Equation (5) shows the calculation scheme starting with the IDR assumption that errors somewhat cancel when calculating the heats of reactions to arrive at a value for ∆ iso f H Given the similarity between BACs and IDRs, it is important to discuss the differences that can affect their performance. As mentioned previously, isodesmic reactions essentially use a much smaller training set to apply what are essentially another form of BACs. One disadvantage of this approach is that if a reference species included in the isodesmic reaction has a significant error, this error will affect the final result much more than if a larger reference set was used for training. However, to mitigate the potential error sensitivity issue arising from the smaller training set, several strategies can be employed. Since isodesmic reactions are usually not uniquely defined for a specific target, multiple valid isodesmic reactions can be constructed using different reference species. To reduce the impact of outliers, a straightforward strategy is to generate several isodesmic reactions for a given target and then calculate the average or median of the values obtained from these reactions. By considering multiple isodesmic reactions, the influence of single reference species with a large uncharacteristic error is reduced, leading to more robust and reliable predictions. Another approach to mitigate the issue is to apply constraints when selecting reference species. By imposing constraints on the reference molecules during the construction of isodesmic reactions, one can ensure that the chosen species are chemically similar to the target molecule. For instance, constraints can be placed on the bonds present in the reaction to ensure that they are similar in nature to each other, allowing for better error cancellation. A notable example of this approach is the bond separation scheme, where reference species are chosen to be the simplest two-heavy-atom fragments that contain the corresponding bond types in a target molecule. Bond separation schemes enable better error cancellation because if a segment of a target molecule has a unique chemical environment, that environment will be directly referenced through a smaller fragment or reference species, rather than the target receiving an averaged correction from training species that may or may not actually possess that specific segment. While the majority of constraints proposed and employed in the literature for isodesmic reactions have focused on atom connectivity and bond environments, we propose that introducing additional constraints targeting other key molecular features can be beneficial in further refining the selection of reference species. For example, our curated reference set includes a diverse set of molecules containing anionic, cationic, zwitterionic, and strained cyclic species. These molecules can often appear in the isodesmic reactions found by the solver for neutral or acyclic targets. Recognizing that reference species with charges or strained rings are more likely to have significant errors from quantum mechanical calculations, we have implemented in the Arkane software to include optional constraints on charges and ring types when constructing IDRs for neutral, acyclic targets.