There are two stages to this step: the first generates QM geometry-optimized structures and energies at the gas-phase, B3LYP-D3BJ/DZVP level of theory 51-55 using psi4. This method and basis set were chosen by the Open Force Field initiative to provide reasonably accurate conformational energies and geometries at moderate computational cost and are consistent with the method used previously. Molecular modeling approaches typically rely upon accurate assessment of low energy minima but there are cases where it is useful to predict higher-energy structures,. The protocol used here does not exclude conformers based on a cut-off for relative QM energy (dE) and indeed some higher-energy local minima were retrieved, < 0.06% for dE >20 kcal/mol. The second stage performs gas-phase MM optimizations using the different forcefields, starting from the minimized QM structures for each molecule conformation. Publicly available compounds on the QCArchive were minimized with the latest generation of each force field family, namely GAFF-2.11, OPLS4 with both custom (OPLS4 CST ) and default (OPLS4 DEF ) parameters, and OpenFF "Sage" v2.0.0. Proprietary compounds were minimized using each OpenFF generation (SMIRNOFF, "Parsley"v1.3.0, "Sage"v2.0.0) and GAFF-2.11, as OPLS4 was not available at all the industry partners. The SMIRNOFF99Frosst version used here is SMIRNOFF99Frosst-1.1.0.offxml.