4-bromo-1-chloro-2-(trifluoromethyl)benzene

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

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

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

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

Procedure: To a vial with 2 mL of anhydrous dimethylformamide under argon atmosphere were added 15.4 mg (0.0168 mmol, 0.05 equivalent) of tris(dibenzyllideneatone) dipalladium(0), 21.0 mg (0.033 mmol, 0.1 equivalent) of BINAP, 220.0 mg (0.675 mmol, 2.0 equivalent) of anhydrous cesium carbonate, 175.1 mg (0.675 mmol, 2.0 equivalent) of 5-bromo-2-chlorobenzotrifluoride, and 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1,2,4]triazin-7-yloxy)-pyridine-carboxylic acid methylamide, in that particular order. Argon gas was bubbled through the mixture for 5 min. Then the vial was capped and the reaction mixture was heated to 120° C. with stirring under argon atmosphere for 18 hours. At this point LC/MS indicated about 40% conversion to the product. As pointed out in the previous examples, the longer reaction times result in the formation of the by-product and partial decomposition. So, the reaction mixture was allowed to cool down to ambient temperature, filtered through 0.3 μm syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1% of TFA. Argon gas was bubbled through the mixture for 5 min Then the vial was capped the longer reaction times result in the formation of the by-product and partial decomposition to cool down to ambient temperature filtered through 0.3 μm syringe filter purified by reverse-phase

Conditions: temp:32.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (0.165 mol) in THF (30 ml) was added dropwise under N2 flow to a suspension of Mg (0.181 mol) and a crystal of I2 in THF (20 ml). The mixture was stirred at 30-35° C. for 2.5 hours and then cooled to 10° C. The mixture was added dropwise at 5° C. under N2 flow to a solution of N-(2-chloro-3-formylphenyl)acetamide (0.0788 mol) in THF (500 ml). The mixture was stirred at RT for 3 hours, poured out into ice and NH4Cl, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 98.5/1.5). The pure fractions were collected and the solvent was evaporated, yielding 22.2 g (74%) of (±)-N-[2-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]hydroxymethyl]phenyl]acetamide (interm. 25). cooled to 10° C The mixture was stirred at RT for 3 hours extracted with EtOAc The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 98.5/1.5) The pure fractions were collected the solvent was evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Six separate oven-dried sealed tubes were charged with 1-allyl-1H-indole-2,3-dione (0.100 g, 0.534 mmol), Pd(P(t-Bu)3)2 (0.0082 g, 0.016 mmol), 4-bromo-1-chloro-2-(trifluoro-methyl)benzene (0.139 g, 0.536 mmol), dry toluene (1 mL), and N-cyclohexyl-N-methyl-cyclohexanamine (0.12 mL, 0.57 mmol) under an atmosphere of N2. The tubes were heated for 16 h at 80° C. in an oil bath, and then the reactions were cooled and concentrated in vacuo. The crude material was used in the subsequent step. Six separate oven-dried sealed tubes the reactions were cooled concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Six separate oven-dried sealed tubes were charged with 1-allyl-1H-indole-2,3-dione (0.100 g, 0.534 mmol), Pd(P(t-Bu)3)2 (0.0082 g, 0.016 mmol), 4-bromo-1-chloro-2-(trifluoro-methyl)benzene (0.139 g, 0.536 mmol), dry toluene (1 mL), and N-cyclohexyl-N-methyl-cyclohexanamine (0.12 mL, 0.57 mmol) under an atmosphere of N2. The tubes were heated for 16 h at 80° C. in an oil bath, and then the reactions were cooled and concentrated in vacuo. The crude material was used in the subsequent step. Six separate oven-dried sealed tubes the reactions were cooled concentrated in vacuo

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

Procedure: A mixture of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (259 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane (15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue was purified by HPLC to give an intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl)phenyl)-5-methylpyrimidin-4-amine as brown solid (200 mg, 62%). A mixture of this intermediate (161 mg, 0.5 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (103 mg, 0.5 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as brown solid (75 mg, 31%). was heated under refluxed for 10 h under argon The solvent was removed the residue was purified by HPLC

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

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160° C. for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS (ES+): m/z 322 (M+H)+. was sealed in a microwave reaction tube irradiated with microwave at 160° C. for 15 min the cap was removed the resulting mixture filtered the filtered solid washed with DCM The filtrate was concentrated the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes)

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

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160° C. for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS (ES+): m/z 322 (M+H)+. was sealed in a microwave reaction tube irradiated with microwave at 160° C. for 15 min the cap was removed the resulting mixture filtered the filtered solid washed with DCM The filtrate was concentrated the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes)

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

Procedure: A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160° C. for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS (ES+): m/z 322 (M+H)+. was sealed in a microwave reaction tube irradiated with microwave at 160° C. for 15 min the cap was removed the resulting mixture filtered the filtered solid washed with DCM The filtrate was concentrated the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes)

Conditions: temp:32.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (0.165 mol) in THF (30 ml) was added dropwise under N2 flow to a suspension of Mg (0.181 mol) and a crystal of I2 in THF (20 ml). The mixture was stirred at 30-35° C. for 2.5 hours and then cooled to 10° C. The mixture was added dropwise at 5° C. under N2 flow to a solution of N-(2-chloro-3-formylphenyl)acetamide (0.0788 mol) in THF (500 ml). The mixture was stirred at RT for 3 hours, poured out into ice and NH4Cl, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 98.5/1.5). The pure fractions were collected and the solvent was evaporated, yielding 22.2 g (74%) of (±)-N-[2-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]hydroxymethyl]phenyl]acetamide (interm. 25). cooled to 10° C The mixture was stirred at RT for 3 hours extracted with EtOAc The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 98.5/1.5) The pure fractions were collected the solvent was evaporated