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This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.

Using X-ray crystallographic screening, fragments 4 and 6 were identified as inhibitors of hematopoietic prostaglandin D2 synthase (H-PGDS). Both fragments induced a small protein movement in the X-ray crystal structure relative to the apo structure, where the highly polar nature of the ligand complemented the induced protein conformation. The manuscript describes the fragment optimisation of 4 and 6 followed by fragment growth to lead molecule 10. This showed favourable physicochemical properties and evidence of oral activity in blocking PGD2 generation in vivo.

Vinyldisiloxanes equilibrate with the corresponding silanolates under basic conditions and subsequently undergo palladium catalysed cross coupling with aryl/heteroaryl iodides and bromides.

Insertion of (E)-(1,2-dihalovinyl)lithium into zirconacyclopentenes was followed by elimination of halide to afford an alkyne which inserts intramolecularly into the resulting carbon–zirconocenium bond to give a methylenecyclopentene, whereas insertion of (2-haloethynyl)lithium gives the same product via a zirconocene alkenylidene.

Acetylenic thiophens, ArC⋮CR (Ar = 2,2′-bithienyl-5-yl or 2-thienyl), have been prepared by a metal-catalysed Grignard coupling reaction, either from ArMgl and BrC⋮CR or from Arl and BrMgC⋮CR; the second method gave the better results. Some side-reactions are discussed.