Catalytic esterification in water has been achieved with the aid of a commercially available polymer-supported lipase, Novozym-435. Remarkably, this well-known biocatalyst demonstrates significant activity towards esterification using just water as the reaction medium. This methodology features representative esterifications of complex acids and alcohols, in the presence of unprotected amines. The work disclosed leading to esters typically requires only two equivalents of alcohol, although conversion for water-soluble alcohols appears to require increased loadings. Recycling of both the aqueous medium and catalyst are documented, highlighting the potential of this new technology, especially using directed evolution on the enzyme involved. Pharmaceutically relevant compounds are efficiently esterified (e.g., Ibuprofen, Tolmetin, and Ticagrelor) and multi-step, onepot chemoenzymatic sequences can be performed to demonstrate the robustness of this catalytic aqueous system. ix II. Palladium-catalyzed reactions that involve functionalized substrates are oftentimes problematic. Those involving aryl or heteroaryl bromides that are either resistant to, or inefficient in such couplings present challenges that are difficult to overcome and may require development of an entirely new route, or worse, no opportunity to install the desired group using a standard coupling strategy. In this report, we describe a solution that allows for the in situ conversion of such bromo educts to transient iodide derivatives that can be made and used under environmentally responsible conditions, for subsequent reactions to highly functionalized, complex targets. III. This chapter presents two case studies highlighting recently developed synthetic methodologies for complex molecule construction. In the first, the green amide coupling reagent DPDTC is used twice in a four-step, one-pot sequence to synthesize a complex ester from Merck Informer Library compound X7. In the second, a nickel-catalyzed deutero-dehalogenation strategy is applied to the preparation of a novel deuterated analog of the API Bitopertin. This latter case study demonstrates the use of pyridyl-fluorides as latent handles for late-stage deuteration of pharmaceutically relevant molecules.