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

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

Procedure: To a solution of 1,1-dimethylethyl(2R)-2-methyl-1-piperazinecarboxylate (2.00 g, 9.99 mmol) in DCM (200 ml) was added DIPEA (3.66 ml, 20.97 mmol) and then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (1.69 ml, 9.99 mmol) and the resulting mixture stirred at room temperature for 90 min. The reaction mixture was then concentrated under vacuum and redissolved in 1,4-dioxane (100 ml). A 4M solution of HCl in 1,4-dioxane (100 ml, 400 mmol) and a few drops of distilled water were added and the mixture stirred for 3 h. The reaction mixture was concentrated under vacuum, redissolved in DCM (200 ml) and washed with 2M aqueous NaOH (2×50 ml). The organic layer was dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in ether and concentrated under vacuum. The oil was dissolved in MeOH (150 ml), applied to an SCX cartridge (50 g), which was washed with MeOH, DCM and MeOH again. The product was eluted from the column with 2M ammonia in methanol, DCM and then 2M ammonia in methanol; concentration under vacuum left the title compound as a transparent yellow oil (2.92 g). The reaction mixture was then concentrated under vacuum redissolved in 1,4-dioxane (100 ml) The reaction mixture was concentrated under vacuum redissolved in DCM (200 ml) washed with 2M aqueous NaOH (2×50 ml) The organic layer was dried (MgSO4) filtered concentrated under vacuum The residue was dissolved in ether concentrated under vacuum The oil was dissolved in MeOH (150 ml) was washed with MeOH, DCM and MeOH again The product was eluted from the column with 2M ammonia in methanol, DCM concentration under vacuum left the title compound as a transparent yellow oil (2.92 g)

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

Procedure: To a solution of 1,1-dimethylethyl(2R)-2-methyl-1-piperazinecarboxylate (2.95 g, 14.7 mmol) in DCM (120 ml) was added DIPEA (5.40 ml, 30.9 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (3.96 g, 16.2 mmol). The reaction mixture was stirred 2.5 hours at rt then washed with water (250 ml), dried on a phase separation cartridge and concentrated in vacuo. The obtained product was dissolved in 1,4-dioxane (60 ml) and treated with 4M HCl in 1,4-dioxane (18.4 ml, 73.6 mmol) overnight. The mixture was concentrated in vacuo then dissolved in EtOAc (150 ml), washed with 2N aq. NaOH solution (200 ml) then dried on a phase separation cartridge and concentrated in vacuo. The product was then dissolved in EtOAc (100 ml) and extracted with 2M HCl (2×200 ml). 2M NaOH solution were added to aqueous layer until basic pH then the product was extracted with EtOAc (500 ml). The organic layer was dried on a phase separation cartridge and concentrated in vacuo to give the title compound (3.76 g). then washed with water (250 ml) dried on a phase separation cartridge concentrated in vacuo The obtained product was dissolved in 1,4-dioxane (60 ml) The mixture was concentrated in vacuo then dissolved in EtOAc (150 ml) washed with 2N aq. NaOH solution (200 ml) then dried on a phase separation cartridge concentrated in vacuo The product was then dissolved in EtOAc (100 ml) extracted with 2M HCl (2×200 ml) 2M NaOH solution were added to aqueous layer until basic pH the product was extracted with EtOAc (500 ml) The organic layer was dried on a phase separation cartridge concentrated in vacuo

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with methylsulfinylmethane (50 mL), 5-bromo-2-nitropyridine (2.2 g, 11 mmol), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (2.2 g, 11 mmol), and potassium carbonate (3.08 g, 22 mmol). See FIG. 8. The system was subjected to three cycles of vacuum/nitrogen flush and heated at 65° C. for 15 h. It was then cooled to room temperature, and partitioned between ethyl acetate (100 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column chromatography eluting with 2:1 (UV) petroleum/ethyl acetate to afford 108a as a yellow solid (1.75 g, 50%). LCMS: [M+H]+ 323 A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser flush It was then cooled to room temperature partitioned between ethyl acetate (100 mL) and water (20 mL) The aqueous layer was separated extracted with ethyl acetate (50 mL×2) The combined organic layer was washed with brine (50 mL) dried over anhydrous sodium sulfate The drying agent was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified on flash column chromatography eluting with 2:1 (UV) petroleum/ethyl acetate

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

Procedure: 3-(5-(tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (50 mg, 0.114 mmol)), HOBt.H2O (34.8, 0.228 mmol), EDCI (43.6 mg, 0.228 mmol), Hunig's base (44.1 mg, 0.341 mmol) and (R)-1-(4-fluorophenyl)-3-methylpiperazine (22.1 mg, 0.114 mmol, prepared from the coupling of (R)-tert-butyl 2-methylpiperazine-1-carboxylate and 1-fluoro-4-iodobenzene using CuI followed with deprotection with TFA) were mixed in dichloromethane (1 mL). The mixture was kept stirring at room temperature for 16 hours before it was diluted with dichloromethane (5 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×3 mL) and hydrochloric acid (0.5 M, 2 mL), dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=1:1 to give (R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (58 mg, 0.094 mmol) as a yellow foam. washed with aqueous sodium hydrogen carbonate (saturated, 1×3 mL) and hydrochloric acid (0.5 M, 2 mL) dried (MgSO4) filtered The solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane=1:1

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

Procedure: 3-(5-(tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (50 mg, 0.114 mmol)), HOBt.H2O (34.8, 0.228 mmol), EDCI (43.6 mg, 0.228 mmol), Hunig's base (44.1 mg, 0.341 mmol) and (R)-1-(4-fluorophenyl)-3-methylpiperazine (22.1 mg, 0.114 mmol, prepared from the coupling of (R)-tert-butyl 2-methylpiperazine-1-carboxylate and 1-fluoro-4-iodobenzene using CuI followed with deprotection with TFA) were mixed in dichloromethane (1 mL). The mixture was kept stirring at room temperature for 16 hours before it was diluted with dichloromethane (5 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×3 mL) and hydrochloric acid (0.5 M, 2 mL), dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=1:1 to give (R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (58 mg, 0.094 mmol) as a yellow foam. washed with aqueous sodium hydrogen carbonate (saturated, 1×3 mL) and hydrochloric acid (0.5 M, 2 mL) dried (MgSO4) filtered The solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane=1:1

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

Procedure: The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M—(CH2═CMe2)—CO2]H+ 236.3, no molecular ion.

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

Procedure: The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M-(CH2═CMe2)-CO2]H+ 236.3, no molecular ion.

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

Procedure: The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M-(CH2═CMe2)-CO2]H+ 236.3, no molecular ion.

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (R)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+). at 40° C. for an additional 7 h The reaction mixture was filtered through Celite (ethyl acetate eluent) concentrated used without further purification

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (R)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+). at 40° C. for an additional 7 h The reaction mixture was filtered through Celite (ethyl acetate eluent) concentrated used without further purification

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (R)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+). at 40° C. for an additional 7 h The reaction mixture was filtered through Celite (ethyl acetate eluent) concentrated used without further purification

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

Procedure: To (R)-1-Boc-2-methylpiperazine (200.0 mg, 0.999 mmol) and sodium triacetoxyborohydride (444.5 mg, 2.097 mmol) in DMF (5 mL) was added acetone (116 mg, 0.147 mL, 1.997 mmol) and acetic acid (90.0 mg, 86 μL, 1.498 mmol). The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was diluted with water and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered, concentrated, and used without further purification. LCMS-ESI+: calc'd for C13H27N2O2 (M+H+): 243.2; Found: 243.2 (M+H+). extracted three times with diethyl ether The combined organics were dried over sodium sulfate filtered concentrated used without further purification