Cl.[NH2:2][C@H:3]([CH:12]([CH3:14])[CH3:13])[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:15][C:16]1[CH:21]=[C:20]([NH:2][C@H:3]([CH:12]([CH3:14])[CH3:13])[C:4]([NH:6][CH2:7][C:8]([F:9])([F:10])[F:11])=[O:5])[CH:19]=[N:18][CH:17]=1In a round bottomed flask equipped with a magnetic stirrer, (R)-2-amino-3-methyl-N-(2,2,2-trifluoroethyl)butanamide hydrochloride (1-3b) (20 g, 85 mmol), 3,5-Dibromopyridine (30.3 g, 128 mmol), Potassium carbonate (35.3 g, 256 mmol) were suspended in DMSO (71 ml, 1.2M) and reaction mixture was purged with nitrogen for 20 minutes, then Copper(I) Iodide (0.974 g, 5.1 mmol) was added and the reaction mixture was slowly heated to 120° C. overnight. The cooled reaction mixture was then partitioned between Isopropanol (IPA):Chloroform (1:3) and Water, the aqueous layer was extracted with three times with IPA:Chloroform mixture. The combined organic layers were extracted with 1M solution of EDTA disodium salt, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude sample. Purification on a silica gel column using a gradient 0-40% ethyl acetate:hexane gave an orange solid which was taken up in ethyl acetate and concentrated to an oil, hexane was added dropwise while stirring, a white solid crystallized which was filtered, washed with hexane and dried under vacuum to give 14 g, (46.4%) the title compound, I-3, as a white solid.
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