Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH:12]([Sn](C=C)(C=C)C=C)=[CH2:13]>CN(C=O)C.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:12]=[CH2:13])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: C=C[Sn](C=C)(C=C)C=C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(CO)nc(Cl)c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodopyridin-3-ol (5.7 g, 20 mmol) is combined with bis (triphenylphosphine) palladium dichloride (1.12 g, 1.6 mmol) in 50 ml DMF under nitrogen. The mixture is treated with tetravinyl tin, is warmed to 60° C. for 6 h followed by 50° C. for 18 h, and at rt for 72 h. The mixture is diluted with 250 ml EtOAc and is extracted with 4×100 ml 2:1:1 water/saturated NaCl/saturated NaHCO3. The organic layer is dried (MgSO4) and is concentrated in vacuo to a yellow oil. The crude material is chromatographed over 200 g SiO2 (230-400 mesh) eluting with 37% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.45 g (39%) of 2-chloro-6-(hydroxymethyl)-4-vinylpyridin-3-ol as a pale yellow solid. MS for C8H8ClNO2 (EI) m/z: 185 (M)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N+:18]([O-])=[C:17]([CH3:24])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:24][N:43]([CH3:42])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (13 mg, 0.029 mmol) in toluene (2 mL) was added benzenesulfonyl chloride (0.2 mL, excess). The mixture was stirred at 80° C. for 1 hour, then cooled to room temperature. N-methylaniline (0.2 mL, excess) and K2CO3 (250 mg, excess) were added. The mixture was stirred at 60° C. for 16 h, then diluted in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (12 mg, 78%). LCMS-ESI+ (m/z): 531.3, 533.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[C@@H:14]([O:16][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[C@@H:14]([OH:16])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CS(=O)(=O)OC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Product: CS(=O)(=O)OC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Process C: (3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (150 mg) was dissolved in dichloromethane (12 mL) and 2,4,6-collidine (0.79 mL) was added to the solution. While this mixture was chilled in an ice water bath, methanesulfonyl chloride (46.2 μL) was added dropwise. The mixture was stirred for 2 hours in the ice water bath and was stored in a refrigerator (3° C.) for 15 hours. Subsequently, the reaction mixture was washed sequentially with water (2 mL), 1 mol/L hydrochloric acid (2×2 mL) and saturated brine (2×2 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate 1:2->ethyl acetate) to give 38.7 mg of (3R,4R)-1-benzyloxycarbonyl-3-methanesulfonyloxy-4-methanesulfonyloxymethylpyrrolidine as a pale yellow syrup and (3R,4R)-1-benzyloxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (133 mg) as a white syrup.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:50][O:51][NH:52][CH3:53].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:52]([O:51][CH3:50])[CH3:53])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:35])([F:34])[F:36])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoic acid (115.8 mg, 0.237 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (86 mg, 0.356 mmol), O,N-dimethyl-hydroxylamine hydrochloride (69 mg, 0.711 mmol) and 0.3 mL of triethylamine dissolved in 2 mL CH2Cl2 was stirred at room temperature overnight. The reaction mixture was quenched with 1M HCl(aq) and the crude material was extracted with CH2Cl2. The crude material was purified with flash chromatography using EtOAc/heptane, 3:7, as eluent to afford 17 mg of analytically pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:29])[N:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: O=C(O)c1csc(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(Br)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate (1.04 g, 5.00 mmol) and 2-bromothiazole-4-carboxylic acid (1.46 g, 5.00 mmol) in Methylene chloride (10 mL, 200 mmol) was added N,N-Diisopropylethylamine (3.48 mL, 20.0 mmol) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (2.28 g, 6.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was purified on silica eluting with 0 to 5% MeOH in DCM with 1% NH4OH (2.41 g, 99.9%). ESIMS m/z=484.1 (M+1).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:29]2[CH2:34][C:33](=[O:35])[O:32][C:31](=[O:36])[CH2:30]2)[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:37][OH:38]>>[CH3:37][O:38][C:33](=[O:35])[CH2:34][N:29]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)[CH2:30][C:31]([OH:36])=[O:32]
Reactant: CO
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N2CC(=O)OC(=O)C2)c1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)OC)c1
Reaction time: 17 h

Procedure:
A solution of 0.469 g of 4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione in 50 ml of methanol was warmed to 50° and then was left at room temperature for 17 hours. The solvent was removed at reduced pressure to give 0.44 g, mp 61°-62° of pure N-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy )phenyl]glycine.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][C:10]2(C)C)(C)(C)C.[O:17]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=O)[CH2:18]1.[O:25]1CCC(C(O)=O)C1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.CCOCC>[O:25]=[SH:13]1([CH2:22][CH:19]2[CH2:20][CH2:21][O:17][CH2:18]2)[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: O=C(Cl)C1CCOC1
Reactant: CC(C)(C)c1cccc2c1SCCC2(C)C
Reactant: O=C(O)C1CCOC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=[SH]1(CC2CCOC2)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 600 mg (2.56 mmol) of 8-tert-butyl-4,4-dimethyl-thiochromane and 0.38 g (2.84 mmol) of (+/-) tetrahydro-3-furoic acid chloride [which is prepared by reacting 1.5 g (12.9 mmol) (+/-) tetrahydro-3-furoic acid with 1.38 mL (15.5 mmol) oxalyl chloride in 40 mL benzene at 50° C. for 1 hour followed by concentration of the volatiles under reduced pressure] in 10 mL benzene at 0° C. is added 0.32 mL (2.73 mmol) tin tetrachloride. The reaction is allowed to stir 1 hour at 0° C. and is then diluted with ether and washed with water and sodium chloride. The product is purified by flash silica gel chromatography, eluting with 7:3 hexane:ethyl acetate to give 257 mg of 8-tert-butyl-4,4-dimethyl-6-(1-oxo-1-(3-tetrahydrofuryl)methylthiochromane.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14].[NH2:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:21][N:20]=1.O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:19]([NH:18][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[O:15])[NH:20][N:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)[nH]n1
Yield: 59.1 %

Procedure:
A solution of 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (0.400 g, 1.19 mmol) and 3-amino-5-t-butylpyrazole (0.165 g, 1.19 mmol) in DMF (1 mL) was stirred at 80° C. overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (230 mg, 59% yield) as a pink foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=6.8 Hz, 1H), 7.20-7.14 (m, 2H), 5.85 (brs, 1H), 1.34 (s, 9H), amine and urea protons not visible; MS (EI) m/z: 327.0 (M+H+).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]2(CNC(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.C([N:30](CC)CC)C.[NH2:35][C:36]1[C:45]([F:46])=[C:44](F)[C:43](C)=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52].CS(C)=O>CO.[C].[Pd]>[NH2:35][C:36]1[C:45]([F:46])=[C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3([NH2:30])[CH2:17][CH2:18]3)[CH2:12]2)[C:43]([CH3:44])=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52]
Reactant: CC(C)(C)OC(=O)NCC1([C@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CCN(CC)CC
Agent: [Pd]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1c(N2CC[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 150 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A 649 mg (1.8 mmol) portion of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminomethylcyclopropyl)pyrrolidine was dissolved in 20 ml of methanol to which was subsequently added 200 mg of 5% (v/v) palladium-carbon to carry out 2 hours of hydrogenation under normal pressure with warming by an infrared lamp. After completion of the reaction, 5% (v/v) palladium-carbon was removed by filtration and methanol was evaporated. The resulting residue was dissolved in 20 ml of dimethyl sulfoxide to which were subsequently added 2 ml of triethylamine and 312 mg (1 mmol) of 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, followed by 18 hours of stirring at 150° C. After completion of the reaction, dimethyl sulfoxide was evaporated, and the resulting residue was mixed with 100 ml of chloroform and washed with 10% citric acid (100 ml×1) and saturated brine (100 ml×1) in that order. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. A 10 ml portion of concentrated hydrochloric acid was added dropwise to the resulting residue under ice cooling, followed by 1 hour of stirring at room temperature. After completion of the reaction, the reaction solution was washed with dichloromethane (20 ml×1). The aqueous layer was adjusted to pH 12 with sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting residue was subjected to a silica gel thin layer chromatography, and the silica gel collected after development by the lower layer of a mixture solvent system of chloroform:methanol:water=7:3:1 was extracted with the same solvent. Thereafter, the thus obtained crude product was recrystallized from chloroform-isopropyl ether to afford 101.5 mg (24%) of the title compound.
Reaction SMILES: [N:1]([C@@:4]1([OH:20])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[CH2:21]([O:23][P:24](O[CH2:30][CH3:31])([O:26]CC)=[O:25])C.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O>[CH2:19]([NH+:11]([CH2:6][CH3:5])[CH2:12][CH3:21])[CH3:17].[P:24]([O:10][CH2:9][C@H:8]1[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5][C@:4]1([N:1]=[N+:2]=[N-:3])[OH:20])([O-:26])([O-:25])=[O:23].[CH2:6]([NH+:11]([CH2:30][CH3:31])[CH2:19][CH3:17])[CH3:5]
Reactant: CCOP(=O)(OCC)OCC
Reactant: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC[NH+](CC)CC
Product: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](COP(=O)([O-])[O-])O2)c(=O)[nH]c1=O
Temperature: 2 °C
Yield: 40 %

Procedure:
A mixture of 100 mg of 3′-azido-thymidine (0.37 mmol) and 0.5 ml triethylphosphate was gradually added to a mixture of 1 ml triethylphosphate and 100 μl phosphorus oxychloride (1.0 mmol) at 0° C. The mixture was maintained at 0-4° C. for 16 h under stirring. Then 10 ml of ice-cold 5% NaHCO3 in water was added and after stirring at 0° C. for 1 hour, the pH was adjusted to 7.0 with NaOH 1M. After further 12 h under stirring, the mixture was extract with 3×10 ml of diethyl ether to remove triethylphosphate. The water solution was subjected to volume reduction (1 ml) and loaded onto a DEAE-cellulose column. The column was eluted with a linear gradient (0.05-0.4 M) of triethylammonium bicarbonate, pH 7.5. Appropriate fractions were evaporated under vacuum. Methanol was added and evaporated again to remove triethylammonium bicarbonate obtaining 3′-azidothymidine-5′-monophosphate triethylammonium salt as white solid (90 mg, 0.15 mmol, yield=40%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.O>S1(CCCC1)(=O)=O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][NH:27][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:2]=2[I:1])[CH:26]=[CH:25][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(I)c(OCC2CO2)c1
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccc(I)c(OCC(O)CNCCc2ccc(OC)c(OC)c2)c1
Yield: 89.8 %

Procedure:
A solution of 5.0 g (0.016 mole) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane, the product of Example 5b. and 3.25 g (0.0179 mole) of homoveratrylamine in 10 ml of sulfolane was heated at 60°-70° C. for 18 hr. Water was added and the precipitate which formed was collected by filtration. It was recrystallized from acetonitrile to give 7.0 g (87% yield) of crystalline 1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-(2-iodo-5-methoxyphenoxy)-2-propanol, mp 83°-88° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1cc(C2CCCC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCCC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.6 g), palladium (II) acetate (225 mg), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (933 mg), tripotassium phosphate (6.4 g) and cyclopentylboronic acid (2 g) were added toluene (30 mL) and water (1.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(5-cyclopentyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). 4-(5-Cyclopentyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in chloroform (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH3:23][I:24]>C(#N)C>[I-:24].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:16]3[CH:17]=[CH:18][N+:19]([CH3:23])=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: Brc1ccc2c(c1)C(c1ccncc1)=Cc1ccccc1O2
Reactant: CI
Solvent: CC#N
Product: C[n+]1ccc(C2=Cc3ccccc3Oc3ccc(Br)cc32)cc1
Product: [I-]

Procedure:
A mixture of 4-(8-bromodibenz[b,f]oxepin-10-yl)pyridine (2.0 g) in acetonitrile (30 ml) containing methyl iodide (1.1 ml) was stirred under reflux in an argon atmosphere for ninety minutes. During this time the starting material gradually dissolved and a yellow solid began to precipitate from solution. The mixture was cooled to -10° and the solids were collected by filtration and were washed in turn with cold acetonitrile and ether to give 2.7 g of 4-(8-bromo-dibenz[b,f]oxepin-10-yl)-1-methylpyridinium iodide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6])[CH3:2].S(Cl)(Cl)=O.CN(C)C=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1(O)CCOCC1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)C1=CCOCC1
Temperature: 100 °C
Yield: 98.6 %

Procedure:
Step B To a solution of 2-(4-hydroxy-tetrahydro-pyran-4-yl)-2-methyl-propionic acid ethyl ester (19.5 g, 90 mmol) in chloroform (100 mL) was added thionyl chloride (13.3 mL, 180 mmol) and dimethylformamide (0.28 mL). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH solution (10 N) to adjust the “pH” of the mixture to basic. The mixture was then extracted with ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionic acid ethyl ester as a brown oil (17.6 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13]P(=O)(OCC)OCC.[H-].[Na+].[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32]([CH:33]=O)=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.O>O1CCCC1>[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32](/[CH:33]=[CH:13]/[C:3]2[N:4]=[C:5]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[S:6][C:2]=2[CH3:1])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1
Reactant: CCOP(=O)(Cc1nc(N2CCCCC2)sc1C)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCCCC2)sc1C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To a solution of diethyl {[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methyl}phosphonate (1.26 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.17 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.88 g) was added to the reaction mixture, and the mixture was heated under reflux for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give 1-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)piperidine as a yellow oil (0.69 g, yield 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13][CH2:14][NH:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:8][CH2:7][C:6]=2[CH:29]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:21]=3)[CH2:8][CH2:7][C:6]=2[CH:29]=1
Reactant: [H][H]
Reactant: Fc1ccc2c(c1)CC[C@H](CN(CCNc1ncccn1)Cc1ccccc1)O2
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2c(c1)CC[C@H](CNCCNc1ncccn1)O2
Yield: 54.1 %

Procedure:
A mixture of 8.4 g of (-)-(R)-N-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl) methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,2-ethanediamine and 150 ml methanol was hydrogenated in the presence of 2 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.5 g (55.1%) of (-)-(R)-N-[(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)methyl]-N'-(2-pyrimidinyl)-1,2-ethanediamine; mp. 103.2° C. [α]D 20 =-76.58° (conc.=1% in CH3OH) (comp. 46).