3-oxopentanenitrile

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1000 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 3-oxopentanenitrile (23) (21.8 g, 135 mmol, 60%) of, 4-formylbenzonitrile (17.7 g, 135 mmol), L-proline (3.65 g, 27 mmol, 0.2 eq) and 200 ml of EtOH. The mixture was stirred at 22° C. for 16 hours and concentrated to a volume of approximately 120 ml. 100 ml of MTBE was added and the mixture was stirred at 22° C. for about 30 min. The precipitate was collected by vacuum filtration. The solid was washed with 50 ml of MTBE. It was dried in a vacuum oven at 50° C. to give the product 24 as a off white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 8.10 (d, 2H), 7.81 (d, 2H), 3.00 (m, 2H), 1.28 (t, 3H). To a 1000 ml, four-necked flask equipped with an overhead stirrer concentrated to a volume of approximately 120 ml 100 ml of MTBE was added the mixture was stirred at 22° C. for about 30 min The precipitate was collected by vacuum filtration The solid was washed with 50 ml of MTBE It was dried in a vacuum oven at 50° C.

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

Procedure: A mixture of 3-oxopentanenitrile (1.0 g, 10.3 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield). to cool to room temperature solvent was removed in vacuo The solid was removed via filtration upon standing at room temperature the solid was collected via filtration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 3-oxopentanenitrile (19.42 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography (eluting with a mixture of 20% ethyl acetate in petroleum ether). The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate, to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.57-7.59 (m, 2H), 7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)+. The reaction mixture was quenched with water extracted with dichloromethane The combined dichloromethane layers were dried over magnesium sulfate concentrated under reduced pressure dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography ( eluting with a mixture of 20% ethyl acetate in petroleum ether) The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate

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

Procedure: A mixture of 3-oxopentanenitrile (1.0 g, 103 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially solidified upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield). to cool to room temperature solvent was removed in vacuo The solid was removed via filtration upon standing at room temperature the solid was collected via filtration

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

Procedure: A mixture of 3-oxopentanenitrile (1.0 g, 103 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially solidified upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield). to cool to room temperature solvent was removed in vacuo The solid was removed via filtration upon standing at room temperature the solid was collected via filtration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 3-oxopentanenitrile (19.42 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography (eluting with a mixture of 20% ethyl acetate in petroleum ether). The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate, to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ7.57-7.59 (m, 2H), 7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)+. The reaction mixture was quenched with water extracted with dichloromethane The combined dichloromethane layers were dried over magnesium sulfate concentrated under reduced pressure dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography ( eluting with a mixture of 20% ethyl acetate in petroleum ether) The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-oxopentanenitrile (500 mg, 5.2 mmol) in DMF (10 mL) was added NaH (248 mg, 6.2 mmol) and stirred at 0° C. for 1 h. Then 1-(bromomethyl)-2,3-dichlorobenzene (1.23 g, 5.2 mmol) was added to the mixture and warmed to room temperature, stirred for 20 h. The mixture was concentrated under reduced pressure to give the crude titled product (1.2 g, 92%), which was used for next step without further purification. warmed to room temperature stirred for 20 h The mixture was concentrated under reduced pressure

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

Procedure: To an ice-cold solution of 3-oxopentanenitrile (14.6 g, 150 mmol) and 2-hydrazinopyridine (13.6 g, 125 mmol) in ethanol (150 mL), acetic acid (14.3 mL, 250 mmol) was added and the resulting mixture was heated under reflux for 5 hours. The solution was allowed to cool to room temperature, and concentrated under reduced pressure, and water was added to the residue. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (21.1 g, 90% yield). NMR (CDCl3) δ: 1.25 (3H, t, J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz), 5.38 (1H, s), 5.90 (2H, br s), 7.04 (1H, ddd, J=1.2 Hz, 5.0 Hz, 7.4 Hz), 7.75 (1H, ddd, J=2.0 Hz, 7.4 Hz, 8.4 Hz), 7.94 (1H, ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz), 8.29 (1H, ddd, J=0.8 Hz, 2.0 Hz, 5.0 Hz). the resulting mixture was heated under reflux for 5 hours concentrated under reduced pressure, and water was added to the residue The solution was made basic by the addition of an aqueous sodium hydroxide solution the organic matter was extracted with ethyl acetate The extract was washed with saturated brine and water dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1)

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

Procedure: The title compound was prepared from methyl propionate, 2,3-dichlorobenzaldehyde, 3-aminopyrazole and 1-cyanobutan-2-one in the same manner as in Example 94.

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1000 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 3-oxopentanenitrile (23) (21.8 g, 135 mmol, 60%) of, 4-formylbenzonitrile (17.7 g, 135 mmol), L-proline (3.65 g, 27 mmol, 0.2 eq) and 200 ml of EtOH. The mixture was stirred at 22° C. for 16 hours and concentrated to a volume of approximately 120 ml. 100 ml of MTBE was added and the mixture was stirred at 22° C. for about 30 min. The precipitate was collected by vacuum filtration. The solid was washed with 50 ml of MTBE. It was dried in a vacuum oven at 50° C. to give the product 24 as a off white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 8.10 (d, 2H), 7.81 (d, 2H), 3.00 (m, 2H), 1.28 (t, 3H). To a 1000 ml, four-necked flask equipped with an overhead stirrer concentrated to a volume of approximately 120 ml 100 ml of MTBE was added the mixture was stirred at 22° C. for about 30 min The precipitate was collected by vacuum filtration The solid was washed with 50 ml of MTBE It was dried in a vacuum oven at 50° C.

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

Procedure: Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 3-oxo-pentanenitrile (1.3 g, 1.1 eq) were combined to yield 5-ethyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (2.5 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.87 (dd, J=7.8, 1.8 Hz, 1H), 8.39 (dd, J=8.4, 1.5 Hz, 1H), 8.12 (s, 1H), 8.06-8.03 (m, 2H), 7.54 (dd, J=8.4, 1.2 Hz, 1H), 5.46 (br s, 2H), 5.40 (s, 1H), 2.49 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 239.2 (M+H+).

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 3-oxopentanenitrile (19.42 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography (eluting with a mixture of 20% ethyl acetate in petroleum ether). The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate, to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.57-7.59 (m, 2H), 7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)+. The reaction mixture was quenched with water extracted with dichloromethane The combined dichloromethane layers were dried over magnesium sulfate concentrated under reduced pressure dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography ( eluting with a mixture of 20% ethyl acetate in petroleum ether) The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate