(2,4,6-trimethylphenyl) carbonochloridate

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

Procedure: 2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H). prepared above (33 mg, 0.17 mmol, 1.2 equiv) was then quenched with NaHCO3 (aq) The layers were separated the aqueous layer was extracted twice more with CH2Cl2 The combined organic extracts were concentrated the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4,6-trimethylphenol (272 mg, 2.00 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.33 mL, 0.3 M) under nitrogen (N2) and cooled to 0° C. Triphosgene (208 mg, 0.700 mmol, 0.35 equiv) was dissolved in CH2Cl2 (3.33 mL) and added dropwise, followed by pyridine (0.162 mL, 2.00 mmol, 1.0 equiv). The mixture was allowed to warm to 25° C. over 18 h, at which point the reaction was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) and extracted with EtOAc. The organic layer was washed with 1 N HCl (aq), dried over Na2SO4, and concentrated to give mesityl chloroformate as an oil (88% purity by 1H NMR spectroscopy). The chloroformate so prepared was used directly in the next step without further purification. added dropwise to warm to 25° C. over 18 h, at which was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) extracted with EtOAc The organic layer was washed with 1 N HCl (aq) dried over Na2SO4 concentrated

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

Procedure: 2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H). prepared above (33 mg, 0.17 mmol, 1.2 equiv) was then quenched with NaHCO3 (aq) The layers were separated the aqueous layer was extracted twice more with CH2Cl2 The combined organic extracts were concentrated the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient)

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

Procedure: 2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H). prepared above (33 mg, 0.17 mmol, 1.2 equiv) was then quenched with NaHCO3 (aq) The layers were separated the aqueous layer was extracted twice more with CH2Cl2 The combined organic extracts were concentrated the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4,6-trimethylphenol (272 mg, 2.00 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.33 mL, 0.3 M) under nitrogen (N2) and cooled to 0° C. Triphosgene (208 mg, 0.700 mmol, 0.35 equiv) was dissolved in CH2Cl2 (3.33 mL) and added dropwise, followed by pyridine (0.162 mL, 2.00 mmol, 1.0 equiv). The mixture was allowed to warm to 25° C. over 18 h, at which point the reaction was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) and extracted with EtOAc. The organic layer was washed with 1 N HCl (aq), dried over Na2SO4, and concentrated to give mesityl chloroformate as an oil (88% purity by 1H NMR spectroscopy). The chloroformate so prepared was used directly in the next step without further purification. added dropwise to warm to 25° C. over 18 h, at which was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) extracted with EtOAc The organic layer was washed with 1 N HCl (aq) dried over Na2SO4 concentrated

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

Procedure: A 16×100 mm vial was charged with 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.100 g, 0.24 mmol), 4-(dimethylamino)pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 mL), and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl carbonochloridate (0.048 g, 0.24 mmol) in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford mesityl 4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenylcarbamate 47 as a bright yellow solid. MS m/z found 580 [MH+]; calc. for C33H37N7O3=579.69. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane)

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

Procedure: 2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H). prepared above (33 mg, 0.17 mmol, 1.2 equiv) was then quenched with NaHCO3 (aq) The layers were separated the aqueous layer was extracted twice more with CH2Cl2 The combined organic extracts were concentrated the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient)

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

Procedure: 2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H). prepared above (33 mg, 0.17 mmol, 1.2 equiv) was then quenched with NaHCO3 (aq) The layers were separated the aqueous layer was extracted twice more with CH2Cl2 The combined organic extracts were concentrated the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4,6-trimethylphenol (272 mg, 2.00 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.33 mL, 0.3 M) under nitrogen (N2) and cooled to 0° C. Triphosgene (208 mg, 0.700 mmol, 0.35 equiv) was dissolved in CH2Cl2 (3.33 mL) and added dropwise, followed by pyridine (0.162 mL, 2.00 mmol, 1.0 equiv). The mixture was allowed to warm to 25° C. over 18 h, at which point the reaction was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) and extracted with EtOAc. The organic layer was washed with 1 N HCl (aq), dried over Na2SO4, and concentrated to give mesityl chloroformate as an oil (88% purity by 1H NMR spectroscopy). The chloroformate so prepared was used directly in the next step without further purification. added dropwise to warm to 25° C. over 18 h, at which was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) extracted with EtOAc The organic layer was washed with 1 N HCl (aq) dried over Na2SO4 concentrated

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

Procedure: A 16×100 mm vial was charged with 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.100 g, 0.24 mmol), 4-(dimethylamino)pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 mL), and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl carbonochloridate (0.048 g, 0.24 mmol) in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford mesityl 4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenylcarbamate 47 as a bright yellow solid. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane)

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

Procedure: A 16×100 mm vial was charged with 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.100 g, 0.24 mmol), 4-(dimethylamino)pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 mL), and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl carbonochloridate (0.048 g, 0.24 mmol) in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford mesityl 4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenylcarbamate 47 as a bright yellow solid. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.5 g of anhydrous aluminium chloride was added to 50 g of 2,4,6-trimethylphenyl chloroformate and the mixture was heated at 180° C. for 1.5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,4,6-Trimethylchlorobenzene was obtained in a yield of 72%. The reaction mixture was then cooled