It took half a century for the CAS database to clear a symbolic milestone of 100M compounds in 2015. Only four years later, this number stands at 156M, attesting to an impressive growth of productivity in a large part driven by drug design and discovery. Yet, the rate of FDA approvals of new molecular entities, excluding the biologics, has been anemic for a long time, oscillating between 10 and 30 annually. Such a small yield was explained, in part, by the lack of truly new and complex structures in the pipeline, which in turn, could be because a very limited number of synthetic reactions happen to dominate the chemical landscape of modern medicinal chemistry. This makes new methods development critically important for synthetic chemistry. Given the recent rise of synthetic photochemistry, which is becoming a broadly accepted tool in the toolbox of organic and medicinal chemistry, our overall goal is to discover new photoinduced reactions and develop them into robust and powerful synthetic methodologies. In this proposal, we will focus our effort on three unprecedented reactions offering rapid access to aromatic polyheterocyclic molecular architectures via (i) a new photoinduced cascade initiated by the excited state proton transfer (ESIPT) with post-photochemical decarboxylative aromatization of the primary photoproducts, (ii) a new photoinduced cascade involving a 6e- electrocyclization in aromatic imines followed by a photoinduced formation of a nitrene and subsequent electrocyclization or rearrangement, and finally (iii) a new hydrogen atom transfer (HAT)-initiated photoinduced cascade leading to complex fused pyrroloquinazolinones. In the context of diversity-oriented synthesis of complex aromatic polyheterocycles, this proposal outlines a clear path to new molecular architectures occupying an unexplored or underexplored areas of chemical space. The broad objective is to generate potential pharmacophores by systematically sampling the chemical space with diversified core structures augmented with a range of peripheral functionalities. Adding three new powerful photoinduced cascades to the arsenal of synthetic chemistry is innovative and impactful. With several indications of biological activity in the preliminary studies, this project will involve targeted biological screening of compounds synthesized in the course of this study. Also, as an AREA R15, this multifaceted project will provide ample training opportunities for undergraduate research students in the PI’s lab. The students will be involved with synthesis, learn photochemistry and photophysics, molecular modeling, spectra analysis and prediction, and gain initial understanding of medicinal chemistry and biological screening.