1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

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

Procedure: To a solution of 4-(chloro(hydroxyimino)methyl)-2-methylbenzoic acid (5.1 g, 23.8 mmol) in DMF (30 mL) at 0° C. was added 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (7.4 g, 28.6 mmol) followed by Et3N (4.8 g, 47.6 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water (30 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (1:1) to EA: MeOH (10:1) to give 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (6 g; yield 58% over 3 steps) as a white solid. MS: m/z=435.8 (M+1, ESI+). extracted with ethyl acetate (60 mL×3) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography over silica gel eluted with PE

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

Procedure: To a solution of 4-(chloro(hydroxyimino)methyl)-2-methylbenzoic acid (5.1 g, 23.8 mmol) in DMF (30 mL) at 0° C. was added 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (7.4 g, 28.6 mmol) followed by Et3N (4.8 g, 47.6 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water (30 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (1:1) to EA: MeOH (10:1) to give 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (6 g; yield 58% over 3 steps) as a white solid. MS: m/z=435.8 (M+1, ESI+). extracted with ethyl acetate (60 mL×3) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography over silica gel eluted with PE

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

Procedure: In a solution of 2.00 g of 3,5-dichloro-4-fluoro-iodobenzene and 0.61 g of tert-butylmethyl ether in 18 mL of hexane, 5.3 mL of n-butyl lithium (1.54M hexane solution) was added dropwise at −10° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 0.57 g of trimethoxyborane in 7 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 30 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 1.80 g of 2-bromo-3,3,3-trifluoropropene, 1.90 g of potassium carbonate, 10 mL of water and 0.005 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 15 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of ethyl acetate twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.20 g of the aimed product as yellow oily substance. stirred at the same temperature for 30 minutes After the completion of the addition dropwise it was stirred at the same temperature further for 30 minutes stirred under nitrogen atmosphere at 60° C. for 15 hours After the completion of the reaction the reaction mixture was left cooled to room temperature insoluble material was filtered off the organic phase was collected the aqueous phase was extracted with 30 mL of ethyl acetate twice The combined organic phases were washed with water dried over saturated sodium chloride aqueous solution anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

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

Procedure: In a solution of 2.00 g of 3,5-dichloro-4-fluoro-iodobenzene and 0.61 g of tert-butylmethyl ether in 18 mL of hexane, 5.3 mL of n-butyl lithium (1.54M hexane solution) was added dropwise at −10° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 0.57 g of trimethoxyborane in 7 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 30 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 1.80 g of 2-bromo-3,3,3-trifluoropropene, 1.90 g of potassium carbonate, 10 mL of water and 0.005 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 15 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of ethyl acetate twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.20 g of the aimed product as yellow oily substance. stirred at the same temperature for 30 minutes After the completion of the addition dropwise it was stirred at the same temperature further for 30 minutes stirred under nitrogen atmosphere at 60° C. for 15 hours After the completion of the reaction the reaction mixture was left cooled to room temperature insoluble material was filtered off the organic phase was collected the aqueous phase was extracted with 30 mL of ethyl acetate twice The combined organic phases were washed with water dried over saturated sodium chloride aqueous solution anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

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

Procedure: In a solution of 2.00 g of 3,5-dichloro-4-fluoro-iodobenzene and 0.61 g of tert-butylmethyl ether in 18 mL of hexane, 5.3 mL of n-butyl lithium (1.54M hexane solution) was added dropwise at −10° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 0.57 g of trimethoxyborane in 7 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 30 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 1.80 g of 2-bromo-3,3,3-trifluoropropene, 1.90 g of potassium carbonate, 10 mL of water and 0.005 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 15 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of ethyl acetate twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.20 g of the aimed product as yellow oily substance. stirred at the same temperature for 30 minutes After the completion of the addition dropwise it was stirred at the same temperature further for 30 minutes stirred under nitrogen atmosphere at 60° C. for 15 hours After the completion of the reaction the reaction mixture was left cooled to room temperature insoluble material was filtered off the organic phase was collected the aqueous phase was extracted with 30 mL of ethyl acetate twice The combined organic phases were washed with water dried over saturated sodium chloride aqueous solution anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

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

Procedure: In a solution of 2.00 g of 3,5-dichloro-4-fluoro-iodobenzene and 0.61 g of tert-butylmethyl ether in 18 mL of hexane, 5.3 mL of n-butyl lithium (1.54M hexane solution) was added dropwise at −10° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 0.57 g of trimethoxyborane in 7 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 30 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 1.80 g of 2-bromo-3,3,3-trifluoropropene, 1.90 g of potassium carbonate, 10 mL of water and 0.005 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 15 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of ethyl acetate twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.20 g of the aimed product as yellow oily substance. stirred at the same temperature for 30 minutes After the completion of the addition dropwise it was stirred at the same temperature further for 30 minutes stirred under nitrogen atmosphere at 60° C. for 15 hours After the completion of the reaction the reaction mixture was left cooled to room temperature insoluble material was filtered off the organic phase was collected the aqueous phase was extracted with 30 mL of ethyl acetate twice The combined organic phases were washed with water dried over saturated sodium chloride aqueous solution anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

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

Procedure: To a solution of the crude compound N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (383 mg, 1.60 mmol) and 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (455 mg, 1.76 mmol) in DMF (12 mL) at rt was added TEA (445 μL, 3.20 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (180 mg; yield 24% over the 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.236 (s, 1 H), 7.803 (d, J=6.5 Hz, 2 H), 7.757-7.770 (m, 2H), 7.693-7.710 (m, 1H), 4.414 (d, J=18.0 Hz, 1 H), 4.316 (d, J=18.0 Hz, 1 H), 1.481 (s, 6 H) ppm; HPLC purity: 99.13% at 220 nm and 99.15% at 254 nm; MS: m/z=461.9 (M+1, ESI+). extracted with EA The organic layer was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by prep-TLC eluted with PE-EA (3:2) purified by combiflash

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.56 g, 8.83 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.85 g, 10.6 mmol), Cs2CO3 (11.5 mL, 2M, 17.7 mmol) and Pd(PPh3)2Cl2 (200 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.3 g; yield 56%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.412 (d, J=6.5 Hz, 2 H), 6.057 (s, 1 H), 5.806 (s, 1 H) ppm. The mixture was cooled to rt partitioned between ether and H2O The aqueous layer was extracted with EA the combined organic layers were dried over Na2SO4 The solvent was removed under reduced pressure the crude product was purified by column chromatography on silica gel eluted with hexanes

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.56 g, 8.83 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.85 g, 10.6 mmol), Cs2CO3 (11.5 mL, 2M, 17.7 mmol) and Pd(PPh3)2Cl2 (200 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.3 g; yield 56%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.412 (d, J=6.5 Hz, 2 H), 6.057 (s, 1 H), 5.806 (s, 1 H) ppm. The mixture was cooled to rt partitioned between ether and H2O The aqueous layer was extracted with EA the combined organic layers were dried over Na2SO4 The solvent was removed under reduced pressure the crude product was purified by column chromatography on silica gel eluted with hexanes

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

Procedure: Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dichloromethane (10 mL), (E)-N-[(4-bromo-3-methylphenyl)methylidene]hydroxylamine (50 mg, 0.23 mmol, 1.00 equiv), 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (60 mg, 0.23 mmol, 1.00 equiv), chlorosylsodium (5 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3×10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 82 mg (75%) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a white solid. Into a 50-mL round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting mixture was washed with 3×10 mL of brine The organic phase was dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 82 mg (75%) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a white solid

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

Procedure: Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dichloromethane (10 mL), (E)-N-[(4-bromo-3-methylphenyl)methylidene]hydroxylamine (50 mg, 0.23 mmol, 1.00 equiv), 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (60 mg, 0.23 mmol, 1.00 equiv), chlorosylsodium (5 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3×10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 82 mg (75%) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a white solid. Into a 50-mL round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting mixture was washed with 3×10 mL of brine The organic phase was dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 82 mg (75%) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a white solid

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 6′-((hydroxyimino)methyl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-carboxylate (0.15 g, 0.49 mmol, 1 eq) in DMF (5.0 mL) was added NCS (84 mg, 0.63 mmol, 1.2 eq) at room temperature in dark under nitrogen atmosphere. Resulting reaction mixture was stirred at 45° C. for 1 hour. After chloro intermediate formation, 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (0.163 g, 0.63 mmol, 1.2 eq.) was added followed by addition of KHCO3 (79 mg, 0.79 mmol, 1.5 eq). Resulting reaction mixture was stirred at room temperature for 16 hours in dark under nitrogen atmosphere. After complete consumption of chloro intermediate, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.2 g, crude). Crude compound was purified by column chromatography in 100-200 mesh size silica gel. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as off white solid (0.14 g, 51%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.88 (d, J=18.4 Hz, 1H), 4.12-4.16 (m, 2H), 4.25 (d, J=18.16 Hz, 1H), 4.35 (dd, J1=3.3 Hz, J2=9.34 Hz, 2H), 5.12 (s, 2H), 7.57 (d, J=6 Hz, 2H), 7.90 (s, 1H), 8.70 (s, 1H). LC-MS (m/z): 562.1 (M+H). Resulting reaction mixture Resulting reaction mixture was stirred at room temperature for 16 hours in dark under nitrogen atmosphere After complete consumption of chloro intermediate, reaction mixture was quenched with water (20 mL) extracted with ethyl acetate (3×20 mL) Combined organic layer was dried over anhydrous Na2SO4 concentrated under reduced pressure to get brown thick oil (0.2 g, crude) Crude compound was purified by column chromatography in 100-200 mesh size silica gel Desired compound was eluted in 25% ethyl acetate in hexane