1,2-dimethylpiperazine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (390 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (392 mg, 84%) as a yellow solid. The residue was purified by ion exchange chromatography The desired product was eluted from the column to afford impure material The concentrated eluent was purified by silica column chromatography eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM Pure fractions were evaporated to dryness

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

Procedure: 5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (390 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (392 mg, 84%) as a yellow solid. The residue was purified by ion exchange chromatography The desired product was eluted from the column to afford impure material The concentrated eluent was purified by silica column chromatography eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM Pure fractions were evaporated to dryness

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

Procedure: 5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (375 mg, 81%) as a yellow solid. The residue was purified by ion exchange chromatography The desired product was eluted from the column to afford impure material The concentrated eluent was purified by silica column chromatography eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM Pure fractions were evaporated to dryness

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

Procedure: 1,2-Dimethylpiperazine (2.284 g, 20.00 mmol) and ethyl 4-fluorobenzoate (1.467 mL, 10 mmol) were dissolved in DMA (12 mL) and sealed in a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction mixture was heated for a further 30 mins at 150° C. and cooled to room temperature. The reaction mixture was evaporated and the crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM with 0.1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.853 g, 32.5%) as a colourless waxy solid. sealed in a microwave tube cooled to room temperature The reaction mixture was heated for a further 30 mins at 150° C. cooled to room temperature The reaction mixture was evaporated the crude product was purified by silica column chromatography eluting with 5% MeOH in DCM with 0.1% 0.880 ammonia Pure fractions were evaporated to dryness

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (0.112 g, 0.50 mmol) was added to a mixture of ethyl 5-bromothiophene-2-carboxylate (0.571 g, 5 mmol), 1,2-dimethyl-piperazine (1.175 g, 5 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) and cesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C. under nitrogen. The resulting suspension was stirred at 110° C. for 23 h. The crude product was purified by ion exchange chromatography, using a SCX2 column. The crude material was dissolved in methanol and then applied to the column. The desired product was eluted from the column using 2M NH3 in methanol and pure fractions were evaporated to dryness to afford the crude product as a brown oil. This material was further purified by silica column chromatography, eluting with a gradient of 1 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.640 g, 47.7%) as a light brown solid. The crude product was purified by ion exchange chromatography The crude material was dissolved in methanol The desired product was eluted from the column were evaporated to dryness to afford the crude product as a brown oil This material was further purified by silica column chromatography eluting with a gradient of 1 to 5% MeOH in DCM Pure fractions were evaporated to dryness

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

Procedure: 1,2-Dimethyl-piperazine (0.914 g, 8.00 mmol) and ethyl 4-fluorobenzoate (0.587 mL, 4 mmol) were dissolved in DMA (6 mL) and sealed into a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction mixture was evaporated and the crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM (containing 0.1% 0.880 ammonia). Pure fractions were evaporated to dryness to afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.380 g, 36.2%) as a colourless waxy solid. sealed into a microwave tube cooled to room temperature The reaction mixture was evaporated the crude product was purified by silica column chromatography eluting with 5% MeOH in DCM (containing 0.1% 0.880 ammonia) Pure fractions were evaporated to dryness

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

Procedure: A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmole) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, 26%). LC-MS (ESI) m/z: 484 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43 (d, J=5.2 Hz, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.33-3.44 (m, 6H), 4.03 (s, 2H), 4.22 (m, 1H), 4.65 (m, 1H), 6.91 (m, 1H), 6.97 (m, 1H), 7.00 (d, J=8 Hz, 2H), 7.23-7.37 (m, 4H), 7.65 (m, 1H), 7.77 (d, J=7.2 Hz, 1H), 9.92 (s, 1H). NaBCNH3 (129 mg, 2.08 mmole) was added the mixture was stirred for another 5 hours After removal of solvents the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1)

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

Procedure: A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmole) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, 26%). LC-MS (ESI) m/z: 484 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43 (d, J=5.2 Hz, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.33-3.44 (m, 6H), 4.03 (s, 2H), 4.22 (m, 1H), 4.65 (m, 1H), 6.91 (m, 1H), 6.97 (m, 1H), 7.00 (d, J=8 Hz, 2H), 7.23-7.37 (m, 4H), 7.65 (m, 1H), 7.77 (d, J=7.2 Hz, 1H), 9.92 (s, 1H). NaBCNH3 (129 mg, 2.08 mmole) was added the mixture was stirred for another 5 hours After removal of solvents the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1)

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

Procedure: A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (150 mg, 0.226 mmol), 1,2-dimethylpiperazine (45.7 mg, 0.40 mmol), sodium triacetoxyborohydride (95 mg, 0.45 mmol) and AcOH (18 μl, 0.314 mmol) in 1,2-dichloroethane (DCE) (6 mL) was stirred overnight at room temperature. LC/MS showed that the reaction was complete. The reaction was diluted with EtOAc; the organic layer washed with dilute aq. NaOH, then sat. aq. NaCl and dried [Na2SO4], then concentrated to a viscous taffy. The material was purified on a Gilson HPLC using reverse phase (acetonitrile-water with 0.1% TFA). Fractions containing the desired product were combined, the MeOH removed, the aqueous layer treated with EtOAc and 1N NaOH. The mixture was vigorously extracted with EtOAc (2×), the extract was washed with a small amount of sat. aq. NaCl; dried [Na2SO4], then concentrated to a glassy, creamy tan, coloured foam (0.1002 g). LC-MS m/z 761.5 (M+H)+, 0.76 min (ret time). the organic layer washed with dilute aq. NaOH sat. aq. NaCl and dried [Na2SO4] concentrated to a viscous taffy The material was purified on a Gilson HPLC Fractions containing the desired product the MeOH removed the aqueous layer treated with EtOAc and 1N NaOH The mixture was vigorously extracted with EtOAc (2×) the extract was washed with a small amount of sat. aq. NaCl dried [Na2SO4] concentrated to a glassy, creamy tan, coloured foam (0.1002 g) LC-MS m/z 761.5 (M+H)+, 0.76 min (ret time)

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

Procedure: A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (150 mg, 0.226 mmol), 1,2-dimethylpiperazine (45.7 mg, 0.40 mmol), sodium triacetoxyborohydride (95 mg, 0.45 mmol) and AcOH (18 μl, 0.314 mmol) in 1,2-dichloroethane (DCE) (6 mL) was stirred overnight at room temperature. LC/MS showed that the reaction was complete. The reaction was diluted with EtOAc; the organic layer washed with dilute aq. NaOH, then sat. aq. NaCl and dried [Na2SO4], then concentrated to a viscous taffy. The material was purified on a Gilson HPLC using reverse phase (acetonitrile-water with 0.1% TFA). Fractions containing the desired product were combined, the MeOH removed, the aqueous layer treated with EtOAc and 1N NaOH. The mixture was vigorously extracted with EtOAc (2×), the extract was washed with a small amount of sat. aq. NaCl; dried [Na2SO4], then concentrated to a glassy, creamy tan, coloured foam (0.1002 g). LC-MS m/z 761.5 (M+H)+, 0.76 min (ret time). the organic layer washed with dilute aq. NaOH sat. aq. NaCl and dried [Na2SO4] concentrated to a viscous taffy The material was purified on a Gilson HPLC Fractions containing the desired product the MeOH removed the aqueous layer treated with EtOAc and 1N NaOH The mixture was vigorously extracted with EtOAc (2×) the extract was washed with a small amount of sat. aq. NaCl dried [Na2SO4] concentrated to a glassy, creamy tan, coloured foam (0.1002 g) LC-MS m/z 761.5 (M+H)+, 0.76 min (ret time)