tert-butyl (2S)-2-methylpiperazine-1-carboxylate

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

Procedure: To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (1.20 g, 5.99 mmol) and DIPEA (5.45 ml, 31.2 mmol) in dry DCM (60 ml) at 0° C. under Ar was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (2.04 g, 6.29 mmol) and the resulting clear solution stirred at 0° C. for 2 h. EtOAc (100 ml) and saturated aqueous NaHCO3 (100 ml) were added, the layers separated, then the organic layer washed with 2M aqueous HCl (100 ml) and passed through an hydrophobic frit. The solvent was removed to leave the title compound (2.36 g). the layers separated the organic layer washed with 2M aqueous HCl (100 ml) The solvent was removed

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

Procedure: To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (1.18 g, 4.98 mmol) in dichloromethane (40 ml) was added DIPEA (2.70 ml, 15.45 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.613 g, 4.98 mmol). The reaction mixture was stirred for 1 h 20 min at room temperature, and then washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum to give the crude title compound (2.5 g) used directly in the next step. washed with water (50 ml) dried on a phase separation cartridge concentrated under vacuum

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

Procedure: To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (2.50 g, 12.5 mmol), DIPEA (4.58 ml, 26.2 mmol) and 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (3.25 g, 12.5 mmol) in DCM (200 ml) was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO3, then brine and concentrated under vacuum. The residue was redissolved in 1,4-dioxane (200 ml), then 4M HCl in dioxane (20 ml) and water (0.5 ml) were added and the mixture stirred overnight. The mixture was concentrated under vacuum and applied to an SCX-2 cartridge (20 g) washing with MeOH. The product was eluted with 0.5M NH3 in MeOH; concentration left the title compound as a white solid (2.56 g). The mixture was washed with saturated aqueous NaHCO3 brine and concentrated under vacuum The residue was redissolved in 1,4-dioxane (200 ml) 4M HCl in dioxane (20 ml) and water (0.5 ml) were added The mixture was concentrated under vacuum washing with MeOH The product was eluted with 0.5M NH3 in MeOH concentration left the title compound as a white solid (2.56 g)

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

Procedure: The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (200 mg, 386 μmol) and (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (155 mg, 773 μmol) using the method from Example 61. After purification by HPLC Method E and deprotection using HCl/dioxan, the title compound (58 mg, 25% yield over two steps) was obtained as off-white solid (HCl-salt). After purification by HPLC Method E and deprotection

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

Procedure: Following the procedures as described for compound 108a, reaction of 5-bromo-2-nitropyridine (1.5 g) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate (2.3 g), gave 107a as a yellow solid (1.5 g, 40%). MS: [M+H]+ 323. See FIG. 7.

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

Procedure: A solution of (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol), 1,1,1-trifluoro-3-iodo-propane (268 mg, 1.2 mmol) and triethylamine (200 mg, 2 mmol) in acetonitrile (10 ml) was stirred at 80° C. for 3 days. After standard work-up (aqueous sodium hydrogencarbonate, dichloromethane), (S)-2-methyl-4-(3,3,3-trifluoro-propyl)piperazine-1-carboxylic acid tert-butyl ester was deprotected under standard conditions with trifluoroacetic acid (1 h) to give (S)-3-methyl-1-(3,3,3-trifluoro-propyl)-piperazine trifluoroacetic acid salt which was used without purification in the next step. LC/MS (method 7): Rt=0.07 min; m/z=197.2 (M+H+).

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 114 (1.60 g, 6.91 mmol) in toluene (21.1 mL) under an argon atmosphere was added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (115, 1.38 g, 6.91 mmol, AK Scientific, Inc., Union City, Calif.), sodium tert-butoxide (0.73 g, 7.60 mmol, Sigma-Aldrich), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (i.e., “X-Phos,” 0.49 g, 1.04 mmol, Sigma-Aldrich). The mixture was degassed under argon and then tris(dibenzylideneacetone)dipalladium (Pd2(DBA)3, 0.63 g, 0.69 mmol, Sigma-Aldrich) was added to form a reaction mixture. The reaction mixture, heated in an oil bath maintained at temperature within the range of from 80° C. to 85° C., was stirred for 1.5 hours. Thereafter, the mixture was cooled to a temperature of about 25° C., poured onto cold water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated to an oil which was chromatographed on a silica gel column eluted with 10:90 EtOAc:hexanes and 20:80 EtOAc:hexanes to provide 1.71 g of 116 as a solid (63% yield). 1H NMR (CDCl3) δ: 1.25 (3H, d, J=6.80 Hz), 1.46 (3H, s), 1.48 (9H, s), 1.53 (3H, s), 2.89 (1H, dt, J=3.29, 13.59 Hz), 3.09 (1H, dd, J=3.73, 12.06 Hz), 3.23 (1H, dt, J=2.85, 13.59 Hz), 3.69 (1H, t, J=7.89 Hz), 3.83 (1H, d, J=12.72 Hz), 3.92 (1H, d, J=13.81 Hz), 4.01 (1H, d, J=12.90 Hz), 4.27 (1H, t, J=6.14 Hz), 4.31 (1H, brs), 5.01 (1H, t, J=7.24 Hz), 7.30 (1H, d, J=1.97 Hz), 7.95 (1H, s). LC/MS (M+1): m/z=396. The mixture was degassed under argon to form a reaction mixture The reaction mixture, heated in an oil bath maintained at temperature within the range of from 80° C. to 85° C. extracted with EtOAc The organic layer was separated washed with brine concentrated to an oil which was chromatographed on a silica gel column eluted with 10:90 EtOAc

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 114 (1.60 g, 6.91 mmol) in toluene (21.1 mL) under an argon atmosphere was added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (115, 1.38 g, 6.91 mmol, AK Scientific, Inc., Union City, Calif.), sodium tert-butoxide (0.73 g, 7.60 mmol, Sigma-Aldrich), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (i.e., “X-Phos,” 0.49 g, 1.04 mmol, Sigma-Aldrich). The mixture was degassed under argon and then tris(dibenzylideneacetone)dipalladium (Pd2(DBA)3, 0.63 g, 0.69 mmol, Sigma-Aldrich) was added to form a reaction mixture. The reaction mixture, heated in an oil bath maintained at temperature within the range of from 80° C. to 85° C., was stirred for 1.5 hours. Thereafter, the mixture was cooled to a temperature of about 25° C., poured onto cold water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated to an oil which was chromatographed on a silica gel column eluted with 10:90 EtOAc:hexanes and 20:80 EtOAc:hexanes to provide 1.71 g of 116 as a solid (63% yield). 1H NMR (CDCl3) δ: 1.25 (3H, d, J=6.80 Hz), 1.46 (3H, s), 1.48 (9H, s), 1.53 (3H, s), 2.89 (1H, dt, J=3.29, 13.59 Hz), 3.09 (1H, dd, J=3.73, 12.06 Hz), 3.23 (1H, dt, J=2.85, 13.59 Hz), 3.69 (1H, t, J=7.89 Hz), 3.83 (1H, d, J=12.72 Hz), 3.92 (1H, d, J=13.81 Hz), 4.01 (1H, d, J=12.90 Hz), 4.27 (1H, t, J=6.14 Hz), 4.31 (1H, brs), 5.01 (1H, t, J=7.24 Hz), 7.30 (1H, d, J=1.97 Hz), 7.95 (1H, s). LC/MS (M+1): m/z=396. The mixture was degassed under argon to form a reaction mixture The reaction mixture, heated in an oil bath maintained at temperature within the range of from 80° C. to 85° C. extracted with EtOAc The organic layer was separated washed with brine concentrated to an oil which was chromatographed on a silica gel column eluted with 10:90 EtOAc

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

Procedure: The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-methylpiperazine-1-carboxylic acid, tert-butyl ester and purified by HPLC. purified by HPLC

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

Procedure: The product of Example 59 step iii) (0.25 g), (S)-2-methylpiperazine-1-carboxylic acid, tert-butyl ester (0.37 g) and sodium triacetoxyborohydride (0.40 g) were stirred in dichloromethane (20 mL) under nitrogen for 16 hours. Water (20 mL) and dichloromethane (20 mL) were then added and the organics separated. The organics were evaporated under reduced pressure. The residue was dissolved in methanol (5 mL) and 4M HCl in 1,4-dioxane (2 mL) added. The mixture was stirred overnight at room temperature. The volatiles were removed under vacuum and the residue purified by HPLC to give the title compound as a solid (0.11 g). The organics were evaporated under reduced pressure The residue was dissolved in methanol (5 mL) 4M HCl in 1,4-dioxane (2 mL) added The volatiles were removed under vacuum the residue purified by HPLC

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

Procedure: The subtitle compound was prepared by the method of Example 11e using (S)-tert-butyl 2-methylpiperazine-1-carboxylate and 6-bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11d)

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

Procedure: The subtitle product was made from 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26 g, 190 mg) by sequential reaction with methanesulfonyl chloride (57 μL) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (240 mg) using a similar method to Example 26 h, to afford the title compound (58 mg) as a white solid. to Example 26 h