309915-46-6

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask were added 1-(4-cyanobenzyl)-5-formylimidazole (250.0 mg, 1.2 mmole) along with titanium(IV)isopropoxide (1.0 ml, 3.65 mmol), (trans) 2,5-Dimethyl-4-tertbutyloxycarbonylpiprizine (253.7 mg, 1.2 mmol) (prepared as described in Step 1), and tetrahydrofuran (0.4 ml). The reaction was heated at 60° C. for 1.25 hour. The reaction was cooled and sodiumcyanoborohydride (95.0 mg, 1.5 mmol) was added along with ethanol (0.5 ml) and the reaction was stirred at RT for 18 hours. The reaction was diluted with methanol/water (3 ml/1 ml) and the mixture filtered through celite. The filtrate was then concentrated to an oil, dissolved into methanol and put through a High Pressure Liquid Chromatography column. The desired fractions were collected, concentrated, and lyophilized to give the ditrifluoroacetic acid salt of the title compound. The reaction was cooled the mixture filtered through celite The filtrate was then concentrated to an oil dissolved into methanol The desired fractions were collected concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask were added 1-(4-cyanobenzyl)-5-formylimidazole (250.0 mg, 1.2 mmole) along with titanium(IV)isopropoxide (1.0 ml, 3.65 mmol), (trans) 2,5-Dimethyl-4-tertbutyloxycarbonylpiprizine (253.7 mg, 1.2 mmol) (prepared as described in Step 1), and tetrahydrofuran (0.4 ml). The reaction was heated at 60° C. for 1.25 hour. The reaction was cooled and sodiumcyanoborohydride (95.0 mg, 1.5 mmol) was added along with ethanol (0.5 ml) and the reaction was stirred at RT for 18 hours. The reaction was diluted with methanol/water (3 ml/1 ml) and the mixture filtered through celite. The filtrate was then concentrated to an oil, dissolved into methanol and put through a High Pressure Liquid Chromatography column. The desired fractions were collected, concentrated, and lyophilized to give the ditrifluoroacetic acid salt of the title compound. The reaction was cooled the mixture filtered through celite The filtrate was then concentrated to an oil dissolved into methanol The desired fractions were collected concentrated

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

Procedure: Under an argon atmosphere, (2R,5S)-tert-butyl 4-benzyl-2,5-dimethylpiperazine-1-carboxylate (2.0 g, 6.57 mmol) was dissolved in methanol (60 mL), and added 10% palladium carbon (670 mg) and formic acid (1.5 g, 32.9 mmol). The mixture was stirred at room temperature for 2 hours. Then, the reaction solution was filtered through a pad of celite, and concentrated in vacuo. The obtained residue was added chloroform and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over sodium sulfate, concentrated in vacuo, and the title compound (1.56 g, >100%) was obtained as a yellow oil. Then, the reaction solution was filtered through a pad of celite concentrated in vacuo The obtained residue was added chloroform a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform dried over sodium sulfate concentrated in vacuo

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

Procedure: Following the procedures as described for compound 101g, (2R,5S)-tert-butyl-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 6.0 mmol), and 5-bromo-2-nitropyridine (1212 mg, 6.0 mmol) were reacted to give 122a as a yellow solid (1500 mg, 75%). LCMS: [M+H]+ 337 were reacted

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

Procedure: Following the procedures as described for compound 101g, (2R,5S)-tert-butyl-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 6.0 mmol), and 5-bromo-2-nitropyridine (1212 mg, 6.0 mmol) were reacted to give 122a as a yellow solid (1500 mg, 75%). LCMS: [M+H]+ 337 were reacted

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask were added 1-(4-cyanobenzyl)-5-formylimidazole (250.0 mg, 1.2 mmole) along with titanium(IV)isopropoxide (1.0 ml, 3.65 mmol), (trans) 2,5-Dimethyl-4-tertbutyloxycarbonylpiprizine (253.7 mg, 1.2 mmol) (prepared as described in Step 1), and tetrahydrofuran (0.4 ml). The reaction was heated at 60° C. for 1.25 hour. The reaction was cooled and sodiumcyanoborohydride (95.0 mg, 1.5 mmol) was added along with ethanol (0.5 ml) and the reaction was stirred at RT for 18 hours. The reaction was diluted with methanol/water (3 ml/1 ml) and the mixture filtered through celite. The filtrate was then concentrated to an oil, dissolved into methanol and put through a High Pressure Liquid Chromatography column. The desired fractions were collected, concentrated, and lyophilized to give the ditrifluoroacetic acid salt of the title compound. The reaction was cooled the mixture filtered through celite The filtrate was then concentrated to an oil dissolved into methanol The desired fractions were collected concentrated

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

Procedure: Following the procedures as described for compound 101g, (2R,5S)-tert-butyl-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 6.0 mmol), and 5-bromo-2-nitropyridine (1212 mg, 6.0 mmol) were reacted to give 122a as a yellow solid (1500 mg, 75%). LCMS: [M+H]+ 337 were reacted

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

Procedure: A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.45 g, 20 mmol), (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (5.14, 24 mmol) and DIPEA (5.14 mL, 30.00 mmol) in DMF (40.0 mL) was heated at 125° C. for 2.5 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by MPLC silica chromatography, eluting with EtOAc. Product fractions were evaporated and triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford (2R,5S)-tert-butyl 2,5-dimethyl-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (6.09 g, 76%) as a white crystalline solid. The reaction mixture was evaporated to dryness redissolved in DCM washed sequentially with 1M aqueous K2CO3, water and saturated brine The organic layer was dried over MgSO4 filtered evaporated The crude product was purified by MPLC silica chromatography eluting with EtOAc Product fractions were evaporated triturated with ether The solid was collected by filtration washed with ether dried under vacuum

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solution of 9.74 g of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate in 25 ml of DMI and 25 ml of acetonitrile were added 5 g of 2,4-difluorobenzonitrile and 11.4 g of cesium carbonate, followed by 2 days of stirring at 120° C. The reaction solution was poured into water, followed by extraction with ethyl acetate. After the organic layer was washed with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 4.66 g of the title compound from an eluate eluted with hexane-ethyl acetate (80:20, v/v). followed by extraction with ethyl acetate After the organic layer was washed with saturated saline, it was dried over anhydrous sodium sulfate The solvent was removed by evaporation the resulting residue was purified by silica gel column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solution of 9.74 g of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate in 25 ml of DMI and 25 ml of acetonitrile were added 5 g of 2,4-difluorobenzonitrile and 11.4 g of cesium carbonate, followed by 2 days of stirring at 120° C. The reaction solution was poured into water, followed by extraction with ethyl acetate. After the organic layer was washed with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 4.66 g of the title compound from an eluate eluted with hexane-ethyl acetate (80:20, v/v). followed by extraction with ethyl acetate After the organic layer was washed with saturated saline, it was dried over anhydrous sodium sulfate The solvent was removed by evaporation the resulting residue was purified by silica gel column chromatography

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

Procedure: Following the procedures as described for compound 101g, (2R,5S)-tert-butyl-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 6.0 mmol), and 5-bromo-2-nitropyridine (1212 mg, 6.0 mmol) were reacted to give 122a as a yellow solid (1500 mg, 75%). LCMS: [M+H]+ 337 were reacted

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

Procedure: Under an argon atmosphere, (2R,5S)-tert-butyl 4-benzyl-2,5-dimethylpiperazine-1-carboxylate (2.0 g, 6.57 mmol) was dissolved in methanol (60 mL), and added 10% palladium carbon (670 mg) and formic acid (1.5 g, 32.9 mmol). The mixture was stirred at room temperature for 2 hours. Then, the reaction solution was filtered through a pad of celite, and concentrated in vacuo. The obtained residue was added chloroform and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over sodium sulfate, concentrated in vacuo, and the title compound (1.56 g, >100%) was obtained as a yellow oil. Then, the reaction solution was filtered through a pad of celite concentrated in vacuo The obtained residue was added chloroform a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform dried over sodium sulfate concentrated in vacuo