(2S)-1,2-dimethylpiperazine

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

Procedure: The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (s, 3 H) 3.13-3.74 (m, 7 H) 7.63 (d, J=6.82 Hz, 1 H) 7.71-7.78 (m, 1 H) 7.90-8.67 (m, 4 H). ESI-MS m/z [M+H]+ 435.3.

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

Procedure: The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (s, 3H) 3.13-3.74 (m, 7H) 7.63 (d, J=6.82 Hz, 1H) 7.71-7.78 (m, 1H) 7.90-8.67 (m, 4H). ESI-MS m/z [M+H]+ 435.3.

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

Procedure: The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (s, 3H) 3.13-3.74 (m, 7H) 7.63 (d, J=6.82 Hz, 1H) 7.71-7.78 (m, 1H) 7.90-8.67 (m, 4H). ESI-MS m/z [M+H]+ 435.3.

Conditions: temp:115.01; pressure:0.00; stir:

Procedure: A mixture of CHLORO(2-DICYCLOHEXYLPHOSPHINO-2',6'-DI-I- PROPOXY-1,1'-BIPHENYL)[2-(2-AMINOETHYLPHENYL)]PALLADIUM(II), METHYL-T- BUTYLETHER ADDUCT (Ru Phos Pd cycle) (69.2 mgs, 0.2eq), sodium tert-butoxide (244 mg, 2.54 mmol) ,2-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (200 mg, 0.42 mmol) , (S)-1,2-dimethylpiperazine (198 mg, 1.06 mmol) in dioxane (20ml) was stirred at 115°C for 1hr, LCMS indicated the completion of reaction. The solid was filtered off through a pad of celite, washed with DCM. The solvent of the filtrate was removed by concentration, taken into 2ml of DMSO, purified with reverse phase chromatography column (eluted with 5% to 50% 0.1%TFA in ACN/0.1%TFA in water), the fractions were combined and lyphlized, to yield 117mgs of product. LCMS indicated 9% of TFA coupled side product. The solid was taken into 10ml sat. NaHCO3 aq, sonicated, until the disapearance of the side product, filtered, washed with water, dried to yield (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (67.0 mg, 34.7 %) as a yellow solid.

Conditions: temp:110.01; pressure:0.00; stir:

Procedure: A mixture of CHLORO(2-DICYCLOHEXYLPHOSPHINO-2',6'-DI-I- PROPOXY-1,1'-BIPHENYL)[2-(2-AMINOETHYLPHENYL)]PALLADIUM(II), METHYL-T- BUTYLETHER ADDUCT (Ru Phos Pd cycle) (43.2 mgs, 0.1eq), sodium tert-butoxide (229 mg, 2.38 mmol), 2-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (250 mg, 0.53 mmol) , (S)-1,2-dimethylpiperazine (198 mg, 1.06 mmol) in dioxane (25ml) was stirred at 105°C for 1hr, LCMS only detected a small peak as product. 2 more equivalent of sodium tert-butoxide was added to the mixture and stirred for overnight under N2, LCMS indicated major peak as starting material; another batch of Ru phos pd cycle was added to the mixture, and the mixture was stirred at 120°C for 1.5hrs. LCMS indicated the completion of reaction. The solvent was removed by concentration, taken into 2ml of DMSO, filtered, the filtrate was purified with reverse phase chromatography column (eluted with 5% to 50% 0.1%TFA in ACN/0.1%TFA in water) and repurified with basic condition (eluted with 5% to 95% ACN/10MM ammonium acetate and 10MM ACN in water), still not pure enough for submission. Repurified again by analytical group, to yield (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (64.0 mg, 26.5 %) as a light yellow solid.

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

Procedure: The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (s, 3 H) 3.13-3.74 (m, 7 H) 7.63 (d, J=6.82 Hz, 1 H) 7.71-7.78 (m, 1 H) 7.90-8.67 (m, 4 H). ESI-MS m/z [M+H]+ 435.3.

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

Procedure: The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (s, 3H) 3.13-3.74 (m, 7H) 7.63 (d, J=6.82 Hz, 1H) 7.71-7.78 (m, 1H) 7.90-8.67 (m, 4H). ESI-MS m/z [M+H]+ 435.3.

Conditions: temp:115.01; pressure:0.00; stir:

Conditions: temp:110.01; pressure:0.00; stir: