1-chloro-3-methylsulfonylpropane

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.055 mmol) in DMF (3 mL) was added 1-chloro-3-(methylsulfonyl)propane (13 mg, 0.083 mmol) followed by K2CO3 (23 mg, 0.165 mmol). The mixture was heated at 40° C. for 16 h, then cooled, poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 76%). The crude material was used directly in the next step without purification. LCMS: 845.2 [M+H]+. cooled filtered

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.055 mmol) in DMF (3 mL) was added 1-chloro-3-(methylsulfonyl)propane (13 mg, 0.083 mmol) followed by K2CO3 (23 mg, 0.165 mmol). The mixture was heated at 40° C. for 16 h, then cooled, poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 76%). The crude material was used directly in the next step without purification. LCMS: 845.2 [M+H]+. cooled filtered

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.1 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (19 mg, 0.12 mmol) followed by K2CO3 (42 mg, 0.3 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (55 mg, 77%). The crude was used to the next step without further purification. LCMS: (M+H)+=715. After cooling to room temperature filtered dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.1 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (19 mg, 0.12 mmol) followed by K2CO3 (42 mg, 0.3 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (55 mg, 77%). The crude was used to the next step without further purification. LCMS: (M+H)+=715. After cooling to room temperature filtered dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (30 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 3 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 88%). The crude product was used to the next step without purification. MS: (M+H)+=763. After cooling to room temperature filtered dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (30 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 3 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 88%). The crude product was used to the next step without purification. MS: (M+H)+=763. After cooling to room temperature filtered dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-3-(methanesulfonyl)-propane (160 g) was added to 1H-indol-4-ol (108.77 g) in 1 L MeCN, and 338 g K2CO3 and 13.36 g KI were added. The reaction mixture was stirred overnight at 80° C., then cooled and filtered through celite. The filtrate was vacuum distilled and solvent replaced with DCM (700 mL). The mixture was filtered, and the solvent removed in vacuo and replaced with MeOH (600 mL). The solvent was partially removed in vacuo at 40° C. and crystallization occurred. After cooling, additional MeOH was added and the slurry was filtered. The collected solid was rinsed with cold MeOH and dried overnight at 35° C. in vacuo under N2 to provide 4-(3-methanesulfonyl-propoxy)-1H-indole (82%). were added cooled filtered through celite distilled The mixture was filtered the solvent removed in vacuo The solvent was partially removed in vacuo at 40° C. crystallization After cooling additional MeOH was added the slurry was filtered The collected solid was rinsed with cold MeOH dried overnight at 35° C. in vacuo under N2

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.055 mmol) in DMF (3 mL) was added 1-chloro-3-(methylsulfonyl)propane (13 mg, 0.083 mmol) followed by K2CO3 (23 mg, 0.165 mmol). The mixture was heated at 40° C. for 16 h, then cooled, poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 76%). The crude material was used directly in the next step without purification. LCMS: 845.2 [M+H]+. cooled filtered

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.1 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (19 mg, 0.12 mmol) followed by K2CO3 (42 mg, 0.3 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (55 mg, 77%). The crude was used to the next step without further purification. LCMS: (M+H)+=715. After cooling to room temperature filtered dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (30 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 3 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 88%). The crude product was used to the next step without purification. MS: (M+H)+=763. After cooling to room temperature filtered dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-3-(methanesulfonyl)-propane (160 g) was added to 1H-indol-4-ol (108.77 g) in 1 L MeCN, and 338 g K2CO3 and 13.36 g KI were added. The reaction mixture was stirred overnight at 80° C., then cooled and filtered through celite. The filtrate was vacuum distilled and solvent replaced with DCM (700 mL). The mixture was filtered, and the solvent removed in vacuo and replaced with MeOH (600 mL). The solvent was partially removed in vacuo at 40° C. and crystallization occurred. After cooling, additional MeOH was added and the slurry was filtered. The collected solid was rinsed with cold MeOH and dried overnight at 35° C. in vacuo under N2 to provide 4-(3-methanesulfonyl-propoxy)-1H-indole (82%). were added cooled filtered through celite distilled The mixture was filtered the solvent removed in vacuo The solvent was partially removed in vacuo at 40° C. crystallization After cooling additional MeOH was added the slurry was filtered The collected solid was rinsed with cold MeOH dried overnight at 35° C. in vacuo under N2

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

Procedure: A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (30 mg, 0.2 mmol) and sodium bicarbonate (110 mg, 1.3 mmol) in DMF (2 ml) was treated with a solution of mixture of 3-bromopropyl methyl sulfone and 3-chloropropyl methyl sulfone (for example, as prepared for Intermediate 19) (124 mg) in DMF (0.5 ml) and the mixture was heated at 150° C. for 15 min in a Smith Creator™ microwave oven. The reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue (126 mg) was purified by MDAP. Appropriate fractions were combined and concentrated in vacuo and the residue (30 mg) was applied to an SCX-2 cartridge (5 g), pre-conditioned with methanol and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo to give the free base of the title compound (21 mg, 18%): This was treated with 1.25 M hydrogen chloride solution in methanol (0.15 ml) and the solution was evaporated in vacuo to give the title compound (22 mg, 89%): LCMS RT=2.49 min, ES+ve m/z 405 (M+H)+. eluted with methanol followed by 10% aqueous 0.88 s concentrated in vacuo the residue (126 mg) was purified by MDAP concentrated in vacuo eluted with methanol followed by 10% aqueous 0.88 s concentrated in vacuo