by a Suzuki condensation of the bromoquinoline intermediate with 115 in accord with the procedure in step 2 of example 24 and subsequent demethylation of the methyl pyridinyl ether in accord with the procedure in step 6 of example 22 to afford I-60. to afford I-60