Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CC([O-])(C)C.[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][C:34]1[C:35]([C:39]([NH2:41])=[O:40])=[N:36][CH:37]=[CH:38][CH:33]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3cccnc3C(N)=O)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a suspension of N-(3-chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.074 g, 3.0 mmol) in DMF (12 mL) was added t-BuOK (539 mg, 4.8 mmol). The mixture was stirred at rt for 30 minutes, then 4-chloropicolinamide (517 mg, 3.3 mmol) was added. The mixture was stirred at 120° C. for 36 hours, then cooled to rt, quenched with 50 mL of water and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=3/1) to give the title compound as a white solid (580 mg, 40.4%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH2:8][Br:12])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Br)c(CBr)c1
Temperature: 100 °C
Reaction time: 42 h
Yield: 74 %

Procedure:
A 75 mL pressure vessel was charged with 2-bromo-3-methyl-5-nitropyridine (540 mg, 2.49 mmol), N-bromo-succinimide (452 mg, 2.54 mmol), 1,1′-azobis(cyclohexanecarbonitrile) (61 mg, 0.25 mmol) and 25 mL CCl4, The vessel was closed with a rubber septum and thoroughly purged with Argon. The rubber septum was switched to a Teflon cap and the reaction mixture was stirred at 100° C. for 42 h. The mixture was cooled to RT, filtered to remove the succinimide byproduct, washed with CCl4 and concentrated under vacuum. The crude residue was purified by chromatography on silica gel (using a solvent gradient from 1% to 20% EtOAc in hexanes) in order to isolate the desired product as a yellow oil (316 mg; 74% yield based on the amount of recovered starting material), along with some dibromonated byproduct (142 mg) and unreacted starting material (228 mg).
Reaction SMILES: Cl.[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C1COCC1.C(Cl)Cl.O>[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH:29][C:38](=[O:39])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:25][CH:26]([CH3:27])[CH3:28])([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C[C@H](N)/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
To a mixture of the amine 7 (1.50 g, 3.79 mmol) in dry THF (15 mL) were added Et3N (1.65 mL, 11.75 mmol), and then a solution of benzyl chloroformate (CbzCl, 0.59 mL, 4.17 mmol) in dry THF (4 mL) at 0° C. The resulting white suspension was allowed to warm to rt and stirred for 5 h, then diluted with DCM and water. The aqueous phase was extracted with DCM (2×), and the combined organic layers were washed with 10% HCl and sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 8:2, hexanes/EtOAc) afforded 1.45 g (72%) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.75-7.65 (m, 4H), 7.50-7.28 (m, 11H), 5.70-5.55 (m, 1H), 5.40 (dd, 1H, J=15.4, 6.2 Hz), 5.11 (s, 2H), 4.58 (m, 1H), 4.21 (m, 1H), 3.71 (t, 2H, J=6.6 Hz), 2.30 (q, 2H, J=6.6 Hz), 1.67 (m, 1H), 1.40-1.22 (m, 2H), 1.07 (s, 9H), 0.92 (m, 6H); HRMS (ESI) m/z calcd for C33H43NO3SiNa 552.2910; found 552.2930.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[Mg]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[N:5]1[CH:6]=[CH:7][C:2]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Brc1cccs1
Reactant: Brc1ccncc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: c1csc(-c2ccncc2)c1

Procedure:
To a 500 ml three-necked roundbottom flask was added 200 ml dry THF, 0.54 gr (1 mmol) Ni(dppp)Cl2 and 87 mmol of P-Br, fleshly prepared from 17 gr of the hydrochloride. To this was added T-MgBr, prepared from 14 gr (87 mmol) of T-Br and 2.5 gr (103 mmol) of magnesium. The mixture was refluxed for 20 hours and subsequently quenched with aqueous ammoniumchloride/HCl. About 100 ml of hexane was added and the organic layer extracted three times with dilute hydrochloric acid. Hereafter, the water layers were combined and made mildly alkaline with a strong sodium hydroxide solution. The product was extracted with three portions of 100 ml of chloroform. The chloroform solution was boiled shortly with a small amount of active coal and filtrated, whereafter the chloroform was removed on a rotation evaporator. Trituration of the remaining brown solid in boiling hexane yielded a clear yellow solution and a black unsoluble residue. After decanting the yellow solution, the solvent was evaporated and the remaining yellow solid dried in vacuo. The product was once recrystallized from 100 ml of hexane (a few hours standing at room temperature and overnight standing at 4° C.). The resulting yellow crystals were filtrated off, washed with cold pentane twice and dried in vacuo, (fraction I). From the collected pentane supernatants a second fraction of product with a lesser purity was obtained, by evaporating the solvent on a rotation evaporator and drying the remaining solid in vacuo. Yield: fraction I: light yellow powder of PT, 3.88 gr (24 mmol, 28%), fraction II: yellow powder of PT 6.00 gr (37.2 mmol, 43%), still containing some P-Br. M.p. (fraction I): 90°-91° C. (litt.: 92.5°-93.5° C.). Elemental analysis: found% (theory%) C 66.87 (67.05), H 4.38 (4.38), N 8.90 (8.69), S 18.7 (19.9). 1H-NMR (300 MHz, CDCl3): ∂=8.59 (2H, dd, J=4.6 and 1.7 Hz), ∂=7.52 (1H, dd, J=3.8 and 1.1 Hz), ∂=7.49 (2H, dd, J=4.6 and 1.7 Hz), ∂=7.43 (1H, dd, J=5.0 and 1.1 Hz), ∂=7.14 (1H, dd, J=3.8 and 5.0 Hz). M/z: 161 D (M.W.=161).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([CH3:19])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:19])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(C)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)c(C)c2)CC1
Yield: 94.8 %

Procedure:
1-Acetyl-4-(3-methyl-4-nitrophenyl)piperazine (0.5 g) and 5% palladium on carbon (0.1 g) in ethanol (20 ml) were hydrogenated at 60° and 60 p.s.i for 2 hours after which the catalyst was filtered off and the filtrate evaporated. The residue was partitioned between dichloromethane and water, and the aqueous layer extracted two more times with dichloromethane. The combined organic layers yielded 0.42 g of residue (of the title compound) on evaporation. This was recrystallized, m.p. 126°-9° (methanol/ethyl acetate).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]([F:34])([F:33])[O:17][C:18]1[CH:32]=[CH:31][C:21]([O:22]/[C:23](=[CH:27]\[C:28]([OH:30])=O)/[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1>CS(O)(=O)=O>[F:33][C:16]([F:15])([F:34])[O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:31][CH:32]=1)[O:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][C:28]2=[O:30]
Reactant: O=C(O)/C=C(\Oc1ccc(OC(F)(F)F)cc1)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C(O)c1cc(=O)c2cc(OC(F)(F)F)ccc2o1
Temperature: 70 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
A solution of phosphorous pentoxide (1.17 g, 8.21 mole) in methanesulfonic acid (14.38 g) is treated with 2-[4-(trifluoromethoxy)phenoxy]fumaric acid (2.00 g, 6.85 mmole), stirred for 16-18 hours at ambient temperatures and for 7 hours at 70° C., cooled to room temperature and poured onto ice. The resultant mixture is filtered and the filtercake is dried to afford the title product, 1.75 g, (93% yield), mp 192°-194 ° C., identified by 1H and 13CNMR, IR, mass spectral and elemental analyses.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C1OCCOCCOCCOCCOCCOC1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:1][CH:2]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1Oc1ccc(C)cc1
Yield: 59.3 %

Procedure:
To a suspension of KH (212 mg, 1.0 eq) in DMF (3 mL) was added a solution of p-cresol (200 mg; 1.85 mmol) in DMF (2 mL) followed by 18-crown-6 (50 mg, 0.2 eq). After stirring the reaction 45 minutes until the foaming subsides, a solution of methyl 2-bromophenylacetate (424 mg, 1.0 eq) in DMF (1 mL) was added, resulting in a purple solution that slowly faded to yellow. The reaction mixture was stirred 2.5 hours and was then concentrated in vacuo. The residue was chromatographed on a flash silica column (130×30 mm) eluted with 5% ethyl actate/hexane to yield 281 mg (62%) of the title compound (Rf =0.38, 5% ethyl acetate/hexane).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCCN=C=O
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Yield: 21.5 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and propylisocyanate (0.26 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (2×150 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2, gradient over 15 min). The product fractions were combined, concentrated and triturated in Et2O/CH2Cl2 (50 mL) for 18 h. The product was isolated by filtration dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.24 g, 29% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 1.63 min (98.92%); mp: 166-168° C.; 1H NMR (DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H, CH3), 1.31-1.46 (m, 2H, CH2), 2.03-2.08 (m, 1H, CHH), 2.45-2.62 (m, 2H, CHH, CHH), 2.82-3.01 (m, 3H, CHH, CH2), 4.36 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.3, 12.6 Hz, 1H, CH), 6.10 (t, J=5.7 Hz, 1H, NH), 6.53 (t, J=6.0 Hz, 1H, NH), 7.71-7.89 (m, 3H, Ar), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.31, 22.01, 23.16, 30.94, 41.20, 42.74, 48.98, 121.54, 123.39, 129.51, 131.53, 133.07, 149.53, 158.03, 167.06, 167.24, 169.84, 172.74; LCMS: MH=373; Anal Calcd for C18H20N4O5+0.1H2O: C, 57.78; H, 5.44; N, 14.97. Found: C, 57.52; H, 5.37; N, 14.76.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[CH:27][CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=1.[CH3:38][S:39]([O:42][C:43]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[C:45]([NH:58][S:59]([CH3:62])(=[O:61])=[O:60])[CH:44]=1)(=[O:41])=[O:40].CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][S:39]([O:42][C:43]1[CH:48]=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[CH:27][CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=2)[CH:46]=[C:45]([NH:58][S:59]([CH3:62])(=[O:61])=[O:60])[CH:44]=1)(=[O:40])=[O:41]
Reactant: C[C@H](Nc1ncnc2c1c(Br)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Product: C[C@H](Nc1ncnc2c1c(-c1cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c1)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (170 mg, 0.29 mmol) was treated with 3-(methylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl methanesulfonate (230 mg, 0.73 mmol, prepared from the title compound of Preparation 105 and methanesulfonyl chloride according to Preparation 37), sodium carbonate (95 mg, 3.06 mmols) and bis(triphenylphosphine)palladium(II) dichloride (70 mg, 0.09 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 82 mg (37% yield) of the title compound. Purity 98%.
Reaction SMILES: [C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.N[C@H:19]1[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@@H:21]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:20]1>>[OH:25][CH2:24][C@@H:19]1[C@@H:23]([CH2:26][OH:27])[O:22][C@@H:21]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:20]1
Reactant: N[C@@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@H](CO)[C@H]1O
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: O=c1ccn([C@H]2C[C@H](CO)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Med. Chem. Vol 22, 1979, 518-525 describes the synthesis of methyl 2,3-dideoxy-3-C-(hydroxymethyl)-β-D-erythropentofuranoside as well as the corresponding dibenzyl- and dibenzoyl derivative. The chloro derivative 5-0-benzoyl-3-C-[(benzoyloxy)methyl)]-2,3-dideoxy-D-erythro-pentafuranosyl chloride was coupled with 2-acetamido-6-chloropurine. The product was processed further to give the two anomers of 2-amino-9-[2,3-dideoxy-3-C-3-(hydroxymethyl)-D-erythro-pentofuranosyl]-9H-purine-6(1H)-thione which were tested for antitumor activity. The synthesis of 2,3'-dideoxy-3'(R)-hydroxymethyl uridine has been described in Nucleosides & Nucleotides 1 (1982) 263-273. Uridine was converted to 1-(3-amino-2,3-dideoxy-β-D-glucopyranosyl)uracil via a multistage sequence, which was further reacted via ring contraction, epimerization and reduction to give 2',3'-dideoxy-3'(R)-hydroxymethyl uridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH2:13][CH2:14][Cl:15])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
To 3-bromophenol (2.23 g, 12.9 mmol) in DMF (100 mL) was added, in small portions, sodium hydride (60% dispersion, 0.54 g, 13 mmol) over 30 min. 1-Bromo-3-chloropropane (2.1 g, 13 mmol) was then added dropwise and the mixture was stirred at r.t. for 24 h. It was then partitioned between ether and water, the organic phase was washed with water and brine, dried (anhydrous MgSO4) and concentrated to afford 1-bromo-3-(3-chloropropoxy)benzene (362, 2.95 g, 91% yield) (used as is with no additional purification).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.ClC1C=C(C=CC=1)C(OO)=[O:37]>>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:37])=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCCc1nc2c(C)cc[n+]([O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 42.8 %

Procedure:
A solution of 7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (9 mg) and m-chloroperoxybenzoic acid (6 mg) CHCl3 (2 mL) was heated to reflux for 2 hours. Concentration and purification (SiO2, 80:20:1 CH2Cl2 /MeOH/NH4OH) gave 4 mg of the title compound as a solid. 1H NMR (300 MHz, CD3OD) δ8.07 (d, 1H, J=6 Hz), 7.60-7.43 (m, 4H), 7.19, (d, 1H, J=6 Hz), 7.09 (s, 4H), 6.14 (s, 2H), 2.82 (t, 2H, J=7.5 Hz), 2.63 (s, 3H), 1.81-1.67 (m, 2H), 0.98 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH2:5][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>O1CCOCC1>[CH:1]1([C:4](=[O:16])[C:5](=[CH:19][N:20]([CH3:22])[CH3:21])[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: O=C(CC(=O)C1CC1)c1ncc(Cl)cc1Cl
Solvent: C1COCCO1
Product: CN(C)C=C(C(=O)c1ncc(Cl)cc1Cl)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)propan-1,3-dione (1.3 g) and N,N-dimethylformamide dimethyl acetal (1.1 ml) in 1,4-dioxane was stirred at room temperature for 4 days and the solvent was evaporated to yield 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)-2-dimethylaminomethylenepropan-1,3-dione (1.73 g).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[N:41]=[CH:40][CH:39]=[N:38]3)=[CH:33][CH:32]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC1CCCO1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[N:41]=[CH:40][CH:39]=[N:38]3)=[CH:33][CH:32]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-n3nccn3)cc2)OC1(C)C
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC1CCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
Pd(dppf)Cl2 (484 mg, 0.59 mmol) was added to a mixture of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2, (2.20 g, 4.94 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (2.01 g, 7.41 mmol), and potassium phosphate (3.95 g, 14.8 mmol) in 2-methyltetrahydrofuran (200 mL) and deionized water (40 mL). The reaction was heated to 60° C. and was vigorously stirred at this temperature overnight. The reaction was diluted with EtOAc (100 mL) and water (100 mL) and was filtered through a celite pad (˜1 inch). The filter pad was washed with EtOAc (100 mL) and the filtrates were combined. The aqueous layer was separated and was extracted with EtOAc (2×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated. The crude material was purified via flash chromatography using a Varian SF25-40 g column and an eluent of EtOAc in hexanes (30-100%) to afford the title compound as a yellow solid (1.54 g, 67.4%). MS (LCMS) m/z 463.0 (M+1). 1H NMR (400 MHz, DMSO-d6) ppm 1.23 (t, 3 H) 1.62 (s, 3 H) 2.18-2.32 (m, 1 H) 2.52-2.66 (m, 1 H) 3.16 (s, 3 H) 3.92-4.07 (m, 2 H) 4.08-4.24 (m, 2 H) 6.59 (d, J=7.81 Hz, 1 H) 7.72-7.84 (m, 2 H) 8.10 (d, J=6.63 Hz, 1 H) 8.12-8.17 (m, 2 H) 8.18 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:14])[C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[C:50]([F:55])[C:49]=1[C:56]1[N:60]=[C:59]([CH3:61])[O:58][N:57]=1>CS(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:54][C:52]1[CH:51]=[C:50]([F:55])[C:49]([C:56]2[N:60]=[C:59]([CH3:61])[O:58][N:57]=2)=[C:48]([C:2]2[CH:3]=[C:4]([F:14])[C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:6][CH:7]=2)[CH:53]=1
Reactant: CC(=O)N[C@H](C)c1ncc(Br)cc1F
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)N[C@H](C)c1ncc(-c2cc(Cl)cc(F)c2-c2noc(C)n2)cc1F
Temperature: 90 °C

Procedure:
A stream of argon was bubbled through a mixture of N—[(R)-1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide (200 mg, 0.766 mmol, intermediate 12) potassium acetate (226 mg, 2.3 mmol) and bis(pinacolato)diboron (253 mg, 0.996 mmol) in DMSO (1.5 ml) in a sealed tube for 10 min. Then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with DCM (31.3 mg, 0.0383 mmol) was added and again a stream of argon was bubbled through the reaction mixture for 10 min. The tube was then sealed and heated to 90° C. for 1.5 h. After cooling to room temperature, potassium carbonate (212 mg, 1.53 mmol), water (198 μl), 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (246 mg, 0.843 mmol, intermediate 10) and additional [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with DCM (31.3 mg, 0.0383 mmol) were added and the reaction mixture was heated to 80° C. for 3 h. The mixture was cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed two times with water and brine, dried with Na2SO4 and evaporated. The remaining brown gum was purified by chromatography (silica gel; heptane/EtOAc 35:65-10:90) and the title compound was obtained as off white foam (200 mg, 66%). MS: 393.1 [M+H]+.
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH3:32][C:33]1([OH:39])CCNCC1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][C:33]([CH3:32])([OH:39])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: CC1(O)CCNCC1
Agent: Cl
Product: CC1(O)CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 276 is synthesized from Intermediate C and Intermediate R according to General Method K. (LC/MS method 16: ES+ m/z 341.2 [M+H]+, Rt=2.50 min)