The network of alchemical transformations was built manually to include cycle closures for error analysis, and is shown in Figure . The overlap for each perturbation was determined using a maximum common substructure search to determine the atoms to be morphed. Each transformation leg was simulated using the SOMD software package 30 for 4 ns, and the first 400 ps were discarded as equilibration. Eleven equally spaced λ windows were employed between 0 and 1, along with the default soft core. The time step was set to 2 fs, with constraints applied to unperturbed hydrogen bonds, and the nonbonded cutoff distance was set to 10 Å. All transformations reported here were run in both forward and backward directions, and in duplicate. Free energy changes were calculated from the output using MBAR and processed by the software FreeEnergyWorkflows 68 to produce the final results and associated error bars. All protocols used and raw data are provided in the accompanying Supporting Data.