for HAA Formation A major challenge in reaction network characterizations is that, absent laborious experimental mechanistic studies, the predicted pathways can only be indirectly validated through comparisons with terminal product yields. Interesting experimental work by Lu et al that used 13 C-labeling to quantify the carbon fluxes from β-D-Glucose to specific positions in HAA provides a unique opportunity to directly test several of the competing mechanistic pathways predicted here (Fig. ). In total, five distinct 13 C-label patterns can be produced from the total of eleven kinetically relevant pathways for HAA formation predicted here (i.e., HAA, which has two carbons, can inherit those carbons from the [1,2], [2,3], [3,4], [4,5], or [5,6] carbons in β-D-Glucose based on the labeling in Fig. ). These five distinct labelled products are consistent with those found experimentally. Seven distinct pathways were discovered to form (5,6)-HAA, while for all other labeled products only one kinetically relevant pathway was found (Fig. ). To compare the kinetic favorability of each HAA-labeling, the overall barriers, absolute barriers and the number of reaction steps are summarized in Table .1 and presented graphically in Figure . To perform a quantitative comparison with the experimental fluxes, we also considered the possibility of doublewater catalyzed reactions (i.e., the network exploration was done considering only single-water catalyzed reactions). A more stable double water-catalyzed TS was discovered for the keto-enol tautomerization of 1,2-Ethenediol (∆G † = 24.88 kcal/mol; the single water-catalyzed barrier is ∆G † = 35.21 kcal/mol). An energy diagram with only single-water catalyzed results is presented in Fig. for comparison.