[(2S)-1-benzylpyrrolidin-2-yl]methanol

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

Procedure: Tert-butyl 4-[8-(tert-butoxycarbonylsulfamoyl)-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (intermediate 47) (0.55 mmol) was dissolved in dry THF (3 mL) and added [(2S)-1-benzylpyrrolidin-2-yl]methanol (0.61 mmol) and triphenylphosphine (0.66 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.66 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent. to warm up freely to rt extracted with EtOAc (3×50 mL) The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL) dried over Na2SO4 filtered concentrated in vacuo The product was purified by flash chromatography on silica

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

Procedure: Tert-butyl 4-[8-(tert-butoxycarbonylsulfamoyl)-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (intermediate 47) (0.55 mmol) was dissolved in dry THF (3 mL) and added [(2S)-1-benzylpyrrolidin-2-yl]methanol (0.61 mmol) and triphenylphosphine (0.66 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.66 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent. to warm up freely to rt extracted with EtOAc (3×50 mL) The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL) dried over Na2SO4 filtered concentrated in vacuo The product was purified by flash chromatography on silica

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

Procedure: The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (S)-1-benzyl-2-pyrrolidinemethanol (27 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, (R)-2-((1-benzylpyrrolidin-2-yl)methyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (8 mg, 11%) was obtained as yellow powder. MS M+H=530; 1H NMR (CDCl3) δ 8.14 (1H, s), 7.22-7.38 (11H, m), 7.10 (2H, d, J=10.0 Hz), 4.61-4.63 (1H, m), 3.50-3.56 (2H, q, J=13.2 Hz), 3.01 (1H, d, J=10.0 Hz), 2.85 (1H, d, J=10.0 Hz), 2.37-2.42 (1H, t, J=10.7 Hz), 1.99-2.02 (2H, m), 1.82-1.95 (1H, m), 1.70-1.80 (2H, m). The title compound was prepared prepared

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

Procedure: To a suspension of sodium hydride (60% in mineral oil, 0.314 g, 7.84 mmol) in THF (20 mL) was added (S)-(1-benzyl-pyrrolidin-2-yl)-methanol (1.0 g, 5.23 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 2,2,2-trifluoroethyl methanesulfonate (1.4 g, 7.84 mmol) was added and stirring was continued at room temperature over night. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.706 g, 37%) as a light yellow liquid. MS: 274.3 (M+H+). stirring was continued at room temperature over night The reaction mixture was quenched with H2O (10 mL) extracted with EtOAc (2×50 mL) Combined organics were dried over Na2SO4 filtered concentrated in vacuo The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH(1% NH4OH)-DCM gradient

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

Procedure: Tert-butyl 4-[8-(tert-butoxycarbonylsulfamoyl)-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (intermediate 47) (0.55 mmol) was dissolved in dry THF (3 mL) and added [(2S)-1-benzylpyrrolidin-2-yl]methanol (0.61 mmol) and triphenylphosphine (0.66 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.66 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent. to warm up freely to rt extracted with EtOAc (3×50 mL) The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL) dried over Na2SO4 filtered concentrated in vacuo The product was purified by flash chromatography on silica