Yet the difference between the de novo peptide lead and the final compound advanced to clinical trials is often profound, and the modifications introduced demand exceptional commitments of labor and state-of-the-art medicinal chemistry . Introducing these modifications earlier in the discovery process would be advantageous. Some important progress has been made, including the introduction of N-Me groups 83 , D-amino acids , β 2 -and β 3 -amino acids, as well as linkers that introduce rings or even appended pharmacophores . Even with these developments, the chemistry available to ribosomally translated-peptides remains limited when compared to the vast array of transformations, functional groups, and architectures that are emblematic of small molecule pharmaceuticals and bioactive natural products. Yudin and others have shown that the introduction of heterocyclic grafts into peptide macrocycles can have profound impacts on passive permeability, bioavailability, and even topological complexity . Quinolines, however, are underrepresented among these grafts; thus, the properties imbued by these motifs represent an area ripe for further exploration. This work was initiated in an attempt to generate ribosomally synthesized peptides with modifications that resemble those found in peptide-derived clinical candidates. We accomplished this goal by installing a reactive β-keto amide functional group at the N-terminus and developing mild Friedländer reaction conditions to convert the β-keto amide into quinoline-peptide hybrids, including those that exist in distinct atropisomeric forms. The same mild Friedländer conditions were deployed as a macrocyclization strategy, embedding a quinoline pharmacophore directly into the backbone of a sequence-encoded macrocycle.