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A continuous-flow quaternization reaction of gramines with MeI (<1 min) followed by a substitution reaction with a chiral nucleophilic glycine-derived Ni-complex ( S )-2 (<1 min) has successfully been developed to afford the corresponding alkylated Ni-complexes 3 in good yields with excellent diastereoselectivity, based on the results of a one-pot quaternization-substitution reaction of gramines with ( S )-2 in a batch process. The continuous-flow process allowed the safe and efficient scale-up synthesis of 3j (84% yield, 99% de, 540 g h -1 ) to give 7-azatryptophan derivative ( S )-4j readily by an acid-catalyzed hydrolysis reaction followed by protection with an Fmoc group. The present method for the rapid and efficient syntheses of enantiopure unnatural tryptophan derivatives from various gramines and ( S )-2 will be useful to further promote peptide and protein drug discovery and development research.