General procedure for the synthesis of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile and 3-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile from cyclopentyl bromide and 3-amino-4-cyanopyrazole: 3-amino-4-pyrazolecarbonitrile (4.32 g, 40.0 mmol), cyclopentyl bromide (7.15 g, 48 mmol) and anhydrous potassium carbonate (6.60 g, 48 mmol) were suspended in 30 mL of anhydrous DMF and reacted at 80 °C and under argon protection overnight. Subsequently, cyclopentyl bromide (3.5 g, 23.5 mmol) and potassium carbonate (3.3 g, 24 mmol) were added supplementally, and the reaction was continued at 80 °C for 6 h. The reaction was completed with the addition of cyclopentyl bromide and potassium carbonate. After completion of the reaction, it was cooled to room temperature and the DMF was removed by rotary evaporator. water (100 mL) was added and the organic phase was extracted with dichloromethane (3 x 100 mL). The combined dichloromethane extracts were washed sequentially with water (50 mL) and brine (50 mL) and dried (magnesium sulfate). The organic phase was concentrated to give a solid product. The solid was purified by rapid chromatography on silica gel (eluent ratio 2:1 hexane:ethyl acetate), and two white solids were isolated: 3-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile (1.67 g, 24% yield) eluting first, and 5-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile (4.56 g, 65% yield) eluting thereafter. 3- Properties of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile: melting point 129-131 °C; MS (ES+) calculated value: 176.22, measured value: 177.05 [M+H]+; 100% purity by HPLC (retention time 9.235 min, Method A); 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H) 5.51 (br s, 2H), 4.45 (m, 1H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H), 1.59 (m, 2H).Properties of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile: melting point 113°C; MS (ES+) calculated value: 176.22, measured value: 177.04 [M +H]+; HPLC purity 88% (retention time 9.752 min, Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 1H), 5.75 (br s, 2H), 4.55 (m, 1H), 1.92 (m, 2H), 1.78 (m, 4H), 1.57 (m, 2H). In addition, pure 3-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile could be obtained in 44% yield without chromatographic purification by grinding the crude product with a minimal amount of dichloromethane. Notably, 3-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile was less soluble in dichloromethane, whereas 5-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile was readily soluble.
