Dicyclohexyl(2'-methyl-[1,1'-biphenyl]-2-yl)phosphine

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:0.00; pressure:0.00; stir:

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

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

Procedure: See Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370. In an oven-dried 1 L flask was Sodium tert-butoxide (13.19 g, 137 mmol), PALLADIUM(II) ACETATE (0.948 g, 4.22 mmol), and 2-(Dicyclohexylphosphino)-2′-methylbiphenyl (1.539 g, 4.22 mmol) weighed in a nitrogen bag. (R)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (35.21 g, 106 mmol), Toluene (106 mL) (degassed in the original bottle by nitrogen gas), and 1-bromo-2,3-difluorobenzene (14.18 mL, 127 mmol) were added under nitrogen. The flask stirred at 80° C. in a pre-heated oil bath for 20 h. Volatiles were stripped off and the residue was partitioned between EtOAc (400 ml) and water (400 ml). The layers were separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic layer was washed with brine, dried and concentrated to a dark oil. It was passed through a plug of silica gel (loaded with CH2Cl2 and eluted with EtOAc/hexane up to 30% EtOAc). The crude product was obtained as a dark red oil (86% mass recovery). 1H NMR showed approximately 6/1 ratio of the desired trans isomer to the cis isomer. MS (ESI)[M+H+]=446.21. In an oven-dried 1 L flask was were added under nitrogen the residue was partitioned between EtOAc (400 ml) and water (400 ml) The layers were separated The aqueous layer was extracted with EtOAc (50 ml) The combined organic layer was washed with brine dried concentrated to a dark oil eluted with EtOAc/hexane up to 30% EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(6-bromo-2-pyridyl)-1-trityl-pyrazolo[5,4-b]pyridine (100 mg, 0.1933 mmol) and (2S)-2-phenylpiperazine (54.56 mg, 0.2320 mmol) in DME (2.500 mL) was treated with sodium t-butoxide (27.87 mg, 0.2900 mmol) followed by dicyclohexyl-[2-(o-tolyl)phenyl]phosphane (7.046 mg, 0.01933 mmol) and Palladium acetate (4.340 mg, 0.01933 mmol). The mixture was allowed to stir at 95 degrees in a sealed tube overnight. The mixture was allowed to cool, filtered through celite and concentrated to give a yellow oil. This was taken up in DCM (6 ml) and cooled to 0° C. Triethylsilane (0.12 mL) and TFA (1 mL) were added and the reaction stirred at 0° C. for 1 hour. The solvent was removed in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (20 mg, 29% Yield). to cool filtered through celite and concentrated to give a yellow oil the reaction stirred at 0° C. for 1 hour The solvent was removed in vacuo the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were collected freeze-dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(6-bromo-2-pyridyl)-1-trityl-pyrazolo[5,4-b]pyridine (100 mg, 0.1933 mmol) and (2S)-2-phenylpiperazine (54.56 mg, 0.2320 mmol) in DME (2.500 mL) was treated with sodium t-butoxide (27.87 mg, 0.2900 mmol) followed by dicyclohexyl-[2-(o-tolyl)phenyl]phosphane (7.046 mg, 0.01933 mmol) and Palladium acetate (4.340 mg, 0.01933 mmol). The mixture was allowed to stir at 95 degrees in a sealed tube overnight. The mixture was allowed to cool, filtered through celite and concentrated to give a yellow oil. This was taken up in DCM (6 ml) and cooled to 0° C. Triethylsilane (0.12 mL) and TFA (1 mL) were added and the reaction stirred at 0° C. for 1 hour. The solvent was removed in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (20 mg, 29% Yield). to cool filtered through celite and concentrated to give a yellow oil the reaction stirred at 0° C. for 1 hour The solvent was removed in vacuo the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were collected freeze-dried

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

Procedure: Anhydrous, de-gassed THF (20 mL) was added to 2-(dicyclohexylphosphino)-2′-methylbiphenyl (1.2 g, 3.2 mmol) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g, 1.4 mmol), and the resulting solution was warmed to 45° C. and sparged with N2. After 20 min, the reaction mixture was allowed to cool to RT, then added to a stirring, degassed mixture of 5-bromo-2-fluoropyridine (4.8 g, 27 mmol), finely ground potassium phosphate tribasic (14 g, 68 mmol), and acetone (100 mL, 1400 mmol) at RT, and the resulting mixture was sparged with N2. After 20 min, the reaction mixture was heated at reflux for 24 h, the reaction mixture was allowed to cool to room temperature, filtered through a 0.45 μm Teflon filter, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (gradient elution; 4:1→2:1 hexane-ethyl acetate) to give 2.3 g (55%) of 1-(6-fluoropyridin-3-yl)propan-2-one as a brown oil. Anhydrous, de-gassed THF (20 mL) sparged with N2 to cool to RT added to a stirring degassed the resulting mixture was sparged with N2 After 20 min the reaction mixture was heated at reflux for 24 h to cool to room temperature filtered through a 0.45 μm Teflon filter the filtrate was concentrated The residue was purified by flash chromatography on silica gel (gradient elution; 4:1→2:1 hexane-ethyl acetate)

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

Procedure: Anhydrous, de-gassed THF (20 mL) was added to 2-(dicyclohexylphosphino)-2′-methylbiphenyl (1.2 g, 3.2 mmol) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g, 1.4 mmol), and the resulting solution was warmed to 45° C. and sparged with N2. After 20 min, the reaction mixture was allowed to cool to RT, then added to a stirring, degassed mixture of 5-bromo-2-fluoropyridine (4.8 g, 27 mmol), finely ground potassium phosphate tribasic (14 g, 68 mmol), and acetone (100 mL, 1400 mmol) at RT, and the resulting mixture was sparged with N2. After 20 min, the reaction mixture was heated at reflux for 24 h, the reaction mixture was allowed to cool to room temperature, filtered through a 0.45 μm Teflon filter, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (gradient elution; 4:1→2:1 hexane-ethyl acetate) to give 2.3 g (55%) of 1-(6-fluoropyridin-3-yl)propan-2-one as a brown oil. Anhydrous, de-gassed THF (20 mL) sparged with N2 to cool to RT added to a stirring degassed the resulting mixture was sparged with N2 After 20 min the reaction mixture was heated at reflux for 24 h to cool to room temperature filtered through a 0.45 μm Teflon filter the filtrate was concentrated The residue was purified by flash chromatography on silica gel (gradient elution; 4:1→2:1 hexane-ethyl acetate)

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

Procedure: A mixture of N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (0.100 g, 0.32 mmol), triethylamine (0.17 ml, 1.25 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.95 ml of 1.0 M in THF solution, 0.95 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.023 g, 0.065 mmol) and palladium acetate (0.0036 g, 0.016 mmol) in 2.0 mL of dioxane in a sealed glass tube was heated in a microwave at 100° C. for 20 min. After cooling to RT, the reaction mixture was transferred to a 50 mL round-bottom flask and treated with 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (0.089 g, 0.26 mmol) and sodium carbonate (1.0 mL of 2.0 M aqueous solution). Tetakis(triphenylphosphine)palladium (0) (9 mg) was added, and the reaction mixture was heated at 110° C. in an oil bath for 5 h. It was cooled to RT, treated with 5 mL of 1 N NaOH and 60 mL of EtOAc. The organic phase was separated, washed with brine, separated from the aqueous layer, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2(EtOAc/hexane=80/20) to give the title compound as a yellow crystalline solid. MS (ESI, pos.ion) m/z: 448.1 (M+1). After cooling to RT the reaction mixture was transferred to a 50 mL round-bottom flask the reaction mixture was heated at 110° C. in an oil bath for 5 h It was cooled to RT The organic phase was separated washed with brine separated from the aqueous layer dried over magnesium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography on SiO2(EtOAc/hexane=80/20)

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

Procedure: A mixture of {2-[(6-chloroquinolin-2-yl)sulfonyl]phenyl}methanol (Step 2, 157 mg, 0.47 mmol), 2,4-difluorobenzeneboronic acid (173 mg, 1.09 mmol), palladium acetate (6 mg, 0.023 mmol), 2-dicyclohexylphosphino-2′-methylbiphenyl (18 mg, 0.05 mmol) and potassium phosphate (313 mg, 1.47 mmol) was degassed. Toluene (2 mL) was added and the mixture degassed again then heated to 90° C. under nitrogen for 1 hour. The cooled reaction mixture was poured into 1M sodium hydroxide solution and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5-10% ethyl acetate/isohexane, followed by recrystallisation from ethyl acetate/isohexane to give the title compound (33 mg, 17%). 1H NMR (500 MHz, CDCl3) δ 8.46 (1H, d, J=8.5 Hz), 8.27 (1H, d, J=8.5 Hz), 8.20 (1H, d, J=7.9 Hz), 8.16 (1H, d, J=8.9 Hz), 8.02 (1H, s), 7.94 (1H, d, J=8.8 Hz), 7.65-7.59 (2H, m), 7.53-7.47 (2H, m), 7.04-6.96 (2H, m), 5.12 (2H, d, J=7.0 Hz), 4.18 (1H, t, J=7.1 Hz); m/z (ES+) 412 [MH+]. was degassed Toluene (2 mL) was added the mixture degassed again The cooled reaction mixture extracted with ethyl acetate (x2) The combined organic layers were washed with brine dried over MgSO4 evaporated The residue was purified by flash column chromatography on silica eluting with 5-10% ethyl acetate/isohexane followed by recrystallisation from ethyl acetate/isohexane