262368-47-8

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 4-(2-morpholinoethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.

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

Procedure: A Smith vial (2-5 mL) is charged with N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound. 1H NMR 600 MHz (DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H), 6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t, J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13 (br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1). After purging with Argon the vial is sealed irradiated at 100° C. for 1.5 hours in a Smith Synthesizer The resulting solution is subjected to purification by reverse-phase LC-MS

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

Procedure: The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.

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 4-(2-morpholinoethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.

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

Procedure: A Smith vial (2-5 mL) is charged with N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound. 1H NMR 600 MHz (DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H), 6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t, J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13 (br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1). After purging with Argon the vial is sealed irradiated at 100° C. for 1.5 hours in a Smith Synthesizer The resulting solution is subjected to purification by reverse-phase LC-MS

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

Procedure: The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.

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

Procedure: Lithium hexamethyldisilazide (1.0 M in THF) 1.1 mL was added dropwise to a mixture of 200 mg of methyl 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoate, 90 mg of 4-[2-(morpholin-4-yl)ethyl]aniline, and 5.0 mL of THF under ice cooling, followed by stirring for 30 minutes at the same temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), thereby obtaining 164 mg of methyl 2,2-dimethyl-5-[(3-{[3-({4-[2-(morpholin-4-yl)ethyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}benzyl)(pentan-3-yl)amino]-5-oxopentanoate. followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1)

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

Procedure: The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.

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

Procedure: Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (from Example 27(A), 54 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e) above, 100 mg, 0.26 mmol). The title compound was obtained as a white solid (77 mg, 59%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.28 (s, 1H), 8.46 (s, 1H), 7.98 (br, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 5.04 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.67 (t, J=4.6 Hz, 4H), 2.76 (m, 2H), 2.54 (m, 2H), 2.47 (m, 4H), 1.99 (m, 4H), 1.78 (m, 1H), 1.61 (m, 2H), 1.46 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.23 (m, 1H).

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

Procedure: Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (49 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 8.45 (s, 1H), 7.50 (br, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.21 (m, 3H), 7.13 (d, J=7.8 Hz, 1H), 6.87 (br, 2H), 4.31 (q, J=7.0 Hz, 2H), 3.69 (br, 4H), 2.96 (t, J=7.4 Hz, 2H), 2.91 (t, J=7.4 Hz, 2H), 2.67 (br, 2H), 2.46 (br, 6H), 2.17 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

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

Procedure: The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.

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

Procedure: The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.