The CPU-time requirements for the semiempirical calculations are relatively modest compared to the DFT refinement calculations. A single meta-MD simulation requires on average 5.4 minutes on a single core of a Intel Xeon E5-2643 v3 (3.4 GHz) for the reactants of the low-barrier reaction dataset. Larger molecules such as the Berkeleyone A precursor (Figure ) require about 25 minutes, but the precise value depends greatly on how fast the reaction occurs; for the steps presented in Figure the average run time for a meta-MD simulation was in the range 17-35 minutes. A single semiempirical barrier estimate typically takes about 14 seconds on the same type of core (13 minutes for the Berkeleyone A precursor) and we usually run five of these in parallel with different settings. For comparison, a typical ωB97X-D/def2-TZVP TS search takes about 6.5 hours on 2 cores.