Since the process involves neutralization, if the fragments that undergo tautomerization are neutral or if neutralization is impossible (e.g. a quarternary ammonium), then both approaches would result in the same canonical tautomer. Therefore, we further filtered out those records and the subset downsized to 0.44% of the total records in ChEMBL32 and then run the tautomerization on this subset for both approaches. We compared the molecules that tautomerized applying both approaches and found out that only 274 molecules (0.01% of the total records in ChEMBL32) were different. Examples of molecules that were tautomerized but resulted in different tautomers in both approaches are shown in Fig. . The two CHEMBL995 (LOSARTAN POTASSIUM, an FDA-approved drug) tautomers are structurally very similar and as will be shown in results and discussion such prototropic tautomerism results in very small free energy difference. The same is also valid for CHEMBL67353. The desalting and neutralization, followed by tautomerization, resulted in the correct tautomer of CHEMBL30219 (METHOHEXITAL SODIUM, an FDAapproved drug).