All bonds involving hydrogen were constrained during the simulations. Polar hydrogens had their vdW contribution removed by setting ε = 0 as the very small parameters caused slow convergence of the long-range correction in OpenMM-7.6.0 which caused the simulations to fail. This was deemed to have a negligible impact on the simulation accuracy as the parameters are placeholders designed to be "small but non-zero" in OpenFF-Sage from which they were transferred. The parameters of DE-FF were then optimised using ForceBalance , which minimises a weighted least squares objective function comparing the calculated and experimental condensed phase properties. The construction of the objective function was exactly the same as that used in the training of OpenFF-Sage and the ForceBalance input files can be found in the Supporting Data. Bonded Parameters. Valence parameters (bonds, angles and proper torsions) were optimised after the non-bonded optimisation procedure described above. The QM target reference dataset comprised a subset of the total data used to fit OpenFF-Sage and was extracted from QCArchive 39 using QCSubmit . Any molecules which would be parameterised with unoptimised nonbonded parameters (S, P, F, I) were filtered out of the dataset. Starting from the OpenFF-Sage valence parameters, the harmonic bond equilibrium length and force constant, harmonic angle equilibrium angle and force constant and proper torsion force constants were optimised using ForceBalance . This resulted in the following numbers of parameters to be optimised: