cyclobutylhydrazine;hydrochloride

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)═:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2H) 2.21 (s, 3H) 2.32-2.43 (m, 2H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2H) 3.26-3.55 (br s, 2H) 4.48-4.59 (m, 1H) 5.36 (s, 1H) After cooling to room temperature the solvent was removed under reduced pressure The phases were separated the aq. phase extracted with EtOAc (3×50 mL) The combined EtOAc extracts were washed with brine dried over MgSO4 filtered concentrated in vacuo The crude residue was purified via silica gel chromatography (eluent The final product was collected as 0.4 g (16%)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)═:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2H) 2.21 (s, 3H) 2.32-2.43 (m, 2H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2H) 3.26-3.55 (br s, 2H) 4.48-4.59 (m, 1H) 5.36 (s, 1H) After cooling to room temperature the solvent was removed under reduced pressure The phases were separated the aq. phase extracted with EtOAc (3×50 mL) The combined EtOAc extracts were washed with brine dried over MgSO4 filtered concentrated in vacuo The crude residue was purified via silica gel chromatography (eluent The final product was collected as 0.4 g (16%)

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

Procedure: In analogy to the procedure described in example 308d, (2S,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as brown oil. MS (ESI): m/z=549.8 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-thiopropionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow foam.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-1-[3-oxo-3-(tetrahydro-pyran-4-yl)-thiopropionyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 393d) was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow oil. MS (ESI): m/z=542.4 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow oil. MS (ESI): m/z=490.1 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as colorless oil. MS (ESI): m/z=456.2 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as orange oil. MS (ESI): m/z=438.3 [M+H]+.

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

Procedure: In analogy to the procedure described in example 308d, a mixture of (2S,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 f) and of (2R,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give a mixture of the title compound and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as white solid. MS (ESI): m/z=472.3 [M+H]+. 158001-21-9) to give

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)=:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2 H) 2.21 (s, 3 H) 2.32-2.43 (m, 2 H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2 H) 3.26-3.55 (br s, 2 H) 4.48-4.59 (m, 1 H) 5.36 (s, 1 H) After cooling to room temperature the solvent was removed under reduced pressure The phases were separated the aq. phase extracted with EtOAc (3×50 mL) The combined EtOAc extracts were washed with brine dried over MgSO4 filtered concentrated in vacuo The crude residue was purified via silica gel chromatography (eluent The final product was collected as 0.4 g (16%)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)═:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2H) 2.21 (s, 3H) 2.32-2.43 (m, 2H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2H) 3.26-3.55 (br s, 2H) 4.48-4.59 (m, 1H) 5.36 (s, 1H) After cooling to room temperature the solvent was removed under reduced pressure The phases were separated the aq. phase extracted with EtOAc (3×50 mL) The combined EtOAc extracts were washed with brine dried over MgSO4 filtered concentrated in vacuo The crude residue was purified via silica gel chromatography (eluent The final product was collected as 0.4 g (16%)