2-Chloroquinoline-3-carbaldehyde (1) was condensed with the acetyl reagents 2a−e under the Claisen-Schmidt reaction conditions. In general, two products were formed, separated by column chromatography and proved by the spectroscopic data to be the two possible conformers E-s-cis-3a-c and E-s-trans-3a-c of the respective chalcones. However, reaction of 1 with 2d gave only one product 3d which has been attributed to the more stable E-s-cis conformer. Condensation of compound 1, on the other hand, with 2e gave the E-s-cis-3e conformer of the respective chalcone in addition to the cyclic flavanone 4. Moreover, 4-chloro-2-oxo-2H-chromene-3-carbaldehyde (5) condensed with the acetyl reagents 2a and 6 to give the E-s-cis conformers 7a,b of the respective chalcones. Similarly, ferrocenecarboxaldehyde (8) reacted with reagents 2c,d yielding the respective E-s-cis chalcones 9a,b. Structures and stereochemistry of the new products have been supported by the elemental microanalysis and the spectroscopic measurements including single crystal X−ray crystallography. The cytotoxicity and in vitro anticancer evaluation of the new compounds have been assessed, in detail, against four solid human cancer cell lines