(2-chloro-5-fluorophenyl)boronic acid

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

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

Procedure: 5-(2-Chloro-5-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 2chloro-5-fluorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 450.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.52 (dd, J=3.0 Hz, 8.0 Hz, 2H); 7.25-7.42 (m, 3H); 7.10 (dt, J=2.5 Hz, 1H); 6.47 (d. J=2.0 Hz, 1H); 5.91 (d, J=2.5 Hz, 1H); 3.70 (s, 3H), 2.62-2.89 (m 4H).

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

Procedure: In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2-chloro-5-fluorophenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′-chloro-5′-fluoro-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 472.9 ([M+H]+)

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

Procedure: In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2-chloro-5-fluorophenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′-chloro-5′-fluoro-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 472.9 ([M+H]+)

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-5-fluorophenyl)boronic acid gave 281. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.12 (dd, J=6.4, 2.7 Hz, 1H), 7.79 (s, 1H), 7.55-7.39 (m, 4H), 5.07 (dd, J=7.0, 4.5 Hz, 1H), 3.99-3.84 (m, 2H), 3.72 (s, 3H), 3.52-3.43 (m, 1H), 3.33-3.24 (m, 1H), 3.15 (s, 3H), 2.33-2.22 (m, 1H), 1.82-1.52 (m, 4H). LCMS (ES+) m/z 495 (M+1).

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-5-fluorophenyl)boronic acid gave 281. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.12 (dd, J=6.4, 2.7 Hz, 1H), 7.79 (s, 1H), 7.55-7.39 (m, 4H), 5.07 (dd, J=7.0, 4.5 Hz, 1H), 3.99-3.84 (m, 2H), 3.72 (s, 3H), 3.52-3.43 (m, 1H), 3.33-3.24 (m, 1H), 3.15 (s, 3H), 2.33-2.22 (m, 1H), 1.82-1.52 (m, 4H). LCMS (ES+) m/z 495 (M+1).

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

Procedure: In the same manner as in Reference Example 19 and using (1S)-1-[5-(3-bromo-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]ethyl acetate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2-chloro-5-fluorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 66%) was obtained as colorless crystals.

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

Procedure: 5-(2-Chloro-5-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 2chloro-5-fluorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 450.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.52 (dd, J=3.0 Hz, 8.0 Hz, 2H); 7.25-7.42 (m, 3H); 7.10 (dt, J=2.5 Hz, 1H); 6.47 (d. J=2.0 Hz, 1H); 5.91 (d, J=2.5 Hz, 1H); 3.70 (s, 3H), 2.62-2.89 (m 4H).

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

Procedure: 5-(2-Chloro-5-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 2chloro-5-fluorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 450.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.52 (dd, J=3.0 Hz, 8.0 Hz, 2H); 7.25-7.42 (m, 3H); 7.10 (dt, J=2.5 Hz, 1H); 6.47 (d. J=2.0 Hz, 1H); 5.91 (d, J=2.5 Hz, 1H); 3.70 (s, 3H), 2.62-2.89 (m 4H).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 1.0000 g, 4.693 mmol), 2-chloro-5-fluorophenylboronic acid (0.9002 g, 5.163 mmol), tetrakis(triphenylphosphine)palladium (0.2712 g, 0.2347 mmol), and sodium carbonate anhydrous (2.487 g, 23.47 mmol) in acetonitrile-water (3:1) (47.00 mL) was stirred at 100° C. After 3 hs, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline as a red syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1H, dd, J=8.4, 1.4 Hz), 8.03 (1H, dd, J=7.6, 1.4 Hz), 7.88 (1H, dd, J=8.4, 7.6 Hz), 7.75 (1H, dd, J=9.0, 5.1 Hz), 7.61 (1H, dd, J=8.6, 3.1 Hz), 7.46-7.53 (1H, m), 2.54 (3H, s); LC-MS (ESI) m/z 307.0 [M+H]+. After 3 hs, the mixture was cooled to room temperature partitioned between EtOAc (100 mL) and water (100 mL) The organic layer was washed with brine (50 mL×2) dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column over 25 min

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

Procedure: A mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.10 g, 3.3 mmol), 2-chloro-5-fluorophenyl boronic acid (0.58 g, 3.3 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol), and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(2-chloro-5 fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (15) as a clear oil (0.57 g, 55%): 1H NMR (300 MHz, DMSO-d6) δ 7.53-7.46 (m, 1H), 7.23-7.14 (m, 2H), 5.79-5.74 (m, 1H), 4.00-3.92 (m, 2H), 3.52 (t, J=5.7 Hz, 2H), 2.40-2.32 (m, 2H), 1.43 (s, 9H). The mixture cooled to ambient temperature the resulting solids were removed by filtration through a Celite pad The filtrate was washed brine solution (4×50 mL) concentrated under reduced pressure The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes)

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

Procedure: 7-chloro-6-cyano-4-oxo-5-pyridin-4-yl-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 3a (537 mg, 1.35 mmol), prepared using the procedure of Example 1, was combined with 2-chloro-5-fluorophenyl-boronic acid (468 mg, 2.69 mmol), Pd(Ph3P)4 (156 mg, 0.135 mmol), sat'd NaHCO3 (15 mL) and 1,4-dioxane (40 mL). The reaction mixture was refluxed for 2 hrs then diluted with sat'd NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated. The solid was recrystallized from EtOAc to give 7-(2-chloro-5-fluoro-phenyl)-6-cyano-4-oxo-5-pyridin-4-yl-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 15 (440 mg) as a pale yellow solid. LC/MS 494, 496 (MH+). The reaction mixture was refluxed for 2 hrs extracted with EtOAc The organic layer was dried (MgSO4) evaporated The solid was recrystallized from EtOAc