This conceptual fragment to drug-like molecule growth exercise (Fig. ) has demonstrated that it is possible to save time, solvent usage, and many synthetic, extraction, work-up and purification bottlenecks (Table ) by combining crude array synthesis and X-ray crystallographic structural determination of the resulting molecules (Fig. ). A crude fragment screen of the DSiP library at Diamond vs PHIP(2), led to a piperazinyl hit F709 (Fig. ). Consequently, we have developed several thousand multi-step, robotic-driven reactions with minimum automated work-up using F709 as the starting fragment (Fig. ). To reduce crude compound analysis time (Table ), a semi-automated LCMS analysis tool MSCheck has been developed to supersede the previous cumbersome manually evaluated LCMS chromatogram methods (Fig. ). Crude reaction mixtures were submitted to XChem for X-ray analysis at high-throughput levels and without compromising crystal integrity thus, bypassing purification steps (Fig. ). This resulted in the identification of crystal binders (Fig. ) which enabled us to map the crystallographic SAR landscape around PHIP(2) defined by our enumeration. We also resolved a previously unidentified binding pose that displaces all 4 bromodomain water (Fig. ) and found one of the crystallographic binders to be active in a biochemical assay (Fig. ).