(2R)-2-methylpiperazine

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

Procedure: 6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.18 mmol) was used in general procedure 3 with (R)-2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give (R)—N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 468.0 (M)+ The product was purified by RP-HPLC

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

Procedure: N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.18 mmol) was used in general procedure 3 with (R)-2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give (R)—N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 450.4 (M)+ The product was purified by RP-HPLC

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2R)-2-Methylpiperazine (241 mg, 2.41 mmol) and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 2 hours. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Acetic anhydride (68 μl) and triethylamine (200 μl) were added to the residue with ice cooling and the resulting mixture was stirred for 1 hour and partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (127 mg, 52%) as a colorless solid. The reaction mixture was partitioned with chloroform and water the organic layer was dried over magnesium sulfate the solvent was concentrated under reduced pressure Acetic anhydride (68 μl) and triethylamine (200 μl) were added to the residue with ice cooling the resulting mixture was stirred for 1 hour partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution The organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography (chloroform:methanol=20:1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An N-methyl-2-pyrrolidone suspension (24 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (2.42 g, 5.82 mmol) and (2R)-2-methylpiperazine (2.92 g, 29.1 mmol) was heated at 120° C. to dissolve and the resulting mixture was stirred at 100° C. for 6 hours. The resulting mixture was left standing to cool, then poured into methylene chloride-methanol (10:1), and washed with water. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1) to give the title compound (2.51 g, 90%) as a pale yellow solid. to dissolve The resulting mixture was left to cool washed with water The organic layer was dried over anhydrous sodium sulfate the mixture was filtrated the filtrate was concentrated under reduced pressure the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1)

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

Procedure: N-Methylpyrrolidone (2 ml) was added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (200 mg, 0.51 mmol) and (2R)-2-methylpiperazine (412 mg, 4.1 mmol) and the resulting mixture was stirred at 120° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give a formate of the title compound (204 mg) as a white solid. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid)

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

Procedure: More specifically, compound 1 is 2,3-dichloro pyridine (2 g); compound 2 is (R)-2-methyl-piperazine; the synthesized compound 3 is 1-(3-chloro-2-pyridyl)-3-methyl-piperazine (8 g, yield 86.8%). From p-dimethyl(vinyl)silyl phenyl isocynate (compound 7c, 200 mg), it gave about 250 mg of compound A-15 (yield about 61.2%).

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

Procedure: Compound A-10 can be synthesized according to method 1. Just of Scheme 1, R1 is —Cl; R2 is -Me; R3 is m-SiMe3. More specifically, compound 1 is 2,3-dichloro pyridine (6 g); compound 2 is (R)-2-methyl piperazine; the synthesized compound 3 is 3-methyl-1-(3-chloro-2-pyridyl)piperazine (8 g, yield about 93.2%). Compound A-10 can be synthesized

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

Procedure: More specifically, compound 1 is 2-chloro-3-trifluoromethylpyridine (2 g); compound 2 is (R)-2-methyl piperazine; the synthesized compound 3 is 3-methyl-1-(3-trifluoromethyl-2-pyridyl)piperazine (2.5 g, yield about 92.6%).

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

Procedure: Compound A-03 can be synthesized according to method 1. Just of Scheme 1, R1 is —CF3; R2 is -Me; R3 is p-SiMe3. More specifically, compound 1 is 2-chloro-3-(trifluoromethyl)-pyridine (2 g); compound 2 is (R)-2-methylpiperazine; the synthesized compound 3 is 3-methyl-1-(3-trifluoromethyl-2-pyridyl)piperazine (2.5 g, yield about 92.6%). Compound A-03 can be synthesized

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

Procedure: Compound A-02 can be synthesized according to method 1. Just R1, R2, and R3 of Scheme 1 are respectively —Cl, -Me and p-SiMe3. More specifically, compound 1 is 2,3-dichloro-pyridine (6 g), compound 2 is (R)-2-methylpiperazine, the synthesized compound 3 is 1-(3-chloro-2-pyridyl)-3-methyl-piperazine (38 g, yield about 93.2%). Compound A-02 can be synthesized

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

Procedure: A solution of 2-chloro-5-methyl-pyridine (127 mg, 1 mmoles), (2R)-2-methyl-piperazine (200 mg, 2 mmoles) in EtOH (3 mL) was heated in microwave to 180° C. for 5 minutes. The mixture was cooled, concentrated under reduced pressure and partitioned with DCM and the saturated aqueous sodium bicarbonate layer. The aqueous solution was extracted three times with additional DCM. The combined organic extracts were washed twice with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound. The mixture was cooled concentrated under reduced pressure partitioned with DCM The aqueous solution was extracted three times with additional DCM The combined organic extracts were washed twice with water dried (MgSO4) filtered The filtrate was concentrated under reduced pressure

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

Procedure: To a mixture of (R)-2-methylpiperazine (3.0 g, 30 mmol), 4-trifluoromethoxy bromo benzene (6.6 g, 27.5 mmol) and sodium tert-butoxide (3.56 g, 37.5 mmol) in dry toluene (50 mL) under nitrogen atmosphere, were added Pd(OAc)2 (0.28 g, 12.5 mmol) followed by BINAP (0.62 g, 1 mmol) and refluxed for 16 h. Then the reaction mixture was concentrated and the crude compound was purified by column chromatography on silica gel using chloroform and methanol as eluent to give the title compound as a dark brown liquid (3 g, 38%). refluxed for 16 h Then the reaction mixture was concentrated the crude compound was purified by column chromatography on silica gel