3-[(4-methylpiperazin-1-yl)methyl]aniline

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

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: A suspension of 1-methyl-4-(3-nitro-benzyl)-piperazine (6.9 g, 29.14 mmol) and Raney Nickel (2 g) in MeOH (150 mL) is stirred for 5 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a yellow solid: ESI-MS: 206.1 [MH]+. The reaction mixture is filtered through a pad of celite concentrated

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

Procedure: A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (385 mg, 2.68 mmol, 1.1 equiv), 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.44 mmol) and 4N HCl in dioxane (7 mL) is heated in a sealed tube to 150° C. for 17.5 h. The solvent is removed and the residue diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM and DCM/MeOH (95:5). The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a beige solid: ESI-MS: 313.2 [MH]+; tR=1.00 min (purity: 100%, system 1); TLC: Rf=0.05 (DCM/MeOH+1% NH3aq, 9:1). The solvent is removed the residue diluted with DCM The aqueous layer is separated extracted with DCM and DCM/MeOH (95:5) The organic phase is washed with brine dried (Na2SO4) filtered concentrated Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5)

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

Procedure: Using an analogous procedure to that described in Example 4, 3-(4-methylpiperazin-1-ylmethyl)aniline was reacted with 2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid to give the title compound in 32% yield; NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.31-2.35 (m, 8H), 3.42 (s, 2H), 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 7.02 (d, 1H), 7.1 (d, 1H), 7.22-7.3 (m, 2H), 7.57-7.65 (m, 3H), 7.84-7.94 (m, 2H), 8.28 (d, 1H), 10.47 (s, 1H), 10.52 (s, 1H); Mass Spectrum: M+H+ 549 and 551.

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

Procedure: A suspension of 1-methyl-4-(3-nitro-benzyl)-piperazine (6.9 g, 29.14 mmol) and Raney Nickel (2 g) in MeOH (150 mL) is stirred for 5 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a yellow solid: ESI-MS: 206.1 [MH]+. The reaction mixture is filtered through a pad of celite concentrated

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

Procedure: A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (385 mg, 2.68 mmol, 1.1 equiv), 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.44 mmol) and 4N HCl in dioxane (7 mL) is heated in a sealed tube to 150° C. for 17.5 h. The solvent is removed and the residue diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM and DCM/MeOH (95:5). The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a beige solid: ESI-MS: 313.2 [MH]+; tR=1.00 min (purity: 100%, system 1); TLC: Rf=0.05 (DCM/MeOH+1% NH3aq, 9:1). The solvent is removed the residue diluted with DCM The aqueous layer is separated extracted with DCM and DCM/MeOH (95:5) The organic phase is washed with brine dried (Na2SO4) filtered concentrated Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5)

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

Procedure: A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (385 mg, 2.68 mmol, 1.1 equiv), 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.44 mmol) and 4N HCl in dioxane (7 mL) is heated in a sealed tube to 150° C. for 17.5 h. The solvent is removed and the residue diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM and DCM/MeOH (95:5). The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a beige solid: ESI-MS: 313.2 [MH]+; tR=1.00 min (purity: 100%, system 1); TLC: Rf=0.05 (DCM/MeOH+1% NH3aq, 9:1). The solvent is removed the residue diluted with DCM The aqueous layer is separated extracted with DCM and DCM/MeOH (95:5) The organic phase is washed with brine dried (Na2SO4) filtered concentrated Purification of the residue by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pd(OAc)2 (16.34 mg, 0.0728 mmol), (±)-BINAP (45.33 mg, 0.0728 mmol) and dimethylformamide (12 mL) were charged in a round-bottom flask flushed with argon. The mixture was stirred under argon for 30 minutes. Then 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (448.4 mg, 2.184 mmol), ethyl 8-iodo-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methylamide (300 mg, 0.728 mmol), K2CO3 (1.508 g, 10.910 mmol) and dimethylformamide (10 mL) were added. The resulting mixture was heated to 80° C. in an oil bath under argon with good stirring for 3 hours. After cooling to room temperature, the reaction mixture was filtered by suction filtration washing with dichloromethane and the filtrate was evaporated to dryness. The crude was purified by flash chromatography on silica gel (eluant; dichloromethane/methanol 95:5) to afford 215 mg (yield 62%) of pure title compound. flushed with argon with good stirring for 3 hours After cooling to room temperature the reaction mixture was filtered by suction filtration washing with dichloromethane the filtrate was evaporated to dryness The crude was purified by flash chromatography on silica gel (eluant; dichloromethane/methanol 95:5)

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

Procedure: Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-(4-methylpiperazinomethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.

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