Fragment screens provide an information-rich starting point for designing derivative compounds that recapitulate key protein-ligand interactions in structure-based drug discovery. Maximizing the compound diversity and interaction sampling of the derivatives is critical to avoid premature convergence on unproductive chemical series, yet traditional catalog procurement typically limits campaigns to <100 compounds due to budget constraints. We developed Syndirella (Synthesis Directed Elaborations), which enables the sampling of 100s–1000s of compounds by generating congeneric series through digitized multi-step synthesis routes for reactant-based purchasing, in-house robotic synthesis, and direct-to-biology testing. Applied to three viral protein targets, Syndirella demonstrated comprehensive pharmacophore diversity, recapitulating known fragment interactions while identifying novel catalytic ones and accessing distinct chemical regions compared to traditional superstructure searches. Experimental validation on a calcium-binding protein fragment screen yielded 13 X-ray crystal structures with binding kinetics from 252 synthesized compounds, achieving 84% cost reduction versus catalog purchasing. By shifting from product to reactant procurement, Syndirella enables order-of-magnitude increases in accessible compounds for structure-activity relationship exploration within typical budgets, fundamentally expanding the breadth-to-depth ratio of fragment-based series.