(2R,6S)-2,6-dimethylpiperazine

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

Procedure: A solution of cis-2,6-dimethylpiperazine (5.0 g) and sulfamide (10.0 g) in 1,4-dioxane (100 ml) was stirred for 72 h at 110° C. The volatiles were removed in vacuo and the residue suspended in EtOAc. The filtrate was evaporated to a yellow solid (4.3 g). 1 g of this material was dissolved in methanol and applied to an SCX cartridge (10 g). The cartridge was washed with 50% aqueous methanol (200 ml) before the subtitle product was eluted with 5% ammonium hydroxide solution/methanol (200 ml). The solvent was removed under reduced pressure to yield the subtitle compound as a yellow solid. Yield: 0.46 g. The volatiles were removed in vacuo The filtrate was evaporated to a yellow solid (4.3 g) 1 g of this material was dissolved in methanol The cartridge was washed with 50% aqueous methanol (200 ml) before the subtitle product was eluted with 5% ammonium hydroxide solution/methanol (200 ml) The solvent was removed under reduced pressure

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

Procedure: 6-chloro-N-(4-chloro-3-(2-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.8 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-nicotin-amide. MS (Q1) 498.1 (M)+ The product was purified by RP-HPLC

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

Procedure: 6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide (0.19 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.57 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-nicotinamide. MS (Q1) 498.0 (M)+ The product was purified by RP-HPLC

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

Procedure: 6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)-2-methylnicotinamide (0.14 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.70 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-2-methylnicotinamide. MS (Q1) 512.0 (M)+ The product was purified by RP-HPLC

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

Procedure: 6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.83 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-nicotinamide. MS (Q1) 498.0 (M)+ The product was purified by RP-HPLC

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

Procedure: 6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methylnicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(4-fluorobenzamido)phenyl))-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)-2-methylnicotinamide. MS (Q1) 496.0 (M)+ The product was purified by RP-HPLC

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

Procedure: 6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(4-fluorobenzamido)phenyl)-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)nicotinamide. MS (Q1) 482.3 (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-chloro-2-methylnicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)-2-methyl-nicotinamide. MS (Q1) 464.0 (M)+ The product was purified by RP-HPLC

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (1 ml) was added to 5-{8-chloro-9-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (100 mg, 0.21 mmol) and cis-2,6-dimethylpiperazine (119 mg, 1.04 mmol) and the resulting mixture was stirred at 140° C. for 1 hour. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give the title compound (95 mg, 82%) as a light brown solid. The reaction mixture was partitioned with chloroform and water 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=9:1)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), cis-2,6-dimethylpiperazine (80 mg, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 2 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (64 mg, 54%) as a light brown solid. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol), cis-2,6-dimethylpiperazine (82 mg, 0.72 mmol), and dimethyl sulfoxide (800 μl) was stirred at 150° C. for 1.5 hours. The reaction mixture was cooled and then partitioned with ethyl acetate and water and the organic layer was washed twice with saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give the title compound (64 mg, 57%) as a light brown solid. The reaction mixture was cooled partitioned with ethyl acetate and water the organic layer was washed twice with saturated brine dried over magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography (chloroform:methanol=9:1)

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

Procedure: A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (112.3 mg, 0.23 mmol) and cis-2,6-dimethylpiperazine (105.7 mg, 0.93 mmol) was heated at 140° C., stirred for 5 hours, and left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. 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 preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (98.2 mg, 89%) as a light brown solid. left to cool the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution 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 preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1)