For outliers, the large energy difference can be attributed to cases where for example tautomerization involves single or multiple proton transfers, which lead to significant structural rearrangements, including but not limited to changes in π-electron density, aromaticity (e.g., conversion of aromatic to antiaromatic ring in heterocycles), exocyclic bonds (carbon-carbon conversion from sp 3 to sp 2 ), ring strain and overall notable shifts in electronic distribution (Fig. ). ChemAxon tautomer of CHEMBL170193 is more stable by 33.4 kcal/mol, and RDKit tautomer of CHEMBL191179 is more stable by 47.2 kcal/mol. In comparison, Fig. shows examples of tautomers with a very small free energy gap, approximately ±0.5 kcal/mol. The tautomerization in CHEMBL1872448 (proton shift between N-1 and N-3) retain similar resonance stabilization in 1,2,3-Triazole and overall molecular structure. It is highly possible that the tautomer predicted to be more stable by ChemAxon or RDKit may not actually represent the most stable form. For example, in the case of CHEMBL1872448 (Fig. ) with 1,2,3-triazole ring and substitutions at positions C4-C5 (derivative of pyrimidone), studies have shown - that both un-substituted and substituted 1,2,3-triazole favor N2-H form, which is more stable by 3.5-4 kcal/mol compared to the N1-H and N3-H forms. This is not unexpected, as canonical tautomer generation do not account for all the environmental conditions that affect the tautomerization ratio and the identification of the most dominant tautomer. Muzanzagenin (CHEMBL455616) is an oxosteroid, a steroid derivative with a carbonyl group (C=O) attached to its core structure. Tautomerization is highly localized, specifically in 1,2-Cyclohexanedione, which exists in two tautomeric forms. Studies have shown that the keto-enol form is more stable than diketo form by approximately 1 kcal/mol , which is in agreement with our findings of 0.53 kcal/mol. In general, smaller Gibbs free energy differences may reflect smaller structural Changes.