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AbstractIsodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional‐group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five‐membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology.