Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[I-:37].[Na+].CNCCNC>O1CCOCC1.C(OCC)(=O)C.[Cu](I)I>[I:37][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1
Reactant: [I-]
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(I)ccc32)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
To a solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (1.18 g, 2.08 mmol), copper iodide (I) (79 mg, 0.416 mmol) and sodium iodide (624 mg, 4.16 mmol) in dioxane (4.2 mL), N,N′-dimethylethylene diamine (89 μL, 0.832 mmol) was added at room temperature. The reaction solution was stirred for 5 hours under heating at 110° C. The temperature of the solution was brought to room temperature, and the solution was diluted with ethyl acetate, which was washed sequentially with a saturated aqueous ammonium chloride solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting solid was washed with hexane and ethyl acetate, whereby the objective compound (995 mg, 78%) was obtained as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[CH:54][N:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]2[CH:61]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=2)=[CH:54][N:53]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ncc(-c2cccc(N)c2)c(OC)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: CN(C)C=O
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c(OC)n1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,4-dimethoxy-pyrimidin-5-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.019 g of product in 69% yield: LCMS (ESI) m/z 434 (MH+).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:12]C)([CH2:10][CH3:11])([CH3:9])[CH3:8]>>[C:7]([O:12][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:10][CH3:11])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OO
Reactant: CCC(C)(C)OC
Product: CCC(C)(C)OOC(C)(C)C

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:36][C:33]2[CH:34]=[CH:35][C:30]([S:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:38])([F:18])[F:37])[CH:21]=3)(=[O:29])=[O:28])=[CH:31][CH:32]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)Nc2cccc(C(F)(F)F)c2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2cccc(C(F)(F)F)c2)cc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-(3-trifluoromethylphenyl)-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.2 (d, 1H), 10.9 (s, 1H), 10.7 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.5 (m, 4H), 7.1 (d, 1H); APCI−MS m/z 515 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.C([Sn](CCCC)(CCCC)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Clc1ncnc2ccc(Br)cc12
Solvent: Cc1ccccc1
Product: Brc1ccc2ncnc(-c3cccs3)c2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
0.6 g 6-bromo-4-chloroquinazoline was dissolved in 18 mL toluene, and 0.82 mL tri-n-butyl(2-thienyl)stannane and 0.14 g tetrakis (triphenylphosphine)palladium (0) were added thereto and stirred at 80° C. for 24 hours under nitrogen atmosphere. After the solvent was evaporated, the residue was purified by silica gel chromatography (hexane/ethyl acetate), to give 0.29 g of the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: Cc1cnc(Br)c([N+](=O)[O-])c1
Product: Cc1cnc(C#N)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A round bottom flask was charged with 2-bromo-5-methyl-3-nitropyridine (60.53 g, 278.9 mmol) and CuCN (27.52 g, 307.3 mmol) The flask was evacuated, and back-filled with nitrogen. DMF (150 mL) was added via cannula. The solution was heated to 70° C. for 1.5 h. After cooling to room temperature, the reaction mixture was poured into EtOAc (500 mL) and water (250 mL). Both phases were filtered through a 1 cm bed of celite. The layers were separated, and the organic phase washed with water (2×100 mL) then with a solution of 1:1 sat. aq. NH4Cl/NH4OH (2×100 mL). The combined aqueous layers were extracted with EtOAc (2×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (36.10 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C2=[C:6]([CH:20]=1)CN(C)CC=C2C1C=CC(F)=CC=1.C(=O)([O-])[O-].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][NH:27][C:6]=2[CH:20]=1
Reactant: c1ccncc1
Reactant: CN1CC=C(c2ccc(F)cc2)c2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc2c(c1)NCCCC2
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of the dihydrobenzazepine (2.43 g, 7.31 mmol) from step F above in pyridine (50 mL) were added potassium carbonate (8.08 g, 58.5 mmol) and p-toluenesulfonylhydrazide (5.45 g, 29.3 mmol) in batches. The reaction solution was heated under reflux for 48 h and then cooled to room temperature. The resultant reaction mixture was filtered through Celite. The Celite bed was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue dissolved in ethyl acetate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (3 to 5% methanol/dichloromethane) to give the desired 8-bromotetrahydrobenzazepine (1.74 g, 71%): 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=2.1 Hz, 1H), 7.20-7.16 (m, 1H), 7.13-7.10 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.49 (br, 1H), 4.24 (d, J=9.3 Hz, 1H), 3.88 (d, J=12.2 Hz, 1H), 3.67 (d, J=14.3 Hz, 1H), 3.12-3.09 (m, 1H), 2.98-2.93 (m, 1H), 2.34 (s, 3H), 2.30-2.23 (m, 1H), 2.08-2.04 (m, 1H); ESI MS m/z 334, 336 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]=1.N1CCCC[CH2:16]1.C(O)(=O)C.C=O>CO>[CH2:16]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:14]
Reactant: C1CCNCC1
Reactant: CCCCCCC(=O)c1cccnc1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: C=C(CCCCC)C(=O)c1cccnc1
Yield: 95 %

Procedure:
To 1 g (5.2 mmol) of compound 3, dissolved in 10 ml of MeOH, was added 0.1 ml of piperidine, 0.1 ml of acetic acid and 3 ml of an aqueous formaldehyde solution (37% formaldehyde in water). The mixture was heated to reflux for 48 hour. The mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a 5% NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to give compound 4 as an oil (1.05 g, 95%). 1H-NMR (200 MHz, CDCl3): δ 8.94 (d, J=2 Hz, 1H), 8.76 (d, J=5 Hz, 2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.35 (m, 1H), 5.94 (s, 1H), 5.64 (s, 1H), 2.48 (bt, J=7 Hz, 2H), 1.60-1.25 (m, 6H), 0.99-0.82 (m, 3H).
Reaction SMILES: Cl.[CH:2]1[C:13]2[C:12](=CCCN3CCCC(C(O)=O)C3)[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.ICI.C(=O)([O-])[O-:34].[K+].[K+]>CN(C)C=O>[CH2:2]1[C:13]2[CH2:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]1=[O:34]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCCN(CCC=C2c3ccccc3OCOc3ccccc32)C1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Product: O=C1C=CC2=C(C1)Cc1ccccc1OCO2
Temperature: 105 °C
Yield: 89.1 %

Procedure:
1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid hydrochloride ##STR4## 2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1 g, 49 mmol) was dissolved in dry dimethylformamide (180 ml). Dried, finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added, and the mixture was heated at 105 ° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate was collected by filtration after 0.5 h, washed with water on the filter and dissolved in a mixture of ethanol (80 ml) and 4 N sodium hydroxide (20 ml). The solution was stirred at reflux temperature for 1 h, cooled and diluted with water (300 ml). The formed crystalline precipitate was filtered off, washed with water (50 ml) and dried in vacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-2-one as a solid (9.5 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([F:18])[CH:20]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COc1ccc(CN)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1F
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a suspension of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.11 g, 0.39 mmol) and 3-fluoro-4-methoxy-benzylamine hydrochloride (75 mg, 0.39 mmol) in tetrahydrofuran (5 mL) is added triethylamine (0.13 mL, 0.98 mmol). After 15 minutes of stirring, the solvent is evaporated under reduced pressure. The solid material is collected by Buchner filtration, washed successively with diethyl ether, water, and methanol, and then dried under house vacuum to give (4Z)-6-bromo-4-{[(3-fluoro-4-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione as an off-white solid (0.11 g, 69%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH3:22])[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:27]>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH:20]([OH:27])[N:19]([CH3:22])[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Solvent: ClCCl
Product: CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
12.56 g of 5-{[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene}-3-methyl-4-thiazolidinone, 1-oxide (the compound of Example 12) was dissolved in 216 ml of methylene chloride and the resultant solution cooled to -78° C. Separately, 6.1 ml of trifluoroacetic anhydride and 72 ml of methylene chloride were placed in a dropping funnel and the solution added dropwise over a 40-minute period (temperature maintained at or below -70° C.) to the previously prepared solution of the compound of Example 12 in methylene chloride. The resulting reaction mixture was stirred at -75° C. for 1 hour, then warmed to 0° C. over 45 minutes, diluted with a volume of methylene chloride, washed with two volumes of water, dried over sodium sulfate and subsequently filtered and evaporated to give 15.8 g of the desired titled product and trace impurities. This product was dissolved in 25 ml of warm ethyl acetate and then added to 450 ml of hexane. As the solution cooled, it became milky and an additional 5 ml of ethyl acetate was added and swirled to clarify. The solution was then allowed to cool to room temperature with precipitate forming overnight. The precipitate was collected by filtration, washed with hexane and dried at room temperature in vacuo overnight. The resultant product was further worked up by adding it to 30 ml of hot ethyl acetate, to which was added an additional 150 ml of hexane. A precipitate began to form. The mixture was allowed to cool to room temperature and stand for 6 hours, after which it was filtered, washed with a volume of hexane and dried in vacuo at 50° C. overnight to render 8.83 g of the desired titled product, m.p. 165°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:6]([N+:19]([O-])=O)[CH:5]=1)([O-])=O.[H][H].CCOCC>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:6]([NH2:19])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(CCc2ccc(N)cc2N)cc1

Procedure:
1.4 g of 1,3-dinitro-4-[2-(4-methylphenyl)ethenyl]benzene prepared as described by S. Saravanan and P. Srinivasan, Synth. Commun. 31(6), pages 823-826 (2001) was dissolved in 50 mL of ethanol and hydrogenated using 0.2 g of Pd/C 10% for 4 hours at 8 bar of hydrogen pressure. The catalyst was then filtered off, and the filtrate was evaporated to dryness. This gave a brownish oil which upon addition of 10 mL of ether crystallized. Yield: 1.1 g of yellowish oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:18][C:17]3([O:36][C:21]4=[CH:22][N:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH:31]=5)[CH:25]=[C:20]4[CH2:19]3)[CH2:16]2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:4]([C:3]1[N:7]=[C:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:18][C:17]4([O:36][C:21]5=[CH:22][N:23]=[C:24]([C:26]6[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH:27]=6)[CH:25]=[C:20]5[CH2:19]4)[CH2:16]3)[CH2:14][CH2:15]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Zinc chloride (0.7 mol/L in tetrahydrofuran, 0.42 mL) is added to a solution of N-hydroxy-isobutyramidine (30 mg) and 1″-cyano-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (100 mg) in tetrahydrofuran (4 mL) and ethyl acetate (4 mL) at room temperature. The solution is heated to 60° C. and stirred at this temperature for 2 h.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN3CCCC3)cc1)c1c-2ccc2ccccc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A 7 g portion of the compound of Example 1 was dissolved in 100 ml of dry dimethylformamide, and to it was added 1.05 g of 50% mineral oil dispersion of sodium hydride and 4 g of 1-(2-chloroethyl)pyrrolidine. The mixture was then stirred at 60° C. for 3 hours and cooled. It was then poured over 500 ml of ice and water, and the mixture was extracted 3 times with 250 ml portions of ethyl acetate. The organic extract was washed with two 50 ml portions of brine, dried and concentrated under vacuum. The residue was chromatographed over a 5 cm×50 cm silica gel column with 3:1 ethyl acetate:toluene, followed by ethyl acetate. The product-containing fractions were combined and concentrated under vacuum to contain 4.5 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][I:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[C:22](OC(C)=O)=[O:23].N1C=CC=C[CH:29]=1>>[CH3:19][C:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[N:12]([C@@H:7]2[O:8][C@:9]([C:10]#[CH:29])([CH2:22][OH:23])[CH:5]=[CH:6]2)[CH:20]=1.[C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][I:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Agent: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
TKD-4-114 (2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine, 4′-ethynyl-d4T) was synthesized by a series of reactions shown in Scheme B, starting from compound 6 which was prepared according to the published procedure: B. V. Joshi and C. B. Reese, Tetrahedron Lett., 32, 2371-2374 (1992).1-(3-O-Acetyl-2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)-thymine (7) A mixture of 6 (5.3 g, 15.05 mmol) and Ac2O (4.3 mL, 45.15 mmol) in pyridine (30 mL) was stirred at room temperature for 13 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (250 mL×3/50 mL). Silica gel column chromatography (hexane/EtOAc=1/1-1/2) of the organic layer gave 7 (5.53 g, 93%) as a foam: 1H NMR(CDCl3)δ 1.96 (3H, s, Me), 2.11 (3H, s, Ac), 2.11-2.16 (1H, m, H-2′a), 2.82 (1H, ddd, Jgem=15.8 Hz, J1′,2′b=8.0 Hz ansd J2′b,3′=5.7 Hz, H-2′b), 3.32-3.39 (2H, m, H-5′), 4.28 (1H, dt, J3′,4′=3.3 Hz and J4′,5′=7.1 Hz, H-4′), 5.48 (1H, dd, J2′b,3′=5.7 Hz and J3′,4′=3.3 Hz H-3′), 6.30 (1H, dd, J1′,2′a=2.8 Hz and J1′,2′b=8.0 Hz, H-1′), 7.38 (1H, d, J6,Me=0.7 Hz, H-6), 8.59 (1H, br, NH); FAB-MS m/z 395(M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product as a yellow solid 2-[4-(4-fluoro-phenyl) 2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (74.3 mg, 65%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:9][CH2:10][CH2:11][NH2:12].[CH3:13][N:14]=[C:15]=[S:16].C(OCC)(=O)C.C(O)C>C(O)C>[CH3:13][NH:14][C:15]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[N:4]=1)=[S:16]
Reactant: CN=C=S
Reactant: Cc1cn(C)c(CSCCN)n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=S)NCCSCc1nc(C)cn1C

Procedure:
The reaction of 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole (derived from the 6.2 g. dihydrobromide) with methyl isothiocyanate (1.34 g.) in ethanol (50 ml.) followed by chromatography on a column of silica gel with ethyl acetate-ethanol (9:1) as eluant gave N-methyl-N'-[2-((1,4-dimethyl-2-imidazolyl)methylthio)ethyl]thiourea (2.1 g.). (Found: C, 46.8; H, 6.9; N, 21.5; S, 24.9. C10H18N4S2 requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).