dicyclohexyl-[2-(2,4,6-tripropylphenyl)phenyl]phosphane

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

Procedure: A mixture of tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1-carboxylate (0.06 g, 0.11 mmol), o-toluidine (0.061 ml, 0.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.005 g, 0.005 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (0.011 g, 0.02 mmol) and potassium carbonate (0.063 g, 0.46 mmol) in DMF (1.5 ml) was degassed and heated in the microwave at 150° C. for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water (×2). The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 10-90% EtOAc in hexane as gradient to afford tert-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.030 g, 0.06 mmol, 52%). LCMS (1) Rt: 2.63 min; m/z (ES+) 507. was degassed The reaction mixture was diluted with EtOAc washed with water (×2) dried over MgSO4 the solvent removed in vacuo The residue was purified by silica gel column chromatography

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4′-(4-bromo-5-chloropyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate generated in Step 2 (9 mg, 0.022 mmol), 2-(isopropylsulfonyl)aniline (4 mg, 0.022 mmol, 1 equiv), Pd2(dba)3 (1.7 mg, 0.002 mmol, 0.1 equiv.), 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (1.8 mg, 0.004 mmol, 0.2 equiv.), and Sodium tert-butoxide (2.7 mg, 0.028 mmol, 1.3 equiv.) are added to THF (1 mL). The resulting mixture is bubbled with N2 gas for 5 minutes and then heated at 150° C. for 4 hours. After cooling to room temperature, the reaction mixture is diluted into EtOAc and washed with H2O. The EtOAc layer is dried over Mg2SO4 and concentrated in vacuo. Silica gel chromatography (hexanes-EtOAc) affords Methyl 4′-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate (254); MS m/z 580.2 (M+1). The resulting mixture is bubbled with N2 gas for 5 minutes After cooling to room temperature the reaction mixture is diluted into EtOAc washed with H2O The EtOAc layer is dried over Mg2SO4 concentrated in vacuo

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4′-(4-bromo-5-chloropyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate generated in Step 2 (9 mg, 0.022 mmol), 2-(isopropylsulfonyl)aniline (4 mg, 0.022 mmol, 1 equiv), Pd2(dba)3 (1.7 mg, 0.002 mmol, 0.1 equiv.), 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (1.8 mg, 0.004 mmol, 0.2 equiv.), and Sodium tert-butoxide (2.7 mg, 0.028 mmol, 1.3 equiv.) are added to THF (1 mL). The resulting mixture is bubbled with N2 gas for 5 minutes and then heated at 150° C. for 4 hours. After cooling to room temperature, the reaction mixture is diluted into EtOAc and washed with H2O. The EtOAc layer is dried over Mg2SO4 and concentrated in vacuo. Silica gel chromatography (hexanes-EtOAc) affords Methyl 4′-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate (254); MS m/z 580.2 (M+1). The resulting mixture is bubbled with N2 gas for 5 minutes After cooling to room temperature the reaction mixture is diluted into EtOAc washed with H2O The EtOAc layer is dried over Mg2SO4 concentrated in vacuo

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

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-3-methylbenzonitrile (0.744 g, 3.79 mmol), N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.60 g, 1.265 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.121 g, 0.253 mmol), potassium phosphate, anhydrous (0.524 mL, 6.32 mmol), and Pd2(dba)3 (0.116 g, 0.126 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a yellow solid as (2-(2-(4-methoxybenzylamino)-3-(tetrahydro-2H-pyran-4-yl) quinolin-6-yl)-3-methylbenzonitrile. was purged with N2 followed by the addition of degassed dioxane (2 mL) degassed water (1.0 mL) was filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-3-methylbenzonitrile (0.744 g, 3.79 mmol), N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.60 g, 1.265 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.121 g, 0.253 mmol), potassium phosphate, anhydrous (0.524 mL, 6.32 mmol), and Pd2(dba)3 (0.116 g, 0.126 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a yellow solid as (2-(2-(4-methoxybenzylamino)-3-(tetrahydro-2H-pyran-4-yl) quinolin-6-yl)-3-methylbenzonitrile. was purged with N2 followed by the addition of degassed dioxane (2 mL) degassed water (1.0 mL) was filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2-bromo-3-methylphenyl)(pyrazin-2-yl)methanol (0.295 g, 1.056 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.25 g, 0.704 mmol, prepared as Example 2, Step 1-2), potassium phosphate tribasic (0.291 mL, 3.52 mmol), Pd2(dba)3 (0.064 g, 0.070 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.067 g, 0.141 mmol) in dioxane/water (3/1.5 mL) was heated in a microwave for 12 min at 140° C. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a brown oil which was re-purified by HPLC to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrazin-2-yl)methanol as a yellow solid. MS (ESI, pos. ion) m/z: 428 (M+1). The mixture was concentrated chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a brown oil which was re-purified by HPLC

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2-bromo-3-methylphenyl)(pyrazin-2-yl)methanol (0.295 g, 1.056 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.25 g, 0.704 mmol, prepared as Example 2, Step 1-2), potassium phosphate tribasic (0.291 mL, 3.52 mmol), Pd2(dba)3 (0.064 g, 0.070 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.067 g, 0.141 mmol) in dioxane/water (3/1.5 mL) was heated in a microwave for 12 min at 140° C. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a brown oil which was re-purified by HPLC to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrazin-2-yl)methanol as a yellow solid. MS (ESI, pos. ion) m/z: 428 (M+1). The mixture was concentrated chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a brown oil which was re-purified by HPLC