4,4-difluoro-3-oxobutanenitrile

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

Procedure: To a solution of 4,4-difluoro-3-oxobutanenitrile in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was heated at reflux for 12 h before cooling to RT. After evaporation in vacuo, the residue was extracted into DCM. The organic layers were washed with water, brine, dried (MgSO4). After filtration, the solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 27% for two steps) as an oil: MS (ESI) m/z: 134.0 [M+1]+. The reaction was heated at reflux for 12 h After evaporation in vacuo the residue was extracted into DCM The organic layers were washed with water, brine dried (MgSO4) After filtration the solvent was evaporated in vacuo The crude product was purified by SiO2 chromatography

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

Procedure: To a solution of 4,4-difluoro-3-oxobutanenitrile in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was heated at reflux for 12 h before cooling to RT. After evaporation in vacuo, the residue was extracted into DCM. The organic layers were washed with water, brine, dried (MgSO4). After filtration, the solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 27% for two steps) as an oil: MS (ESI) m/z: 134.0 [M+1]+. The reaction was heated at reflux for 12 h After evaporation in vacuo the residue was extracted into DCM The organic layers were washed with water, brine dried (MgSO4) After filtration the solvent was evaporated in vacuo The crude product was purified by SiO2 chromatography

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

Procedure: A mixture of 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 273 mg (1.03 mmol) 4,4-difluoro-3-oxobutanenitrile (Example 14A), 0.067 ml (1.17 mmol) acetic acid and 9.3 μl (0.094 mmol) piperidine in dry dichloromethane (4 ml) containing 4 Å molecular sieve was stirred under reflux for 12 h. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-propanol (2 ml) and acetic acid (1 ml) under argon, and 510 mg (3.75 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] were added. The solution was stirred under reflux for 6 h. Upon cooling, the mixture was evaporated to dryness, and the residue was treated with toluene (4 ml) containing a small amount of p-toluenesulfonic acid. The mixture was stirred under reflux for further 12 h. Upon cooling, the mixture was evaporated to dryness again, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 39 mg (11% of th.) of the racemic title compound. containing 4 Å molecular sieve under reflux for 12 h Then, the mixture was filtered the filtrate was concentrated under reduced pressure The residue was dissolved in 2-propanol (2 ml) 34, 42 (1969)] were added The solution was stirred under reflux for 6 h Upon cooling the mixture was evaporated to dryness the residue was treated with toluene (4 ml) containing a small amount of p-toluenesulfonic acid The mixture was stirred under reflux for further 12 h Upon cooling the mixture was evaporated to dryness again the residue was dissolved in ethyl acetate The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with water dried over sodium sulfate concentrated under reduced pressure The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient)

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

Procedure: To a solution of 4,4-difluoro-3-oxobutanenitrile in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was heated at reflux for 12 h before cooling to RT. After evaporation in vacuo, the residue was extracted into DCM. The organic layers were washed with water, brine, dried (MgSO4). After filtration, the solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 27% for two steps) as an oil: MS (ESI) m/z: 134.0 [M+1]+. The reaction was heated at reflux for 12 h After evaporation in vacuo the residue was extracted into DCM The organic layers were washed with water, brine dried (MgSO4) After filtration the solvent was evaporated in vacuo The crude product was purified by SiO2 chromatography