5-AMINO-2-METHYLPHENYLBORONIC ACID, PINACOL ESTER

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

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

Procedure: The title compound was prepared according to a procedure similar to that described in Example 225, using 6-chloro-1-(1,1,1-trifluoropropan-2-yloxy)phthalazine and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine as starting materials. MS (ESI, pos. ion) m/z: 348.1 (M+1). The racemic material was subjected to Preparative SFC separation using a chiral column to afford its (R)- and (S)-enantiomers. The racemic material was subjected to Preparative SFC separation

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

Procedure: 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.14 mmol) was treated with methanesulfonyl chloride (162 μl, 2.10 mmol) according to the method described in Preparation 15b to give 550 mg (83% yield) of the title compound. Purity 98%.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromo-1-methyl-3-morpholinopyridin-2(1H)-one (1.0 equiv.) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.2 equiv.) in DME and 2M sodium carbonate (3:1, 0.14 M) was added PdCl2(dppf)-DCM adduct (0.1 equiv.) in a microwave vial equipped with a stir bar. The reaction was heated to 120° C. for 15 min in the microwave. The solution was partitioned between water and ethyl acetate, the organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 100% ethyl acetate followed by 10% methanol in ethyl acetate. The pure fractions were concentrated and dried under vacuo to afford 5-(5-amino-2-methylphenyl)-1-methyl-3-morpholinopyridin-2(1H)-one in 31% yield. LCMS (m/z) (M+H)=300.2, Rt=0.41 min. vial equipped with a stir bar The solution was partitioned between water and ethyl acetate the organic phase was dried with sodium sulfate filtered concentrated The crude material was purified via silica gel column chromatography eluting with 100% ethyl acetate The pure fractions were concentrated dried under vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4,4′-(6-chloropyrimidine-2,4-diyl)dimorpholine (1.0 equiv.) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.5 equiv.) in DME and 2M sodium carbonate (3:1, 0.2 M) was added PdCl2(dppf)-DCM adduct (0.100 equiv.) in a microwave vial equipped with a stir bar. The reaction was heated to 120° C. for 20 min in the microwave. The reaction mixture qas quenched with water and the aqueous layer was separated and extracted with EtOAc (×3). The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified via silica gel column chromatography eluting with 100% DCM to 10% MeOH/DCM to afford 3-(2,6-dimorpholinopyrimidin-4-yl)-4-methylaniline in 96% yield. LCMS (m/z) (M+H)=356.2, Rt=0.44 min. vial equipped with a stir bar The reaction mixture qas quenched with water the aqueous layer was separated extracted with EtOAc (×3) The combined organic layer was dried over magnesium sulfate filtered concentrated in vacuo The material was purified via silica gel column chromatography eluting with 100% DCM to 10% MeOH/DCM

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

Procedure: To a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.) and 3-(trifluoromethyl)benzoic acid (1.1 equiv.) in DMF (0.27 M) was added HOAt (1.3 equiv.) and EDC (1.3 equiv.) After 3 h the reaction mixture was diluted with water and then extracted with EtOAc. The organic phase was washed sequentially with 1 M aqueous sodium hydroxide and brine and was then dried over sodium sulfate. The solution was concentrated and dried under vacuo to give N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide in 91% yield. LCMS (m/z) (M+H)=407.1, Rt=1.13 min. extracted with EtOAc The organic phase was washed sequentially with 1 M aqueous sodium hydroxide and brine was then dried over sodium sulfate The solution was concentrated dried under vacuo

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

Procedure: EDC (1.3 equiv.) was added to a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.), 2-(2-cyanopropan-2-yl)isonicotinic acid (1.2 equiv.), HOAt (1.3 equiv.) in DMF (0.19 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated to yield 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide in 97% yield. LCMS (m/z) (M+H)=406.2, Rt=1.10 min. extracted with ethyl acetate The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine dried over sodium sulfate filtered concentrated

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

Procedure: To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.) in THF (0.1 M) at 0° C. was added 3-trifluoromethylbenzoylchloride (1.0 equiv.) and the reaction was stirred at room temperature for 3 h. The solution was concentrated and dried under vacuo to give N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide as a tan solid in 96% yield. LCMS (m/z) (M+H)=406.2, Rt=1.24 min. The solution was concentrated dried under vacuo

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

Procedure: A solution of 5-amino-2-methylphenylboronic acid pinacol ester (1.001 g, 4.294 mmol), 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (1.112 g, 4.746 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.446 g, 4.691 mmol) in DMF (20 mL) at ambient temperature was added ethyldiisopropylamine (0.98 mL, 5.6 mmol), the mixture stirred at room temperature for 3 d and poured into water (100 ml). The aqueous phase was washed with diethyl ether, treated with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane, and then 0-20% methanol in DCM modified with 1% ammonia) to afford the title compound as a white solid (456 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=8.2, 2.0 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.3 Hz, 1H), 3.57 (s, 2H), 2.52 (s, 3H), 2.5 (br s, 8H), 2.31 (s, 3H), 1.35 (s, 12H). LCMS: M+H+=450.4. The aqueous phase was washed with diethyl ether treated with saturated aqueous sodium bicarbonate extracted twice with ethyl acetate The combined ethyl acetate extracts were washed with brine dried over sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane

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

Procedure: A solution of 5-amino-2-methylphenylboronic acid pinacol ester (1.001 g, 4.294 mmol), 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (1.112 g, 4.746 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.446 g, 4.691 mmol) in DMF (20 mL) at ambient temperature was added ethyldiisopropylamine (0.98 mL, 5.6 mmol), the mixture stirred at room temperature for 3 d and poured into water (100 ml). The aqueous phase was washed with diethyl ether, treated with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane, and then 0-20% methanol in DCM modified with 1% ammonia) to afford the title compound as a white solid (456 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=8.2, 2.0 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.3 Hz, 1H), 3.57 (s, 2H), 2.52 (s, 3H), 2.5 (br s, 8H), 2.31 (s, 3H), 1.35 (s, 12H). LCMS: M+H+=450.4. The aqueous phase was washed with diethyl ether treated with saturated aqueous sodium bicarbonate extracted twice with ethyl acetate The combined ethyl acetate extracts were washed with brine dried over sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (1.053 g, 3.617 mmol), 5-amino-2-methylphenylboronic acid pinacol ester (1.2607 g, 5.4081 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.1311 g, 0.1852 mmol), and potassium carbonate (1.385 g, 10.02 mmol) was added 1,4-dioxane (20 mL, 200 mmol) and water (2 mL, 100 mmol). The reaction mixture was then heated at 90° C. for 2 hours and then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted twice with dichloromethane. The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 1.3653 g (119%) of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): M+H=318.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (dd, J=8.5, 1.5 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.60-6.49 (m, 2H), 4.93 (s, 2H), 2.14-2.02 (m, 4H), 0.85 (dd, J=12.4, 6.1 Hz, 4H). cooled to room temperature extracted twice with dichloromethane The combined organics were dried over MgSO4 filtered evaporated in vacuo The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (1.053 g, 3.617 mmol), 5-amino-2-methylphenylboronic acid pinacol ester (1.2607 g, 5.4081 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.1311 g, 0.1852 mmol), and potassium carbonate (1.385 g, 10.02 mmol) was added 1,4-dioxane (20 mL, 200 mmol) and water (2 mL, 100 mmol). The reaction mixture was then heated at 90° C. for 2 hours and then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted twice with dichloromethane. The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 1.3653 g (119%) of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): M+H=318.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (dd, J=8.5, 1.5 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.60-6.49 (m, 2H), 4.93 (s, 2H), 2.14-2.02 (m, 4H), 0.85 (dd, J=12.4, 6.1 Hz, 4H). cooled to room temperature extracted twice with dichloromethane The combined organics were dried over MgSO4 filtered evaporated in vacuo The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane)