A retrospective is presented highlighting the synthesis of selected "first-in-kind" natural products, their synthetic analogues, structure elucidations, and rationally designed bioactive synthetic compounds that were accomplished because of collaborations with past and present pharmaceutical and agrochemical companies. Medicinal chemistry projects involving structure-based design exploiting cocrystal structures of small molecules with biologically relevant enzymes, receptors, and bacterial ribosomes with synthetic small molecules leading to marketed products, clinical candidates, and novel drug prototypes were realized in collaboration. Personal reflections, historical insights, behind the scenes stories from various long-term projects are shared in this retrospective article.