[4-fluoro-2-(trifluoromethyl)phenyl]boronic acid

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

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

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

Procedure: A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) of the title compound as an amorphous foam. mp 70° FDMS: m/e=391. α[D]589 =+55.81 (c=0.60, chloroform). fitted with a reflux condenser the stirred mixture was heated at 80°, under nitrogen, for 24 h The mixture was cooled washed with brine (2×25 mL) The combined organic extracts were dried over sodium sulfate concentrated purified by silica gel chromatography (ethyl acetate eluent)

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

Procedure: A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) of the title compound as an amorphous foam. mp 70° FDMS: m/e=391. α[D]589 =+55.81 (c=0.60, chloroform). fitted with a reflux condenser the stirred mixture was heated at 80°, under nitrogen, for 24 h The mixture was cooled washed with brine (2×25 mL) The combined organic extracts were dried over sodium sulfate concentrated purified by silica gel chromatography (ethyl acetate eluent)

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

Procedure: A vessel capable of sealing was charged with a mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine (123 mg, 0.495 mmol), 4-fluoro-2-(trifluoromethyl) phenylboronic acid (123 mg, 0.594 mmol), PdCl2(dppf)-CH2Cl2 adduct (20.21 mg, 0.0.025 mmol), dioxane (6 mL), and a 2.0 M aqueous solution of K3PO4 (0.74 mL, 1.485 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3 hours. Upon cooling, the reaction mixture was diluted with CH2Cl2 and filtered with CH2Cl2/MeOH washing. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 40%-60% CH2Cl2/hexanes at 30 mL/min. Concentration of appropriate fractions provided the title compound (150 mg, 91% yield) as a white solid. LC/MS: Example 101A @ 3.94 min (RT) (Condition G). MS (ES): m/z=331.94, [M+H]+. The vessel was sealed Upon cooling filtered with CH2Cl2/MeOH washing The filtrate was concentrated under reduced pressure The residue was dissolved in CH2Cl2 washed with water, brine dried over anhydrous Na2SO4 concentrated under reduced pressure The crude material was purified by BIOTAGE® eluting with 40%-60% CH2Cl2/hexanes at 30 mL/min

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

Procedure: A vessel capable of sealing was charged with a mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine (123 mg, 0.495 mmol), 4-fluoro-2-(trifluoromethyl) phenylboronic acid (123 mg, 0.594 mmol), PdCl2(dppf)-CH2Cl2 adduct (20.21 mg, 0.0.025 mmol), dioxane (6 mL), and a 2.0 M aqueous solution of K3PO4 (0.74 mL, 1.485 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3 hours. Upon cooling, the reaction mixture was diluted with CH2Cl2 and filtered with CH2Cl2/MeOH washing. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 40%-60% CH2Cl2/hexanes at 30 mL/min. Concentration of appropriate fractions provided the title compound (150 mg, 91% yield) as a white solid. LC/MS: Example 101A @ 3.94 min (RT) (Condition G). MS (ES): m/z=331.94, [M+H]+. The vessel was sealed Upon cooling filtered with CH2Cl2/MeOH washing The filtrate was concentrated under reduced pressure The residue was dissolved in CH2Cl2 washed with water, brine dried over anhydrous Na2SO4 concentrated under reduced pressure The crude material was purified by BIOTAGE® eluting with 40%-60% CH2Cl2/hexanes at 30 mL/min

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (0.27 g, 1.2 mmol), [4-fluoro-2-(trifluoromethyl)phenyl]boronic acid (0.61 g, 2.9 mmol), Na2CO3 (0.6 g, 5.7 mmol) and palladium tetrakis(triphenylphosphine) (96 mg, 0.083 mmol) in toluene/water (10:1, 10 ml) was stirred at 110° C. for 1.5 h under N2. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (3:1 to 1:3 hexane:ethyl acetate) to give the title compound (0.23 mg, 62%) as a pale yellow solid. The reaction mixture was cooled to room temperature The mixture was washed with water and brine dried over sodium sulfate concentrated on a rotary evaporator The resulting residue was purified by silica-gel column chromatography (3:1 to 1:3 hexane:ethyl acetate)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (0.27 g, 1.2 mmol), [4-fluoro-2-(trifluoromethyl)phenyl]boronic acid (0.61 g, 2.9 mmol), Na2CO3 (0.6 g, 5.7 mmol) and palladium tetrakis(triphenylphosphine) (96 mg, 0.083 mmol) in toluene/water (10:1, 10 ml) was stirred at 110° C. for 1.5 h under N2. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (3:1 to 1:3 hexane:ethyl acetate) to give the title compound (0.23 mg, 62%) as a pale yellow solid. The reaction mixture was cooled to room temperature The mixture was washed with water and brine dried over sodium sulfate concentrated on a rotary evaporator The resulting residue was purified by silica-gel column chromatography (3:1 to 1:3 hexane:ethyl acetate)

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

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

Procedure: A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) of the title compound as an amorphous foam. mp 70°. FDMS: m/e=391. α[D]589 =+55.81 (c=0.60, chloroform). fitted with a reflux condenser the stirred mixture was heated at 80°, under nitrogen, for 24 h The mixture was cooled washed with brine (2×25 mL) The combined organic extracts were dried over sodium sulfate concentrated purified by silica gel chromatography (ethyl acetate eluent)

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

Procedure: A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) of the title compound as an amorphous foam. mp 70°. FDMS: m/e=391. α[D]589 =+55.81 (c=0.60, chloroform). fitted with a reflux condenser the stirred mixture was heated at 80°, under nitrogen, for 24 h The mixture was cooled washed with brine (2×25 mL) The combined organic extracts were dried over sodium sulfate concentrated purified by silica gel chromatography (ethyl acetate eluent)

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

Procedure: Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-fluoro-2-(trifluoromethyl)benzeneboronic acid (available from Frontier Scientific, Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-fluoro-2′-trifluoromethyl-biphenyl-2-carboxylic acid (4 mg, 3%). 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.26 (d, J=6.6 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H). the acid was purified