Transitions that pose difficulty for participants involve a protonated nitrogen and keto-enol neutral state tautomerism. Chemical transformations involving a protonated nitrogen in terminal nitrogen groups, 1,2,3-triazoles, and isoxazoles were all found to occur in molecules that have high levels of disagreement in sign prediction. Depictions of some of these types of transitions are presented in Figure . Predictions for these transitions were substantially divided on the predicted sign -roughly half of the methods predict a positive sign, while the other half predict a negative sign. This means methods could not agree on the preferred state at the reference pH. The number of positive, negative, and neutral sign predictions per microstate is available in Table In several cases, the SAMPL input files provided a reference microstate with unspecified stereochemistry, then a separate but otherwise equivalent microstate with specified stereochemistry (SM35_micro002, SM36_micro002, SM37_micro003). Experiments were done on the compound with specified stereochemistry, so participants were instructed to assume that the reference microstate (which had unspecified stereochemistry) had the same free energy as the microstate with specified stereochemistry.