Achieving a molecular level understanding of chemical reactions on the surface of solid-state nanomaterials is important but challenging. For example, two-dimensional (2D) layered transitionmetal chalcogenides (TMCs) can display unique reactivities due to their unusual anisotropic nature where the edges consisting of unsaturated metals and chalcogens may promote atomic rearrangement and catalysis, but the basal plane is believed to be rather inert and its surface chemistry is poorly explored. Herein, we show a molecular approach for selective activation of the basal plane on 2D layered TMCs using Lewis acids to initiate electrophilic addition selectively onto sulfide moieties, followed by transmetalation, which results in nanopores. This approach is generally operative not only in various compositions of TMCs, but also in crystal geometry such as 1T and 2H. Nanoporous NbS₂ materials obtained by this method was found to have an enhanced electrochemical energy storage capacity of 302 mF/cm², the highest reported to date for 2D nanostructure-based electrodes with longterm durability.