For each pair, a RBFE protocol was set up using BioSimSpace 33 (v2020.1.0 py37h9bf148f_593). For each benzene derivative pair in RBFE-Space, SMILES for ligand 1 and ligand 2 were parsed and an MCS was found while allowing ring breaking and ring size changing. After aligning ligands 1 and 2, a single, perturbable merged ligand was created from the two input molecules that contained the properties of both input ligands; the atom mapping used was stored to describe which R-groups were being perturbed into which between ligands. This 'merged ligand' was then solvated in a 3 nm 3 cubic box with TIP3P waters. Simulations were set up with the engine SOMD using 10000 moves, 50 cycles and a 2 fs timestep, adding up to 1 ns simulation time per λ window. Each perturbation was set to consist in 11 equidistant λ windows (i.e. λ ∈ [0.0, 0.1, .. 1.0]). Each perturbation was run in quintuplicate.