(2-bromo-3-methylphenyl)-pyrrolidin-1-ylmethanone

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

Procedure: A microwave vessel was charged with (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.081 g, 0.301 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol), potassium phosphate (0.106 g, 0.502 mmol), 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid (0.073 g, 0.251 mmol), dioxane (1.6 mL) and water (0.8 mL). The vessel was purged with argon, sealed and heated by microwave radiation at 140° C. for 15 min. The mixture was concentrated, diluted with EtOAc (10 mL) and the suspension was filtered through celite rinsing with EtOAc. The filtrate was washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The material was purified by column chromatography on silica gel (33 mL) which had been deactivated with Et3N (3.3 mL) eluting with 1.5% MeOH/EtOAc to afford (2-(2-amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 435 (M+1). The vessel was purged with argon sealed The mixture was concentrated diluted with EtOAc (10 mL) the suspension was filtered through celite rinsing with EtOAc The filtrate was washed with saturated brine (5 mL) dried over sodium sulfate concentrated The material was purified by column chromatography on silica gel (33 mL) which eluting with 1.5% MeOH/EtOAc

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

Procedure: A microwave vessel was charged with (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.081 g, 0.301 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol), potassium phosphate (0.106 g, 0.502 mmol), 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid (0.073 g, 0.251 mmol), dioxane (1.6 mL) and water (0.8 mL). The vessel was purged with argon, sealed and heated by microwave radiation at 140° C. for 15 min. The mixture was concentrated, diluted with EtOAc (10 mL) and the suspension was filtered through celite rinsing with EtOAc. The filtrate was washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The material was purified by column chromatography on silica gel (33 mL) which had been deactivated with Et3N (3.3 mL) eluting with 1.5% MeOH/EtOAc to afford (2-(2-amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 435 (M+1). The vessel was purged with argon sealed The mixture was concentrated diluted with EtOAc (10 mL) the suspension was filtered through celite rinsing with EtOAc The filtrate was washed with saturated brine (5 mL) dried over sodium sulfate concentrated The material was purified by column chromatography on silica gel (33 mL) which eluting with 1.5% MeOH/EtOAc

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

Procedure: A mixture of (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.256 g, 0.953 mmol), 3-(2-ethylmorpholino)-N-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.16 g, 0.318 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.030 g, 0.064 mmol), potassium phosphate, anhydrous (0.132 mL, 1.589 mmol), and Pd2(dba)3 (0.029 g, 0.032 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 0-5% MeOH/DCM to afford a light yellow oil. To this product was added TFA (15 mL, 195 mmol) and heated at 70° C. for 18 h until the starting material was consumed. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a light yellow solid as (2-(2-amino-3-(2-ethylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 445 (M+1). 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 0-5% MeOH/DCM to afford a light yellow oil heated at 70° C. for 18 h until the starting material was consumed The mixture was concentrated chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM

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

Procedure: A mixture of (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.115 g, 0.429 mmol), (R)—N-(4-methoxybenzyl)-3-(3-methylmorpholino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.07 g, 0.143 mmol), potassium phosphate, anhydrous (0.121 g, 0.572 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.014 g, 0.029 mmol), and Pd2(dba)3 (0.013 g, 0.014 mmol) was purged with N2 followed by the addition of degassed dioxane (1 mL) and degassed water (0.5 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 0-5% MeOH/DCM to afford a yellow oil. To the product was added TFA (10 mL, 130 mmol) and the solution was heated at 60° C. for 18 h until the starting material was consumed. The mixture was concentrated and chromatographed on silica gel using 0-5% 2 M NH3 in MeOH/DCM to afford a yellow solid as (R)-(2-(2-amino-3-(3-methylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 431 (M+1). was purged with N2 followed by the addition of degassed dioxane (1 mL) degassed water (0.5 mL) was filtered concentrated chromatographed on silica gel using 0-5% MeOH/DCM to afford a yellow oil the solution was heated at 60° C. for 18 h until the starting material was consumed The mixture was concentrated chromatographed on silica gel using 0-5% 2 M NH3 in MeOH/DCM

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

Procedure: A mixture of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (47.8 mg, 0.10 mmol), (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (323 mg, 1.2 mmol), N-(4-methoxybenzyl)-3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (477 mg, 1.0 mmol), Pd2(dba)3 (45.9 mg, 0.050 mmol), K3PO4 (0.25 mL, 3.0 mmol), and 1,4-dioxane (7 mL)/water (3.50 mL) was heated in a microwave at 140° C. for 12 min. The reaction mixture was filtered then concentrated in vacuo. The crude product was purified by silica flash chromatography (0-10% MeOH/DCM) to give (2-(2-(4-methoxybenzylamino)-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as an orange oil. The reaction mixture was filtered then concentrated in vacuo The crude product was purified by silica flash chromatography (0-10% MeOH/DCM)

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

Procedure: 2-Bromo-3-methylbenzoic acid (5.0 g, 23.3 mmol) was dissolved in THF (100 mL) and added N,N′-carbonyldiimidazole (4.52 g, 27.9 mmol). The reaction mixture was stirred at ambient temperature for 14 h. Pyrrolidine (6.8 mL, 81 mmol) was added in one portion. The mixture was stirred for 8 h and then partitioned between EtOAc and water. The organic layer was washed with water, diluted HCl, saturated bicarbonate, water and brine. The solution was then concentrated in vacuo to afford (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a white crystalline solid, upon standing overnight at RT. The mixture was stirred for 8 h partitioned between EtOAc and water The organic layer was washed with water, diluted HCl, saturated bicarbonate, water and brine The solution was then concentrated in vacuo

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

Procedure: 2-Bromo-3-methylbenzoic acid (5.0 g, 23.3 mmol) was dissolved in THF (100 mL) and added N,N′-carbonyldiimidazole (4.52 g, 27.9 mmol). The reaction mixture was stirred at ambient temperature for 14 h. Pyrrolidine (6.8 mL, 81 mmol) was added in one portion. The mixture was stirred for 8 h and then partitioned between EtOAc and water. The organic layer was washed with water, diluted HCl, saturated bicarbonate, water and brine. The solution was then concentrated in vacuo to afford (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a white crystalline solid, upon standing overnight at RT. The mixture was stirred for 8 h partitioned between EtOAc and water The organic layer was washed with water, diluted HCl, saturated bicarbonate, water and brine The solution was then concentrated in vacuo

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-3-methylbenzoic acid (1.03 g, 4.79 mmol) was dissolved in thionyl chloride (15 mL, 206 mmol) and stirred at 80° C. for 30 min. The solution was evaporated to dryness under reduced pressure and the white solid residue dried under high vacuum. It was dissolved in DCM and added to a solution of pyrrolidine (0.80 mL, 9.58 mmol) and DIEA (1.67 mL, 9.58 mmol) in DCM (50 mL) and the reaction stirred overnight. Water (100 mL) and DCM (100 mL) were added and the phases mixed and separated. The organic was washed with 1N HCl (50 mL) then 1N sodium hydroxide (60 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a clear oil that solidified into a waxy solid on standing. Step 2: A mixture of (E)-ethyl 3-(6-bromo-2-(tert-butylamino)quinolin-3-yl)-2-methylacrylate (2.2 g, 5.62 mmol), potassium acetate (1.05 mL, 16.87 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.23 g, 0.28 mmol) and bis(pinacolato)diboron (1.71 g, 6.75 mmol) in degassed dioxane 40 mL was heated at 85° C. overnight. The mixture was cooled to RT and filtered through a pad of celite. The filtrate was collected and concentrated. The crude material was purified by column chromatography with 20-45% EtOAc/hexane to give (E)-ethyl 3-(2-(tert-butylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-2-methylacrylate. Step 3: (2-Bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.39 g, 1.44 mmol), 2-dicyclohexylphosphino-2′,4′,6%-triisopropylbiphenyl (0.057 g, 0.120 mmol), (E)-ethyl 3-(2-(tert-butylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-2-methylacrylate (0.53 g, 1.20 mmol), palladium diacetate (0.013 g, 0.060 mmol), and potassium acetate (0.35 g, 3.61 mmol) were suspended in a mixture of ethanol (2 mL) and water (0.5 mL) and heated to 145° C. for 30 min in the microwave. The crude was partitioned between ethyl acetate (60 mL) and water (50 mL) and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired (E)-ethyl 3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylate. This material was dissolved in methanol (50 g, 12.02 mmol) in water (15 mL). The mixture was heated to reflux for 45 min after which 2N HCl (6 mL) was added and the solution concentrated under reduced pressure to ˜25 mL. Water (100 mL) and DCM (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness to give (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylic acid which was used without purification. Step 4: (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylic acid (0.082 g, 0.17 mmol) was dissolved in N-methylpyrrolidinone (0.75 mL) and treated with methylamine (33% wt. solution in absolute ethyl alcohol, 0.050 mL, 0.48 mmol) and Knorr's reagent (0.081 g, 0.25 mmol). The mixture was stirred for 5 min then water (25 mL) and DCM (10 mL) were added and the phases mixed and separated. The organic was dried and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in DCM gradient) gave (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-N, 2-dimethylacrylamide. This material was dissolved in methanol (30 mL) and DCM (10 mL) and palladium on carbon (10% by wt, 0.019 g, 0.017 mmol) was added. The slurry was stirred under hydrogen for 40 min after which the reaction was filtered through a pad of celite and evaporated to dryness under reduced pressure. The crude was dissolved in trifluoroacetic acid (40 mL) and heated to gentle reflux for 80 min. The solution was then evaporated to dryness under reduced pressure, free based with DCM and saturated sodium bicarbonate, and purified using silica chromatography (0-10% methanol in DCM gradient) to give 3-(2-amino-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-N,2-dimethylpropanamide. MS (ESI, pos. ion) m/z: 431 (M+1). The crude was partitioned between ethyl acetate (60 mL) and water (50 mL) the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure Purification

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-3-methylbenzoic acid (1.03 g, 4.79 mmol) was dissolved in thionyl chloride (15 mL, 206 mmol) and stirred at 80° C. for 30 min. The solution was evaporated to dryness under reduced pressure and the white solid residue dried under high vacuum. It was dissolved in DCM and added to a solution of pyrrolidine (0.80 mL, 9.58 mmol) and DIEA (1.67 mL, 9.58 mmol) in DCM (50 mL) and the reaction stirred overnight. Water (100 mL) and DCM (100 mL) were added and the phases mixed and separated. The organic was washed with 1N HCl (50 mL) then 1N sodium hydroxide (60 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a clear oil that solidified into a waxy solid on standing. Step 2: A mixture of (E)-ethyl 3-(6-bromo-2-(tert-butylamino)quinolin-3-yl)-2-methylacrylate (2.2 g, 5.62 mmol), potassium acetate (1.05 mL, 16.87 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.23 g, 0.28 mmol) and bis(pinacolato)diboron (1.71 g, 6.75 mmol) in degassed dioxane 40 mL was heated at 85° C. overnight. The mixture was cooled to RT and filtered through a pad of celite. The filtrate was collected and concentrated. The crude material was purified by column chromatography with 20-45% EtOAc/hexane to give (E)-ethyl 3-(2-(tert-butylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-2-methylacrylate. Step 3: (2-Bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.39 g, 1.44 mmol), 2-dicyclohexylphosphino-2′,4′,6%-triisopropylbiphenyl (0.057 g, 0.120 mmol), (E)-ethyl 3-(2-(tert-butylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-2-methylacrylate (0.53 g, 1.20 mmol), palladium diacetate (0.013 g, 0.060 mmol), and potassium acetate (0.35 g, 3.61 mmol) were suspended in a mixture of ethanol (2 mL) and water (0.5 mL) and heated to 145° C. for 30 min in the microwave. The crude was partitioned between ethyl acetate (60 mL) and water (50 mL) and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired (E)-ethyl 3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylate. This material was dissolved in methanol (50 g, 12.02 mmol) in water (15 mL). The mixture was heated to reflux for 45 min after which 2N HCl (6 mL) was added and the solution concentrated under reduced pressure to ˜25 mL. Water (100 mL) and DCM (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness to give (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylic acid which was used without purification. Step 4: (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylic acid (0.082 g, 0.17 mmol) was dissolved in N-methylpyrrolidinone (0.75 mL) and treated with methylamine (33% wt. solution in absolute ethyl alcohol, 0.050 mL, 0.48 mmol) and Knorr's reagent (0.081 g, 0.25 mmol). The mixture was stirred for 5 min then water (25 mL) and DCM (10 mL) were added and the phases mixed and separated. The organic was dried and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in DCM gradient) gave (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-N, 2-dimethylacrylamide. This material was dissolved in methanol (30 mL) and DCM (10 mL) and palladium on carbon (10% by wt, 0.019 g, 0.017 mmol) was added. The slurry was stirred under hydrogen for 40 min after which the reaction was filtered through a pad of celite and evaporated to dryness under reduced pressure. The crude was dissolved in trifluoroacetic acid (40 mL) and heated to gentle reflux for 80 min. The solution was then evaporated to dryness under reduced pressure, free based with DCM and saturated sodium bicarbonate, and purified using silica chromatography (0-10% methanol in DCM gradient) to give 3-(2-amino-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-N,2-dimethylpropanamide. MS (ESI, pos. ion) m/z: 431 (M+1). The crude was partitioned between ethyl acetate (60 mL) and water (50 mL) the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure Purification

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

Procedure: 2-Bromo-3-methylbenzoic acid (1.03 g, 4.79 mmol) was dissolved in thionyl chloride (15 mL, 206 mmol) and stirred at 80° C. for 30 min. The solution was evaporated to dryness under reduced pressure and the white solid residue dried under high vacuum. It was dissolved in DCM and added to a solution of pyrrolidine (0.80 mL, 9.58 mmol) and DIEA (1.67 mL, 9.58 mmol) in DCM (50 mL) and the reaction stirred overnight. Water (100 mL) and DCM (100 mL) were added and the phases mixed and separated. The organic was washed with 1N HCl (50 mL) then 1N sodium hydroxide (60 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a clear oil that solidified into a waxy solid on standing. Step 2: A mixture of (E)-ethyl 3-(6-bromo-2-(tert-butylamino)quinolin-3-yl)-2-methylacrylate (2.2 g, 5.62 mmol), potassium acetate (1.05 mL, 16.87 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.23 g, 0.28 mmol) and bis(pinacolato)diboron (1.71 g, 6.75 mmol) in degassed dioxane 40 mL was heated at 85° C. overnight. The mixture was cooled to RT and filtered through a pad of celite. The filtrate was collected and concentrated. The crude material was purified by column chromatography with 20-45% EtOAc/hexane to give (E)-ethyl 3-(2-(tert-butylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-2-methylacrylate. Step 3: (2-Bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.39 g, 1.44 mmol), 2-dicyclohexylphosphino-2′,4′,6%-triisopropylbiphenyl (0.057 g, 0.120 mmol), (E)-ethyl 3-(2-(tert-butylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-2-methylacrylate (0.53 g, 1.20 mmol), palladium diacetate (0.013 g, 0.060 mmol), and potassium acetate (0.35 g, 3.61 mmol) were suspended in a mixture of ethanol (2 mL) and water (0.5 mL) and heated to 145° C. for 30 min in the microwave. The crude was partitioned between ethyl acetate (60 mL) and water (50 mL) and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired (E)-ethyl 3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylate. This material was dissolved in methanol (50 g, 12.02 mmol) in water (15 mL). The mixture was heated to reflux for 45 min after which 2N HCl (6 mL) was added and the solution concentrated under reduced pressure to ˜25 mL. Water (100 mL) and DCM (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness to give (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylic acid which was used without purification. Step 4: (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-2-methylacrylic acid (0.082 g, 0.17 mmol) was dissolved in N-methylpyrrolidinone (0.75 mL) and treated with methylamine (33% wt. solution in absolute ethyl alcohol, 0.050 mL, 0.48 mmol) and Knorr's reagent (0.081 g, 0.25 mmol). The mixture was stirred for 5 min then water (25 mL) and DCM (10 mL) were added and the phases mixed and separated. The organic was dried and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in DCM gradient) gave (E)-3-(2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-N, 2-dimethylacrylamide. This material was dissolved in methanol (30 mL) and DCM (10 mL) and palladium on carbon (10% by wt, 0.019 g, 0.017 mmol) was added. The slurry was stirred under hydrogen for 40 min after which the reaction was filtered through a pad of celite and evaporated to dryness under reduced pressure. The crude was dissolved in trifluoroacetic acid (40 mL) and heated to gentle reflux for 80 min. The solution was then evaporated to dryness under reduced pressure, free based with DCM and saturated sodium bicarbonate, and purified using silica chromatography (0-10% methanol in DCM gradient) to give 3-(2-amino-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinolin-3-yl)-N,2-dimethylpropanamide. MS (ESI, pos. ion) m/z: 431 (M+1). The solution was evaporated to dryness under reduced pressure the white solid residue dried under high vacuum It was dissolved in DCM the reaction stirred overnight the phases mixed separated The organic was washed with 1N HCl (50 mL) 1N sodium hydroxide (60 mL) before drying with magnesium sulfate evaporating to dryness under reduced pressure Purification

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

Procedure: A microwave vessel was charged with (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.081 g, 0.301 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol), potassium phosphate (0.106 g, 0.502 mmol), 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid (0.073 g, 0.251 mmol), dioxane (1.6 mL) and water (0.8 mL). The vessel was purged with argon, sealed and heated by microwave radiation at 140° C. for 15 min. The mixture was concentrated, diluted with EtOAc (10 mL) and the suspension was filtered through celite rinsing with EtOAc. The filtrate was washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The material was purified by column chromatography on silica gel (33 mL) which had been deactivated with Et3N (3.3 mL) eluting with 1.5% MeOH/EtOAc to afford (2-(2-amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 435 (M+1). The vessel was purged with argon sealed The mixture was concentrated diluted with EtOAc (10 mL) the suspension was filtered through celite rinsing with EtOAc The filtrate was washed with saturated brine (5 mL) dried over sodium sulfate concentrated The material was purified by column chromatography on silica gel (33 mL) which eluting with 1.5% MeOH/EtOAc

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

Procedure: A mixture of (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.256 g, 0.953 mmol), 3-(2-ethylmorpholino)-N-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.16 g, 0.318 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.030 g, 0.064 mmol), potassium phosphate, anhydrous (0.132 mL, 1.589 mmol), and Pd2(dba)3 (0.029 g, 0.032 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 0-5% MeOH/DCM to afford a light yellow oil. To this product was added TFA (15 mL, 195 mmol) and heated at 70° C. for 18 h until the starting material was consumed. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a light yellow solid as (2-(2-amino-3-(2-ethylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 445 (M+1). 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 0-5% MeOH/DCM to afford a light yellow oil heated at 70° C. for 18 h until the starting material was consumed The mixture was concentrated chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM