In this research we have generated a pharmacophore model of triple uptake inhibitor compounds based on novel asymmetric pyran derivatives and the newly developed asymmetric furan derivatives. The distances between the FM19G11 benzhydryl moiety as well as the isomer 9a furthermore. Likewise intermediate 8 upon hydroboration and oxidation response yielded inseparable diastereomers (84%) mostly favoring the isomer 9b. The diasteromeric combination of 9 and 10a had been after that mesylated with methanesulfonyl chloride using triethylamine in anhydrous dichloromethane (DCM) and separated by column chromatography to cover substance 11a as the main isomer in 69% and 12a as the minimal isomer in 15 produces. Similarly diasteromeric combination of 9b and 10 upon mesylation provided separable isomers 11b and 12b in 67% and 17% produces respectively. The stereochemistry from the isomer 9a continues to be established inside our previous studies thoroughly.35 Main isomers 11a and 11 were then put through SN2 nucleophilic substitution reaction using sodium azide in anhydrous DMF to provide intermediates 13 and 13b in 86% and 88% produces respectively. Hydrogenation of 13a and 13b with 10 Pd/C in methanol led to matching intermediate 23 was put through SN2 FM19G11 nucleophilic substitution response using sodium azide to produce intermediate 25 which provided the generated trifluoroacetic acidity. Furthermore unreacted alcoholic beverages was also retrieved in significant quantities. It was FM19G11 noted that addition of triethylamine neutralized free acid and significantly reduced the formation of the acetal side product.39 The reaction was carried out in a sealed tube and heated to 50 °C to force the equilibrium in the forward direction. Thus 30 was obtained in moderate yield (50%) along with the recovery of unreacted alcohol (38%) which was recycled in the FM19G11 synthesis. The unstable intermediate 30 was immediately subjected to RCM reaction in the presence of Grubbs catalyst (1st generation) at room temperature. The reaction was optimized by warming to 50 °C and carrying out for a longer time period (6h) along with the portion-wise addition of the catalyst over 3 h. The producing intermediate 31 obtained in 53% yields was then reacted with 9-BBN followed by oxidation to obtain an inseparable mixture of diastereomers 32 and 33. The diasteromeric combination was mesylated with methanesulfonyl chloride using triethylamine in anhydrous dichloromethane. In contrast to the pyran derivatives the producing diastereomers 34 and 35 were inseparable at this stage and were thus carried to the next step without further purification. The SN2 nucleophilic substitution reaction with sodium azide gave separable diastereomers 36 (major) and 37 (minor) which were purified by column chromatography. The assignment of complete stereochemistry and structural elucidation of major diasteromer 36 was performed using 1H and 2D NMR experiments and details has been provided in the supporting information. Similar experiments were performed to characterize the minor azide diasteromer 37. After determining their stereochemistry the azide intermediates 36 and 37 were hydrogenated to obtain the corresponding amines 38 and 39 in quantitative yields. The amines were then subjected to reductive amination reaction Bmp3 with appropriate aldehydes according to the method explained above to furnish the final compounds 40 in 35-45% yields. Plan 4a FM19G11 a Reagents and Conditions: (a) Vinylmagnesium bromide CuI anhyd. THF ?78 °C- rt overnight 75 (b) Ethylvinyl ether Hg(OCOCF3)2 50 °C 12 h 50 (c) Grubb’s catalyst (1st gen) anhyd. benzene 50 °C 6 h 53 (d) … 2.2 Stereochemical assignment of the intermediate 36 Structural elucidation for compound 36 is summarized. By the knowledge of chemical shift in the aliphatic region the most downfield proton at 4.66 ppm (1H NMR (CDCl3) spectrum) should be H-2 which is next to the H-1 (3.92 ppm) FM19G11 of the benzhydryl group. The splitting was doublet of triplet (dt) from couplings with H-1 H-3a (2.25 ppm) and H-3b (2.00 ppm) protons (Table 1). Furthermore 2 gradient double quantum-filtered correlation spectroscopy (2D-gDQFCOSY) and 1 homonuclear decoupling experiments also supported this observation. The decoupling experiment revealed that irradiation of protons at 1.75 and 2.25 ppm separately has collapsed the doublet of triplet peak of H-2 into a triplet. This validated that this protons at 1.75 and 2.25 ppm are the immediate neighbouring protons of H-2. Further experiments confirmed that this protons at 2.25 ppm is H-3a and.