The facile introduction of varied substituents about an aromatic or heteroaromatic core during structure-activity relationship studies is a recurring problem encountered in the development of medicinal agents that are based on small organic molecules. Within this context, new and general strategies for the regiospecific construction of aromatic, heteroaromatic, and related molecules of medicinal interest (quinones, pyrones) are important to the overall mission of the NIH. In this renewal proposal, a variety of new synthetic methods for the construction of substituted quinones, aromatics, benzannulated heteroaromatics, pyrones, cycloheptadienones, and cyclooctadienones are described. The majority of the methods center on transition metal and thermally mediated transformations of cyclobutenones bearing reactive functionality at the 4-position. In a number of cases, transition metal mediated chemistry is used to construct the requisite precursors. Successful development of the newly suggested synthetic strategies will introduce powerful new methods for the synthesis of important cyclic organic molecules such as quinones, aromatic and heteroaromatic molecules, and pyrones. It is anticipated that the proposed chemistry could have a significant impact on the development of medicinal agents possessing anticancer, antibiotic, antifungal, and possibly antiviral activities.