3-环丙丙醇-2-腈

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidine hydrochloride (Example 129, Step C, 50.2 mg, 0.148 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 69.1 mg, 0.742 mmol) were suspended in acetonitrile (742 μL, 0.148 mmol). DBU (88.8 μL, 0.594 mmol) was added to the reaction mixture and heated at 45° C. for 15 hours. The reaction mixture was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient. The resultant solid was diluted in Et2O, sonicated, filtered and washed with Et2O to afford the title compound as a light yellow solid (9.3 mg, 17% yield). MS (apci) m/z=359.2 (M+H). The reaction mixture was purified by reverse phase HPLC The resultant solid was diluted in Et2O sonicated filtered washed with Et2O

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 100 mL flask, methyl 5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate hydrochloride (0.300 g, 1.07 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.300 g, 3.22 mmol) were suspended in DMF (5.36 mL, 1.07 mmol) and DBU (0.722 mL, 4.83 mmol) added in one portion. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted in EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated down to a yellow oil. Purification of the crude material by silica chromatography using a gradient of 50-100% EtOAc afforded methyl 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.127 g, 0.378 mmol, 35.2% yield) as a yellow oil. MS (apci) m/z=337.2 (M+H). washed with water and brine The combined organic layers were dried over MgSO4 filtered concentrated down to a yellow oil Purification of the crude material by silica chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 20 mL flask, 2-(5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)-5-methyl-1,3,4-thiadiazole (17.4 mg, 0.0614 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 17.2 mg, 0.184 mmol) were dissolved in DMF (614 μL, 0.0614 mmol). To this was added DBU (23.0 μA, 0.154 mmol) and stirred at ambient temperature for 40 h. The reaction was incomplete, so another portion of DBU (23.0 μA, 0.154 mmol) and 3-cyclopropylacrylonitrile (17.2 mg, 0.184 mmol) were added. After 4 hours, the reaction mixture was diluted in EtOAc, and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to a yellow oil. The crude material was purified by silica chromatography using a 0-10% MeOH/EtOAc gradient to afford 3-cyclopropyl-3-(4-(7-(5-methyl-1,3,4-thiadiazol-2-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (7.2 mg, 31% yield). MS (apci) m/z=377.2 (M+H). After 4 hours washed with water and brine The organic layer was dried with MgSO4 filtered concentrated down to a yellow oil The crude material was purified by silica chromatography

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flask charged with 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.0600 g, 0.2046 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.1048 g, 1.125 mmol) was added 1 mL of acetonitrile and DBU (0.04588 mL, 0.3068 mmol) at ambient temperature with stirring. The flask was then sealed and heated to 50° C. overnight. The reaction mixture was diluted with dichloromethane and loaded directly onto a silica gel column and eluted with ethyl acetate with 0.5% ammonium hydroxide to afford the title compound (0.047 g, 0.1204 mmol, 58.86% yield). MS (apci) m/z=387.2 (M+H). The flask was then sealed eluted with ethyl acetate with 0.5% ammonium hydroxide

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation; K-1; 0.130 g, 0.490 mmol) in dry DMF (2 mL) was added DBU (89.5 mg, 0.588 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.183 g, 1.96 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. Additional 3-cyclopropylacrylonitrile (0.046 g, 0.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was added to H2O (8 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO4/activated carbon. The solution was eluted through a short SiO2 column (15 mL course frit funnel, ½ full of SiO2) eluting first with EtOAc, then with 10% MeOH/EtOAc. The 10% MeOH/EtOAc fraction was concentrated and the resulting residue treated with Et2O and sonicated to give a granular suspension. The precipitate was allowed to settle, Et2O decanted off, solid washed with Et2O and then dried under vacuum to provide a 3-cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (40 mg, 23% yield) as a white powder. MS (apci) m/z=359.2 (M+H). the reaction mixture was stirred at ambient temperature for 72 hours mixed extracted with EtOAc The combined EtOAc extracts were washed with saturated NaCl dried over MgSO4/activated carbon The solution was eluted through a short SiO2 column (15 mL course frit funnel, ½ full of SiO2) eluting first with EtOAc The 10% MeOH/EtOAc fraction was concentrated the resulting residue treated with Et2O sonicated to give a granular suspension Et2O decanted off solid washed with Et2O dried under vacuum

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.44 g, 12.6 mmol), 3-cyclopropylacrylonitrile (Preparation B; 2.34 g, 25.1 mmol) (as a mixture of isomers) and DBU (1.88 mL, 12.6 mmol) were suspended in MeCN (10 mL) and stirred at 40° C. for 3 days. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 25-35% EtOAc/Hexanes) to furnish 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (2.48 g, 8.64 mmol, 68.8% yield). MS (apci) m/z=288.2 (M+H). The reaction mixture was cooled to ambient temperature concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 25-35% EtOAc/Hexanes)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 7-chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.107 g, 0.4872 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.3403 g, 3.654 mmol) in 2 mL of acetonitrile was added DBU (0.1457 mL, 0.9744 mmol). The reaction mixture was sealed and heated to 50° C. and stirred overnight. To the reaction mixture was added more 3-cyclopropylacrylonitrile (0.100 g, 0.107 mmol) and DBU (0.072 mL, 0.448 mmol) and the reaction mixture was sealed and heated to 60° C. for 4 hours. The reaction mixture was loaded onto directly onto a column of silica gel and eluted with a gradient of 50-75% ethyl acetate in hexanes with 0.5% ammonium hydroxide to afford the title compound (0.119 g, 0.3729 mmol, 76.54% yield). MS (apci) m/z=313.1 (M+H). The reaction mixture was sealed the reaction mixture was sealed heated to 60° C. for 4 hours eluted with a gradient of 50-75% ethyl acetate in hexanes with 0.5% ammonium hydroxide