1,4-diazabicyclo[2.2.2]octan-2-ylmethanamine

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

Procedure: Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 330 mg, 0.57 mmol) was added to a solution of 1-(1,4-diazabicyclo[2.2.2]oct-2-yl)methanamine (EP748807, 407 mg, 2.88 mmol) and N,N-Diisopropylethylamine (0.38 mL, 2.88 mmol) in N-methyl 2-pyrrolidinone (5 mL) and the resulting reaction mixture was stirred for 20 h at 80° C. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduce pressure to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform) to afford 80 mg (20.5%) of ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate as an off-white solid. the resulting reaction mixture The reaction mixture was cooled to room temperature extracted with ethyl acetate (3×50 mL) The combined organic layer was washed with brine dried over anhydrous sodium sulphate concentrated to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform)

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

Procedure: Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 330 mg, 0.57 mmol) was added to a solution of 1-(1,4-diazabicyclo[2.2.2]oct-2-yl)methanamine (EP748807, 407 mg, 2.88 mmol) and N,N-Diisopropylethylamine (0.38 mL, 2.88 mmol) in N-methyl 2-pyrrolidinone (5 mL) and the resulting reaction mixture was stirred for 20 h at 80° C. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduce pressure to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform) to afford 80 mg (20.5%) of ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate as an off-white solid. the resulting reaction mixture The reaction mixture was cooled to room temperature extracted with ethyl acetate (3×50 mL) The combined organic layer was washed with brine dried over anhydrous sodium sulphate concentrated to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform)

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

Procedure: Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 330 mg, 0.57 mmol) was added to a solution of 1-(1,4-diazabicyclo[2.2.2]oct-2-yl)methanamine (EP748807, 407 mg, 2.88 mmol) and N,N-Diisopropylethylamine (0.38 mL, 2.88 mmol) in N-methyl 2-pyrrolidinone (5 mL) and the resulting reaction mixture was stirred for 20 h at 80° C. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduce pressure to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform) to afford 80 mg (20.5%) of ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate as an off-white solid. the resulting reaction mixture The reaction mixture was cooled to room temperature extracted with ethyl acetate (3×50 mL) The combined organic layer was washed with brine dried over anhydrous sodium sulphate concentrated to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform)