In this study, we assess the performance of MD simulations at generating accurate conformational ensembles of non-peptidic and semi-peptidic macrocyclic compounds by comparing the results with nuclear Overhauser effect (NOE) upper distance bounds from NMR experiments in chloroform, water, or DMSO. We compare between four popular force fields for organic molecules: the second version of the general AMBER force field (GAFF2), OPLS/AA , OpenFF version 2.0.0 (Sage) , and the recently reported XFF force field in combination with DASH partial charges, on eleven public and six in-house compounds. To ensure sufficient sampling, we employ the sampling-enhancement technique replica exchange with solute scaling (REST2) , which is based on replica-exchange MD (REMD) . We show that REST2 can be used to sample the configurational space of macrocycles. In several cases, we find excellent agreement with the experimental data, while also highlighting cases where the ensembles violate the experimental constraints. Additionally, we compare two different schemes to distribute replicas in REST2, showing that the quadratic scheme performs better. We also find that bond-angle terms need to be included in REST2 to ensure proper sampling for one compound with a strained ring system.