COCs can be synthesised via direct covalent-bond forming reactions between components, either via a step-wise approach, or "one-pot" methods. Cryptands, arguably the first COCs, first reported by Lehn and co-workers in the late 1960s, were originally synthesised using the former method; iterative amide bond formation followed by reduction were used to synthesise first a macrocyclic precursor (35) and subsequently the macrobicyclic cryptand in an overall yield of ~25% (Fig. ). In a similar vein, the stepwise formation of amide 103 and ether-based 104 systems (e.g. 38) have been demonstrated. Ringclosing of acyclic precursors is also possible: Lee and Moore reported the elegant multi-step synthesis of cage 39 (Fig. ) via a series of Sonogashira reactions and use of protecting group strategies, with a final, intramolecular, double Sonogashira step. Conversely, "one-pot" approaches entail multiple bondforming reactions between components. The simplest of these involve reactions between two complementary building blocks to form [1+1] products. Macrobicyclic systems have been synthesised in this manner through homodimerisation of selfcomplementary units (Fig. ), such as by alkyne homocoupling (e.g. 41) and Yamamoto coupling (e.g. 43), and through heterodimerisation (Fig. ) using CuAAC chemistry (e.g. 46), Sonogashira coupling, 109 and nucleophilic substitution (e.g. 49). Likewise, multi-component one-pot approaches have been reported. Such multi-component reactions are advantageous as the building blocks are relatively easy to access; however, yields can often suffer. Vögtle reported the synthesis of a macrotricyclic system through amide condensation: synthesis of the cage directly from a bis-acid chloride and trisamine in a [3+2] reaction yielded the desired cage in only 1.5% yield, whilst the [1+1] reaction between a tris-acid chloride, requiring a multi-step synthesis, and trisamine proceeded in 13% yield. Capsules have been prepared from oligomerisation of precursors (Fig. ), such as tetrameric capsule 51 that was synthesised from the condensation of 50 with paraformaldehyde, 112 and cages such as 53 were synthesised through Rh-catalysed [2+2+2] cycloaddition of bis-alkyne precursors. Reactions between complementary building blocks have also been used to good effect, such as the [3+2] CuAAC reaction between bis-azide 54 and trialkyne 55 114 and bicyclooxacalixarenes (e.g. 58) synthesised via nucleophilic aromatic substitution. Reactions involving more than two reactive groups, such as the Ugi reaction, have also been used to generate structurally complex COCs (e.g. 62; Fig. ). Whilst far from exhaustive, these examples demonstrate the versatility of chemistries that can be used for the synthesis of COCs.