Computing accurate reaction enthalpies represents for large molecules represents a significant challenge to computational chemistry. Sengupta and Raghavachari 1 recently demonstrated that their connectivity-based hierarchy (CBH) protocol 2 can be used to compute reaction enthalpies that, on average, are within 1-2 kcal/mol of G4 theory 3 , using density functional theory and triple-zeta basis sets (DFT/TZV). While encouraging, the computational cost of the DFT/TZV calculations are still too high to be routinely applied to large biomolecular systems. Here we test the accuracy of the CBH approach using computationally more efficient methods such as DFT/DZV, minimal basis set Hartree-Fock, tight-binding DFT, and neglectof-diatomic-differential-overlap (NDDO)-based semi-empirical methods, using the Sengupta and Raghavachari 1 data set. As part of the work we have completely automated the CBH approach so that it only requires a SMILES string representation of the molecule, which is easily generated using chemical drawing programs such as ChemDraw.