The SILVR method enables an equivariant diffusion model to be conditioned to generate molecules based on a reference structure, such as a fragment from a crystallographic screen. The V-SYNTHES approach makes use of on-demand libraries for hit-finding by decomposing compounds from purchasable databases into reactive scaffolds and synthons, and using the highest scoring docked fragments as seeds for further growth. One particularly noteworthy example is the use of fragment merging to design hits against the nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Fragments from a crystallographic screen were merged using the Fragmenstein package, ensuring placement of molecular substructures onto the original fragments, and subsequently used as templates for searching on-demand chemical space. In this way, fragments were rapidly elaborated into a 0.4 µM hit (representing a >400-fold improvement in affinity).