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

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

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

Procedure: 1-(3-Chloro-propyl)-4-methyl-piperazine hydrochloride (1.7 g, 9.6 mmol, 1.2 eq.) is added in one portion to a mixture of 4-aminophenol (893 mg, 8.0 mmol) and finely powdered sodium hydroxide (808 mg, 20 mmol, 2.5 eq.) in DMF (27 ml). The reaction mixture is stirred for 17 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×50 ml). The aqueous layer is back-extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3) provides 1.86 g of the title compound as a yellow-brown oil: ESI-MS: 250.2 [MH]+; TLC: Rf=0.31 (DCM/MeOH, 7:3). The resulting dark suspension is filtered The filtrate is diluted with DCM (200 ml) washed with brine (2×50 ml) The aqueous layer is back-extracted with DCM The organic phase is dried (sodium sulfate) filtered concentrated Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3)

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

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

Procedure: Into a Microwave vial, 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (0.104 g, 0.000404 mol), 4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenylamine (0.221 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 15% methanol). The collected fractions afforded {4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (25 mg, 14%). MP 135-139° C. LCMS (E/I+) 444.8 (M+H). NMR 1H (DSMO-d6)-9.38-9.46 (m, 2H), 9.03 (s, 1H), 8.66 (d, 1H, J=8.08 Hz), 8.61 (d, 1H, J=4.67 Hz), 7.60-7.70 (m, 3H), 7.32 (d, 1H, J=4.81 Hz), 6.98 (d, 1H, J=4.80 Hz), 6.93 (d, 2H, J=9.00 Hz), 4.03 (t, 2H, J=5.26 Hz), 2.30-3.60 (m, 13H), 1.95-2.10 (bm, 2H). The reaction was microwaved on 300 watts, 170° C. for 50 minutes The solvent was removed under vacuum

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

Procedure: Into a Round bottom flask, 1-Methyl-4-[3-(4-nitro-phenoxy)-propyl]-piperazine (4.10 g, 0.0147 mol), 10% Pd/C (10:90, Palladium:carbon black, 1.6 g, 0.0015 mol), and Ethanol (100 mL, 2 mol) were added. The mixture was evacuated under house vacuum and charged with a hydrogen balloon (3×). The reaction was stirred at room temperature under an atmosphere of Hydrogen via a balloon. The solid was filtered. The solvent was removed under vacuum to give 4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenylamine a white solid (2.86, 78%). 1H (DSMO-d6)-6.62 (dd, 1H, J=2.08, 4.57 Hz), 6.49 (dd, 2H, J=2.16, 5.64 Hz), 4.56 (bs, 2H), 3.82 (t, 2H, J=6.40 Hz), 2.20-2.45 (m, 10H), 2.13 (s, 3H), 1.70-1.83 (m, 2H) The mixture was evacuated under house vacuum charged with a hydrogen balloon (3×) The solid was filtered The solvent was removed under vacuum

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

Procedure: 1-(3-Chloro-propyl)-4-methyl-piperazine hydrochloride (1.7 g, 9.6 mmol, 1.2 eq.) is added in one portion to a mixture of 4-aminophenol (893 mg, 8.0 mmol) and finely powdered sodium hydroxide (808 mg, 20 mmol, 2.5 eq.) in DMF (27 ml). The reaction mixture is stirred for 17 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×50 ml). The aqueous layer is back-extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3) provides 1.86 g of the title compound as a yellow-brown oil: ESI-MS: 250.2 [MH]+; TLC: Rf=0.31 (DCM/MeOH, 7:3). The resulting dark suspension is filtered The filtrate is diluted with DCM (200 ml) washed with brine (2×50 ml) The aqueous layer is back-extracted with DCM The organic phase is dried (sodium sulfate) filtered concentrated Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3)