for different LOTs or reaction classes as defined previously. However, two complexities merit consideration. First, not all species can be calculated using the IDR approach. This limitation is particularly evident when a certain type of bond or constraint is present in only a small number of species within the reference set. In such cases, it may be impossible to construct an isodesmic reaction using only the species in the reference set (excluding the target species) that satisfies the desired constraints. Consequently, the inadequate training set problem becomes more pronounced for higher-order and more constrained reaction classes, as the number of available species that can form a valid isodesmic reaction decreases. To account for this issue, we indicate and consider the difference in population size (i.e., the number of species that could be calculated) for each constraint level when analyzing the results to provide a more accurate and comprehensive understanding of the performance of the IDR approach under different conditions. Second, while a certain reaction class might be specified, the median isodesmic reaction used for the final value of ∆ iso f H • in the auto-IDR algorithm, as implemented in this work, may also belong to a higher-order reaction class. This complexity makes it challenging to test the performance of strictly defined reaction classes, such as RC2 reactions that exclude RC3, because reactions satisfying RC3 conditions inherently satisfy RC2 conditions as well. To address this issue, as previously explained in the method section, we refer to RC2 as a class of reactions that satisfy at least RC2 conditions when analyzing the results. This approach allows for a more comprehensive analysis of the performance of different reaction classes, while acknowledging the potential overlap between higher-order and lower-order classes.