As more macrocycle structures are utilized to drug intracellular targets, new platforms are needed to facilitate the discovery of cell permeable compounds in this unique chemical space. Herein, a method is disclosed that allows for the efficient synthesis and permeability evaluation of novel organo-peptide macrocycle libraries. Thoughtful library design allows for the collection of crude permeability data using supercritical fluid chromatography mass spectrometry (SFC-MS) (EPSA) by mass-encoding the stereochemistry, ring size, and organic linker of the desired macrocycles. Library synthesis was aided via the development of a new on-resin N-arylation reaction. Further insights on the permeation of these organo-peptide macrocycles will be discussed, such as the permeability enhancement when utilizing a 2-substituted phenethyl linker versus a 3-substituted phenethyl linker. Lastly, selected macrocycles were scaled up and tested in the MDCK-II permeability assay, and the results of this assay reiterated the permeability trends from the crude SFC-MS data.