2-chloro-4-fluoro-1-iodobenzene

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:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round-bottom flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and a N2 inlet was charged with 5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50.0 g, 197 mmol; Intermediate 3), bis(pinacolato)diboron (50.4 g, 199 mmol), and anhydrous 2-methyltetrahydrofuran (393 mL) followed by Pt(PPh3)4 (1.83 g, 1.5 mmol). This mixture was degassed with three vacuum/N2 cycles, heated at 83° C. (internal temperature; oil bath at 95° C.) for 5 h under N2, and then allowed to cool to room temperature. 2-Methyltetrahydrofuran (393 mL), cesium carbonate (128.1 g, 393 mmol), and water (11.8 mL, 1.5% v/v) were added, and the reaction was cooled to 4° C. 4-Iodobenzaldehyde (45.6 g, 197 mmol) and PdCl2(PPh3)2 (6.90 g, 9.8 mmol) were added, and the reaction was degassed with three vacuum/N2 cycles. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous KOH solution (4M, 275 mL, 1100 mmol) and 2-chloro-4-fluoroiodobenzene (70.6 g, 275 mmol) were added. The reaction was degassed with three vacuum/N2 cycles, heated at 75° C. (internal temperature; oil bath at 90° C.) for 7 h under N2, and then allowed to cool to room temperature. The layers were separated, and the organic layer was washed with brine (800 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give the title compound (82.6 g, 7:1 mixture of regioisomers) as a pale yellow foam. Data for major isomer; (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde: 1H NMR (300 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m, 2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H), 3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44-2.36 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H); LCMS: 405 [(M-THP+H)+H]+. A round-bottom flask equipped with a magnetic stir bar, a reflux condenser This mixture was degassed with three vacuum/N2 cycles to cool to room temperature the reaction was cooled to 4° C the reaction was degassed with three vacuum/N2 cycles to warm to room temperature The reaction was degassed with three vacuum/N2 cycles heated at 75° C. (internal temperature; oil bath at 90° C.) for 7 h under N2 to cool to room temperature The layers were separated the organic layer was washed with brine (800 mL) dried over sodium sulfate filtered concentrated The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round-bottom flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and a N2 inlet was charged with 5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50.0 g, 197 mmol; Intermediate 3), bis(pinacolato)diboron (50.4 g, 199 mmol), and anhydrous 2-methyltetrahydrofuran (393 mL) followed by Pt(PPh3)4 (1.83 g, 1.5 mmol). This mixture was degassed with three vacuum/N2 cycles, heated at 83° C. (internal temperature; oil bath at 95° C.) for 5 h under N2, and then allowed to cool to room temperature. 2-Methyltetrahydrofuran (393 mL), cesium carbonate (128.1 g, 393 mmol), and water (11.8 mL, 1.5% v/v) were added, and the reaction was cooled to 4° C. 4-Iodobenzaldehyde (45.6 g, 197 mmol) and PdCl2(PPh3)2 (6.90 g, 9.8 mmol) were added, and the reaction was degassed with three vacuum/N2 cycles. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous KOH solution (4M, 275 mL, 1100 mmol) and 2-chloro-4-fluoroiodobenzene (70.6 g, 275 mmol) were added. The reaction was degassed with three vacuum/N2 cycles, heated at 75° C. (internal temperature; oil bath at 90° C.) for 7 h under N2, and then allowed to cool to room temperature. The layers were separated, and the organic layer was washed with brine (800 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give the title compound (82.6 g, 7:1 mixture of regioisomers) as a pale yellow foam. Data for major isomer; (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde: 1H NMR (300 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m, 2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H), 3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44-2.36 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H); LCMS: 405 [(M-THP+H)+H]+. A round-bottom flask equipped with a magnetic stir bar, a reflux condenser This mixture was degassed with three vacuum/N2 cycles to cool to room temperature the reaction was cooled to 4° C the reaction was degassed with three vacuum/N2 cycles to warm to room temperature The reaction was degassed with three vacuum/N2 cycles heated at 75° C. (internal temperature; oil bath at 90° C.) for 7 h under N2 to cool to room temperature The layers were separated the organic layer was washed with brine (800 mL) dried over sodium sulfate filtered concentrated The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-4-fluoro-1-iodobenzene (0.307 g, 1.199 mmol) in THF (Volume: 1.622 ml) cooled to −10° C. was added isopropylmagnesium chloride, 2M in THF (0.699 ml, 1.399 mmol) in one portion. After 30 min, 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.200 g, 0.999 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min, then allowed to warm to room temperature and stirred overnight. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 1 hr, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueous phase was extracted with CH2Cl2 (5×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 60-100% EtOAc in hexanes over 23 min, tr=9 min) gave the title compound (0.029 g, 0.074 mmol, 7.44% yield) as an orange solid. to warm to room temperature stirred overnight After stirring for 1 hr The layers were separated The aqueous phase was extracted with CH2Cl2 (5×) dried over Na2SO4 filtered concentrated to afford an orange residue to be chromatographed Purification of the crude material by silica gel chromatography an ISCO machine (24 g column, 35 mL/min, 60-100% EtOAc in hexanes over 23 min, tr=9 min)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-4-fluoro-1-iodobenzene (0.307 g, 1.199 mmol) in THF (Volume: 1.622 ml) cooled to −10° C. was added isopropylmagnesium chloride, 2M in THF (0.699 ml, 1.399 mmol) in one portion. After 30 min, 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.200 g, 0.999 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min, then allowed to warm to room temperature and stirred overnight. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 1 hr, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueous phase was extracted with CH2Cl2 (5×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 60-100% EtOAc in hexanes over 23 min, tr=9 min) gave the title compound (0.029 g, 0.074 mmol, 7.44% yield) as an orange solid. to warm to room temperature stirred overnight After stirring for 1 hr The layers were separated The aqueous phase was extracted with CH2Cl2 (5×) dried over Na2SO4 filtered concentrated to afford an orange residue to be chromatographed Purification of the crude material by silica gel chromatography an ISCO machine (24 g column, 35 mL/min, 60-100% EtOAc in hexanes over 23 min, tr=9 min)

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

Procedure: n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 2-chloro-4-fluoro-1-iodobenzene (19.6 mmol, 5.0 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-chloro-4-fluorophenyl)boronic acid as a white precipitate. The white precipitate (1.10 g, 33%) was filtered and dried. 1H NMR (CDCl3, 300 MHz): 7.96 (1H, t, J 8.1 Hz), 7.11 (1H, dd, J 8.8 and 2.5 Hz), 7.04 (1H, td, J 8.4 and 2.5 Hz), 5.28 (2H, s.) was added over twenty minutes extracted into EtOAc The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which

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

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

Procedure: n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 2-chloro-4-fluoro-1-iodobenzene (19.6 mmol, 5.0 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-chloro-4-fluorophenyl)boronic acid as a white precipitate. The white precipitate (1.10 g, 33%) was filtered and dried. 1H NMR (CDCl3, 300 MHz): 7.96 (1H, t, J 8.1 Hz), 7.11 (1H, dd, J 8.8 and 2.5 Hz), 7.04 (1H, td, J 8.4 and 2.5 Hz), 5.28 (2H, s.) was added over twenty minutes extracted into EtOAc The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which

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

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-4-fluoro-1-iodo-benzene (3.6 g, 14.3 mmol) and 3-trifluoromethyl-1H-pyrazole (1.9 g, 14.4 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (2.4 g, 17.2 mmol), and the resulting mixture was heated at 135° C. for 12 h. The reaction mixture was cooled to room temperature, poured in cold water (80 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexanes to afford the title compound (4.2 g) as a white solid. The reaction mixture was cooled to room temperature extracted with dichloromethane (2×40 mL) The combined organic extracts were dried (Na2SO4) concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexanes