A four-stage reaction sequence has been designed and developed for the synthesis of highly functionalized enolate esters as key building blocks for the synthesis of novel heteropolycyclic compounds of potential pharmaceutical value. The sequence starts with simple commercially available indoles and proceeds via 3-(indol-3-yl)-3-oxopropanenitriles, which react with 2-bromobenzaldehyde to form the corresponding chalcones; these are readily reduced to dihydrochalcones, which are in turn acylated to form the enolate esters. The compounds in this sequence have been characterized by IR and 1 H and 13 C NMR spectroscopy, by mass spectrometry and by elemental analysis. The molecular and supramolecular structures are reported for representative examples, namely ( E )-3-(2-bromophenyl)-2-(1-methyl-1 H -indole-3-carbonyl)acrylonitrile, C 19 H 13 BrN 2 O, (I b ), (2 RS )-2-(2-bromobenzyl)-3-(1-methyl-1 H -indol-3-yl)-3-oxopropanenitrile, C 19 H 15 BrN 2 O, (II b ), and (2 RS )-3-(1-benzyl-1 H -indol-3-yl)-2-(2-bromobenzyl)-3-oxopropanenitrile, C 25 H 19 BrN 2 O, (II c ), the latter two of which crystallize with Z ′ = 2, and ( E )-1-(1-acetyl-1 H -indol-3-yl)-3-(2-bromophenyl)-2-cyanoprop-1-en-1-yl acetate, C 22 H 17 BrN 2 O, (III), and ( E )-1-(1-benzyl-1 H -indol-3-yl)-3-(2-bromophenyl)-2-cyanoprop-1-en-1-yl benzoate, C 32 H 23 BrN 2 O, (IV). The structure of the related chalcone ( E )-2-benzoyl-3-(2-bromophenyl)prop-2-enenitrile, (V), has been redetermined at 100 K, where it is monoclinic, as opposed to the triclinic form reported at ambient temperature.