The hits from the XChem targets SARS-COV-2 MPro (cysteine protease) and Mac1 domain of SARS-COV-2 NSP3 (macrodomain ADP-ribosylhydrolase) , were downloaded from Fragalysis () and filtered for inclusion in the DSi-Poised library . The templates used were PDB:6LU7 for MPro and PDB:6WOJ for Mac1, these were energy minimised with PyRosetta with the FastRelax mover constrained by its density-map . Their hits were combined (merged/linked) with the aim of quantifying the failure rate and the synthetic accessibility. Additionally, to explore the thermodynamic cost of fidelity to the reference compounds, alternative approaches were adopted, namely merging solely by maximum common substructure and merging by BRICS Steps in a combination operation. For combinations, the positional overlap is calculated with any ring collapsed. This is done to prevent overlap issues (first inset, detail in SI Figure ). Both rules share the atomic positional overlap mapping (middle inset, further detail in Supplementary figure ). After which, the merger is rectified based on certain rules listed in its GitHub repository. B. The effect of adherence to atomic positions can be seen in a test where a furan and a benzene with centres of mass at different distances yield different molecules ranging from a single ring to two linked rings. C. Steps in a placement operation. The provided compound is mapped to each hit with a multistep MCS scheme (Supplementary figure ), the mapping with the larger coverage is chosen and the other hits are mapped via a MCS restricted by their atomic overlap with the primary hit. For both combination and positioning, after the stitched together conformer is created, it is energy minimised locally, with strong constraints and with a topology parameterised from an ideal conformer.