tert-butyl 2-(4-methoxyphenyl)acetate

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1 h then allowed to warm to room temperature overnight. The reaction miLture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H—) 8.74 (1H, d pyrazine H—) 9.25 (1H, d pyrazine H—) was added to warm to room temperature overnight The solution was extracted with ether (3×250 cm3) washed with brine dried over magnesium sulphate filtered evaporated under reduced pressure to give a solid The solid was purified by chromatography evaporated under reduced pressure

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1 h then allowed to warm to room temperature overnight. The reaction miLture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H—) 8.74 (1H, d pyrazine H—) 9.25 (1H, d pyrazine H—) was added to warm to room temperature overnight The solution was extracted with ether (3×250 cm3) washed with brine dried over magnesium sulphate filtered evaporated under reduced pressure to give a solid The solid was purified by chromatography evaporated under reduced pressure

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

Procedure: 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (21-D), (163 mg, 0.500 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol), Cs2CO3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050 mmol), and palladium(f1) acetate (33.7 mg, 0.150 mmol) in a microwave vial in dioxane (4.5 mL) was evacuated and backfilled with nitrogen for three times, and then was heated in an oil bath at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite to remove insoluble material. The filtrate was washed with water, and brine. After drying with sodium sulfate, the solvents were removed and the product was purified by ISCO column (4 g) chromatography, eluting with hexane containing 0 to 35% EtOAc to afford 167 mg of the Boc-PMB-protected product which was dissolved in DCM (6 ml), added TFA (3 ml), and left stirring at room temperature for 30 min. Removal of the solvent. The crude was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (143 mg) as a solid which was used on next step as such. was evacuated The reaction mixture was cooled to room temperature diluted with EtOAc filtered through celite to remove insoluble material The filtrate was washed with water, and brine After drying with sodium sulfate the solvents were removed the product was purified by ISCO column (4 g) chromatography eluting with hexane containing 0 to 35% EtOAc

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

Procedure: 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (21-D), (163 mg, 0.500 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol), Cs2CO3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050 mmol), and palladium(f1) acetate (33.7 mg, 0.150 mmol) in a microwave vial in dioxane (4.5 mL) was evacuated and backfilled with nitrogen for three times, and then was heated in an oil bath at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite to remove insoluble material. The filtrate was washed with water, and brine. After drying with sodium sulfate, the solvents were removed and the product was purified by ISCO column (4 g) chromatography, eluting with hexane containing 0 to 35% EtOAc to afford 167 mg of the Boc-PMB-protected product which was dissolved in DCM (6 ml), added TFA (3 ml), and left stirring at room temperature for 30 min. Removal of the solvent. The crude was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (143 mg) as a solid which was used on next step as such. was evacuated The reaction mixture was cooled to room temperature diluted with EtOAc filtered through celite to remove insoluble material The filtrate was washed with water, and brine After drying with sodium sulfate the solvents were removed the product was purified by ISCO column (4 g) chromatography eluting with hexane containing 0 to 35% EtOAc

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1 h then allowed to warm to room temperature overnight. The reaction miLture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H—) 8.74 (1H, d pyrazine H—) 9.25 (1H, d pyrazine H—) was added to warm to room temperature overnight The solution was extracted with ether (3×250 cm3) washed with brine dried over magnesium sulphate filtered evaporated under reduced pressure to give a solid The solid was purified by chromatography evaporated under reduced pressure

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1h then allowed to warm to room temperature overnight. The reaction mixture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H-) 8.74 (1H, d pyrazine H-) 9.25 (1H, d pyrazine H-) was added to warm to room temperature overnight The solution was extracted with ether (3×250 cm3) washed with brine dried over magnesium sulphate filtered evaporated under reduced pressure to give a solid The solid was purified by chromatography evaporated under reduced pressure

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

Procedure: 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (21-D), (163 mg, 0.500 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol), Cs2CO3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050 mmol), and palladium(f1) acetate (33.7 mg, 0.150 mmol) in a microwave vial in dioxane (4.5 mL) was evacuated and backfilled with nitrogen for three times, and then was heated in an oil bath at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite to remove insoluble material. The filtrate was washed with water, and brine. After drying with sodium sulfate, the solvents were removed and the product was purified by ISCO column (4 g) chromatography, eluting with hexane containing 0 to 35% EtOAc to afford 167 mg of the Boc-PMB-protected product which was dissolved in DCM (6 ml), added TFA (3 ml), and left stirring at room temperature for 30 min. Removal of the solvent. The crude was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (143 mg) as a solid which was used on next step as such. was evacuated The reaction mixture was cooled to room temperature diluted with EtOAc filtered through celite to remove insoluble material The filtrate was washed with water, and brine After drying with sodium sulfate the solvents were removed the product was purified by ISCO column (4 g) chromatography eluting with hexane containing 0 to 35% EtOAc

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1 h then allowed to warm to room temperature overnight. The reaction miLture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H—) 8.74 (1H, d pyrazine H—) 9.25 (1H, d pyrazine H—) was added to warm to room temperature overnight The solution was extracted with ether (3×250 cm3) washed with brine dried over magnesium sulphate filtered evaporated under reduced pressure to give a solid The solid was purified by chromatography evaporated under reduced pressure