Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:6]
Reactant: C1CCNC1
Reactant: Cc1cccc(C(=O)O)c1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)N2CCCC2)c1Br
Temperature: 80 °C
Reaction time: 0.5 h

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).