Synthetic routes developed in academic laboratories are often at odds with the requirements for an industrial process. This holds particularly true for biocatalytic syntheses, which typically give low substrate and product titers (in the 10 mM range and below), byproduct formation, incomplete conversion of starting materials and/or high salt concentrations. In the case of biocatalytic nucleoside synthesis, product mixtures typically contain residual starting material, excessive water as solvent and buffer salts, in addition to the desired product. Historically, this has necessitated extensive chromatographic purification to obtain the product in sufficient purity, which went hand-inhand with significant waste accumulation in the form of solvent. From a sustainability or efficiency perspective, this sub-optimal downstream processing of enzymatic reaction mixtures has thus far prevented nucleoside phosphorylasecatalyzed transformations from setting themselves apart from their chemical counterparts. To date, there have been relatively few studies which include the development of a downstream processing workflow in a biocatalytic nucleoside synthesis scheme. Indeed, most studies do not go beyond showing that the desired product is present in the reaction mixture and relegate the isolation of the product to potential future scaleup studies. Notable exceptions to this trend are the syntheses of islatravir and molnupiravir 21 reported by Merck. While islatravir was prepared through a slurry-toslurry process going from a suspension of the insoluble nucleobase to a suspension of the insoluble nucleoside (which only required filtration), the more soluble key intermediate of molnupiravir was accessed by an elegant extraction and recrystallization process. In both processes, a clever exploitation of solubility properties enabled a chromatography-free isolation of the product in high purity. While similar strategies based on the precipitation of purine nucleosides have been employed in early examples by Zuffi et al. and Ubiali et al., comparable approaches have thus far been lacking for pyrimidine nucleosides. To fill this gap, we believe that a closer partnership between biochemists and chemical engineers will be necessary to weigh the requirements of the biocatalytic reaction against those of the overall process, including an efficient downstream processing strategy.