To understand the result for the out-of-sample set, we show three different reactions in Figure . Reaction a, where the first step is an Aldol reaction, where the deprotonation occurs at the least substituted C-H site next to the ketone (black arrow). Our ML model predicts an ML predicted pK a value of 24.7 for the experimental site of reaction. However, our ML model predicts the reaction site should occur at the highlighted circle. Here, we predict an ML predicted pK a value of 16.4. It is generally accepted that the most substituted C-H site next to a ketone will be the more stable carbanion (thermodynamic anion). Whereas the least substituted carbanion will be the least stable carbanion (kinetic anion). This can generally be controlled by the type of base used. For reaction a they use n-BuLi that are usually known to lead to the kinetic anion. Our ML model relies on the principle of lowest energy, thereby only reporting the lowest ML predicted pK a value as the site of reaction (thermodynamic carbanion) and does not account for the type of base used.