From here, the procedure for generating transition state (TS) guesses branches into four distinct schemes based on two methodological decisions (Fig. ). The first decision concerns how input geometries of the targeted reaction are generated: schemes SSI and SSIII employ a minimal sampling approach using joint-optimization to generate a single aligned reactant-product pair from the user-inputted reaction geometry, while SSII and SSIV utilize the more extensive RCS method reported in our prior work. The second decision is whether to perform additional TS conformational sampling on the initial TS guess: SSI and SSII only perform basic TS alignment (see below) with the model reaction, whereas SSIII and SSIV conduct additional constrained conformational sampling using the CREST package following the procedure of Pracht et al. These binary choices create four schemes of increasing computational sophistication (Fig. ). The most basic approach, SSI, combines minimal input sampling with basic TS alignment to produce a single TS guess. SSII extends this by using RCS-based input sampling to generate N conf conformers that are subjected to basic TS alignment to generate up to N 1 TS guesses. SSIII uses minimal input sampling but applies TS conformational sampling to generate up to N 2 TS guesses. The most thorough scheme, SSIV, combines extensive input sampling and TS sampling to generate up to N 2 TS guesses. In summary, the four sampling schemes yield 1, N 1 , N 2 and N 2 TS initial guesses, respectively, where N 1 , N 2 and N conf are all user supplied values. The TS guesses are ranked by the GFN2-xTB energy where applicable.