In order to access our intended series of thionucleoside derivatives, a scalable and reliable method for the synthesis of 4-thio-D-ribofuranose 1 was required (Scheme 1). Starting from commercially available 2, the anomeric acetate was hydrolysed using H2O/BF3•OEt2 in 91% yield on 100 g scale. The resultant hemi-acetal was used crude and converted to the corresponding oxime 3 via treatment with O-methoxyhydroxylamine hydrochloride and Et3N. This material was isolated as a mixture of oxime isomers (3/1 ratio) in 90% yield, again on multigram scale. Manipulation of the C4 position in 3 to facilitate conversion to the final thiofuranose, with retention of the C4-riboconfiguration, was explored next. Direct halogenation and inversion of stereochemistry at C4 using CBr4 or Br2 with PPh3 proved unsuccessful, returning only starting material. Instead, the C4-OH in 3 was converted to an arylsulfonyl leaving group. Initially here we targeted a 4-nitrobenzenesulfonate, but persistent low yields (maximum obtained = 31%) and a requirement for chromatography led us to explore other options. An earlier report of a less common 2,3,5-tricholorobenzensulfonate proved fruitful, delivering 4 in 72% yield. Purification of 4 was achieved using trituration from Et2O, enabling easy isolation as a white solid. This material could be prepared in multigram amounts in 56% overall yield for three steps from 2 and required no column chromatography. Nucleophilic displacement of the 4-sulfonyl group within 4 was explored using LiBr in a Finkelstein-type reaction. The use of DMI/THF as the solvent at 60 °C for 16 h resulted in a mixture of C4 diastereoisomers (3/1, S/R, see SI Figure ), presumably forming via a second nucleophilic displacement of bromide 5 to give the unwanted the C4-R epimer. Similar issues surrounding unwanted C4 epimerisation were encountered by Codée and co-workers during their synthesis of 4thiofuranosides. Reducing the reaction time to 2 h in the same solvent system improved the diastereomeric outcome (10/1, S/R), however, this was accompanied by incomplete consumption of 4. Switching solvent to 2-butanone and heating at 80 °C for 18 h delivered diastereomerically pure C4bromide 5 in 89% yield. C NMR analysis of 5 confirmed an upfield shift of C4 to δC 47.8 ppm, from δC 79.6 ppm. Treatment of bromide 5 with glyoxylic acid at 70 °C effected hydrolysis of the oxime to the corresponding aldehyde in 92% yield, which was used immediately for conversion to the desired 4thiofuranose 6. This proceeded via reaction with NaSH, effecting SN2 displacement of the C4 bromide followed by ring closure onto the C1-aldehyde, obtaining 6 as a mixture of anomers in 76% yield. Crude 6 was treated with Ac2O in pyridine with catalytic DMAP to obtain the acetylated product 1 as a mixture of anomers (4/1, β/α). Simple trituration from MeOH isolated the β-anomer of 1 exclusively in a satisfactory 50% yield from 5, with analytical data confirming those reported previously for Dribothiofuranoses. The development of this synthetic route to 1 required no column chromatography and was completed starting from 100 g of 2, delivering 1 in an overall yield of 25% for the seven steps and in 25 g quantity.