C(CN[C:5]([C@@H:7]1[CH2:11][C@@H:10](S(C2C=CC=CC=2)(=O)=O)[CH2:9][C@H:8]1[C:21](N1CCOCC1)=[O:22])=[O:6])#N.Cl.CN(C)CCCN=C=NCC.[OH:41][C:42]1[C:50]2N=NNC=2C=CC=1.C(N(C(C)C)C(C)C)C.Cl.[F:61][C:62]1([F:66])[CH2:65][NH:64][CH2:63]1.CN(C)C=[O:70]>>[CH2:42]([O:41][C:21]([C@@H:8]1[CH2:9][C:10](=[O:70])[CH2:11][C@H:7]1[C:5]([N:64]1[CH2:65][C:62]([F:66])([F:61])[CH2:63]1)=[O:6])=[O:22])[CH3:50]To a mixture of (1R,2R,4R)-4-Benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid cyanomethyl-amide (3 g, 15 mmol, example 1, step 1) in dimethylformamide (40 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.86 g, 30 mmol), hydroxybenzotriazole (3.1 g mg, 22 mmol) and ethyldiisopropylamine (15.4 mL, 90 mmol). After 45 mM, 3,3-difluoroazetidine hydrochloride (1.94 g, 15 mmol) was added and the reaction mixture was stirred for 24 h then partitioned between ethyl acetate and an aqueous saturated solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (2:1 then 1:1 v/v) as eluant to afford the title compound (2.35 g, 57%) as yellow solid. MS (EI): 276.2 (M+H)+.
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