Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][OH:11].[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]1([CH2:15][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH2:9][CH2:10][OH:11])[CH2:14][CH2:13]1
Reactant: OCCOc1ccccc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCOc1ccccc1OCC1CC1
Yield: 114.5 %

Procedure:
2-Hydroxy-1-(2-hydroxyethyloxy)benzene (4 g, 26.0 mmol), cyclopropylmethyl-bromide (5.0 g, 37.0 mmol), and potassium carbonate (5.0 g, 36.2 mmol) were combined in acetone (80 mL) and the mixture was refluxed for 18 hours. The mixture was cooled and filtered. The filtrate was evaporated and the residue was dissolved in ether. The solution was washed with water 2N sodium hydroxide, and then brine, and dried over magnesium sulfate. Evaporation gave 2-cyclopropylmethyloxy-1-(2-hydroxyethyloxy)benzene (6.2 g) as an oil.
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([CH3:33])[C@H:8]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:31]#[N:32])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:31]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=2)[C:22]([OH:23])=[C:13]([C:11]([NH:10][C@H:8]([CH3:9])[C@H:7]([CH3:33])[C:6]([OH:34])=[O:5])=[O:12])[N:14]=1)#[N:32]
Reactant: C[C@H](C(=O)OC(C)(C)C)[C@@H](C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](C(=O)O)[C@@H](C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of (2S,3R)-3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-methyl-butyric acid tert-butyl ester (32 mg, 0.069 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (2 mL) at 0° C., and the mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a pale pink solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=N[N:5]([CH3:11])[C:6]=1[N:7]=[S:8]([CH3:10])[CH3:9].NC1N(C)N=C[C:14]=1[Br:19].N1C=CC=CC=1.ClS(C1N=C2N(C(OCC)=NC(F)=C2)N=1)(=O)=O>ClCCl>[Br:19][C:14]1[CH:3]=[CH:2][C:6]([N:7]=[S:8]([CH3:10])[CH3:9])=[N:5][CH:11]=1
Reactant: Cn1ncc(Br)c1N=S(C)C
Reactant: Cn1ncc(Br)c1N
Agent: CCOc1nc(F)cc2nc(S(=O)(=O)Cl)nn12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(C)=Nc1ccc(Br)cn1
Temperature: -10 °C
Yield: 428.9 %

Procedure:
A mixture containing about 53 mmol of N-(4-bromo-1-methyl-5-pyrazolyl)-S,S-dimethylsulfilimine in about 28 mL of dichloromethane solution prepared in Example 7 omitting the recovery step was cooled to -10° C. and 1.0 g (5.7 mmol) of 5-amino-4-bromo-1-methylpyrazole, 0.54 g (6.8 mmol) of pyridine, 11.8 mmol of 2-chlorosulfonyl-5-ethoxy-7-fluoro[1,2,4]triazolo[1,5-c]pyrimidine, and 5 mL of dichloromethane were added sequentially with stirring and cooling at about -10° C. The mixture was allowed to stir at ambient temperature for 2 days. The solids present were recovered by filtration, washed with a small amount of 2-propanol, and dried to obtain 5.7 g of the title compound as a white solid. A purer sample amounting to 4.6 g (26 percent of theory) was obtained dissolving this in dimethyl sulfoxide and then adding water to reprecipitate it.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:50][CH3:51])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1B(O)O>[Pd].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.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.COCCOC>[Cl:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[C:31]1[N:32]=[C:33]([CH2:50][CH3:51])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Reactant: Cc1ccc(B(O)O)c(Cl)c1
Agent: [Pd]
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(C)cc2Cl)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether, 2-chloro-4-methyl phenyl boronic acid and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.37-7.13, 6.99-6.90, 5.37, 4.64, 4.31, 2.69, 2.54, 2.40, 2.30, 1.29-1.17; HRMS (FAB) calcd for C24H26ClN3O+H 408.1842, found 408.1848. Anal. Calcd for C24H26ClN3O: C, 70.66; H, 6.42; N, 10.30. Found: C, 70.93; H, 6.78; N, 10.01.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL of methylene chloride at 0° C. was treated with oxalyl chloride (0.44 mL, 4.9 mmol) followed by 2 drops of dimethylformamide. The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride. To a solution of 4-trifluoromethylthiazol-2-ylamine (0.50 g, 3.0 mmol) in 10 mL THF at 0° C. was added a solution of the freshly prepared acid chloride in 5 mL of THF and 2 mL of methylene chloride, followed by triethylamine (1.0 mL, 6.6 mmol). The reaction mixture was warmed to 65° C. and stirred 8 hours. The mixture was diluted with ethyl acetate and washed twice with water, then brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 30-50% ethyl acetate/hexanes gradient) afforded 0.47 g (50%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.66 (t, J=6.95 Hz, 3H), 4.38 (q, J=6.89 Hz, 2H), 7.03-7.10 (m, 2H), 7.17 (d, J=7.80 Hz, 1H), 7.42 (s, 1H), 8.29 (dd, J=7.97, 1.86 Hz, 1H). MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][CH2:14][OH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCBr
Reactant: OCCc1ccccc1
Product: BrCCCCOCCc1ccccc1

Procedure:
(2.85 g), T.l.c. [K] Rf 0.41, from 1,4-dibromobutane (10.6 g) and benzeneethanol (2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1cc(Cl)c(Br)cn1
Reaction time: 14 h
Yield: 100.7 %

Procedure:
To a stirred solution of 4-chloropyridin-2-amine (8 g, 62.2 mmol) in acetonitrile (600 mL) at rt was added NBS (11.08 g, 62.2 mmol) in portions and the reaction was stirred for 14 h. The reaction mixture was concentrated under reduced pressure. The residue was reconstituted in ethyl acetate and water. The organics were extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over sodium sulphate. The organics were concentrated under reduced pressure to afford 5-bromo-4-chloropyridin-2-amine as yellow solid (13 g, 99% yield) that was used without further purification in the next step. LCMS (ESI) m/e 207.0 [(M+H)+, calcd for C5H5BrClN2 206.9]; LC/MS retention time (method B): tR=0.8 min; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 6.63 (s, 1H), 4.59 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl>CN(C)C=O>[C:1]([N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])[C:5]#[N:6])(=[O:3])[CH3:2]
Reactant: ClCCCCCCCl
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)N(C#N)CCCCCCN(C#N)C(C)=O

Procedure:
106.1 g (1.0 mol) of sodium acetylcyanamide and 77.5 g (0.5 mol) of 1,6-dichlorohexane are reacted in 750 ml of dimethylformamide at 146°-147° C. for 8 hours, the mixture is then filtered with suction and the filtrate is concentrated on a rotary evaporator at 80° C. in vacuo. 125 g (99.9% of theory) of a crude product, which is recrystallised from a mixture of acetone/diisopropyl ether (3:5), are obtained. The yield of pure substance is 58.8 g (46.9% of theory) and the product has a melting point of 59°-61° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[C:11]1([CH2:17][C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>>[C:18]([CH:17]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:19]
Reactant: N#CCc1ccccc1
Reactant: COC(=O)/C=C\C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C#N)c1ccccc1
Yield: 87.9 %

Procedure:
Into a 200 ml, one-neck flask is placed 35 grams of sodium methyl maleate (0.23 moles), 85 grams (0.73 moles) of phenyl acetonitrile and 80 g (1.1 moles) dimethyl formamide. The reaction mixture is heated to 135°-140° C. for five hours and then distilled in vacuo. The residue is extracted three times with 300 ml ether. The solid (56 grams) is then dissolved in water and acidified with 23 grams conc. HCl in 50 mls water. The liquid that separates out is dissolved in ether and washed with water to remove unreacted starting materials. The ether is distilled off to give a residue of 50 grams of product (yield: 88°). The structure is verified by NMR (in CDCl3): ##STR39## CH2 (a) ABX multiplet at 2.50-3.00δ CH(b) multiplet, 3.30-3.56δ
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>CN(C=O)C>[CH3:34][S:35]([N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:37])=[O:36]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3ccn4S(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (80 mg) in DMF (0.80 ml) was added 60% NaH (8.7 mg) at 0° C., followed by stirring at room temperature for 0.5 hour. Methanesulfonyl chloride (21.1 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 98:2) to obtain 1-(methylsulfonyl)-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (15.6 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:19][CH:16]([CH:17]=[CH2:18])[CH:4]([CH:5]([O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])[CH2:6][CH:7]=[N:8][OH:9])[O:3]1.C(N(CC)CC)C.Cl[O-].[Na+]>C(Cl)Cl.C(OCC)C>[CH3:20][C:2]1([CH3:1])[O:3][CH:4]2[CH:5]([O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])[CH2:6][C:7]3[CH:17]([CH2:18][O:9][N:8]=3)[CH:16]2[O:19]1
Reactant: C=CC1OC(C)(C)OC1C(CC=NO)OC(C)OCC
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)OC1CC2=NOCC2C2OC(C)(C)OC12
Temperature: 0 °C
Reaction time: 11 h
Yield: 53.4 %

Procedure:
One gram of 4,5- (dimethylmethylenedioxy) -3-(1-ethoxyethoxy)-6-heptenal oxime was dissolved in 15 ml of methylene chloride, and 0.2 ml of triethylamine was added at 0° C. Then, 8 ml of a 10% sodium hypochlorite aqueous solution was added, and the mixture was stirred at 0° C. for 11 hours. The reaction mixture was diluted with ethyl ether, and washed with a sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 530 mg of 4,5-(dimethylmethylenedioxy)-6-(1-ethoxyethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following properties.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:15].C(N)CN.S1(CCCC1)(=O)=O>[Cu]I.CCCCCC>[I:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: NCCN
Solvent: O=S1(=O)CCCC1
Solvent: CCCCCC
Product: Ic1ccc(-c2ccccc2)cc1
Temperature: 130 °C
Reaction time: 23 h
Yield: 93.5 %

Procedure:
A Schlenk tube was charged with CuI (19.5 mg, 0.102 mmol, 10 mol %), 4-bromobiphenyl (234 mg, 1.00 mmol), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. Ethylenediamine (13.5 μL, 0.202 mmol, 20 mol %) and sulfolane (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 23 h. The resulting suspension was allowed to reach room temperature, poured into hexane (20 mL) and washed with water (3×20 mL). The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by flash chromatography on silica gel (hexane) to provide 262 mg (94% yield) of 4-iodobiphenyl as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:11][C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH2:11][C:12]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1(CO)CCC1
Reactant: Cc1cc(O)ncc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(COc2cc(C)c(Br)cn2)CCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
In tetrahydrofuran (11 mL) were dissolved 5-bromo-4-methylpyridin-2-ol (639 mg), ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (538 mg) and triphenylphosphine (1.07 g), 40% diethyl azodicarboxylate-toluene solution (1.86 mL) was added dropwise to the solution at room temperature, and then, the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (638 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(Cl)c(Cl)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 16.8 %

Procedure:
To a solution of 1-(3,4-dichlorophenyl)-2-phenylethanone (Intermediate 19) (100 mg, 0.38 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (74.4 mg, 0.38 mmol), and urea (68.5 mg, 1.14 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 47 (32 mg, yield 17.0%). 1H NMR (DMSO-d6 300 MHz) δ 10.28 (s, 1H), 8.85 (s, 1H), 7.58 (s, 1H), 7.48 (t, J=7.5 Hz, 2H), 7.41 (d, J=1.8 Hz, 1H), 7.13-7.05 (m, 5H), 6.88 (t, J=1.8 Hz, 2H), 5.25 (d, J=2.7 Hz, 1H), 4.02 (m, 2H), 1.32 (t, J=6.9 Hz, 3H); MS (ESI): m/z 499.9 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32].N>CO.C(Cl)Cl.C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[NH:32])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCn1c(-c2ccc([N+](=O)[O-])cc2)cc2cc(N)ccc21
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CN1CCCC1CCn1c(-c2ccc([N+](=O)[O-])cc2)cc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 24 h
Yield: 27.8 %

Procedure:
Compound 20 (97 mg, 0.266 mmol) and anhydrous ethanol (10 mL) were charged to a dry argon purged flask fitted with magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (98.7 mg, 0.346 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 46 hours at which time, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 (developed twice) shows incomplete consumption of 20. A condenser was added and the mixture heated to reflux for 5 hours. An additional amount of the thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.2 eq) was added and stirring continued at 65° C. for an additional 24 hours. A further portion of thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.2 eq) and ethanol (10 mL) were added and stirring continued for an additional 72 hours at reflux. Thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 (developed twice) shows incomplete consumption of 20. A further portion of thiophene-2-carboximidothioic acid methyl ester hydroiodide (1.0 eq) was added and the mixture heated to reflux for 6 hours then stirred at ambient temperature for 48 hours. The mixture was filtered through a sintered glass funnel to remove insolubles, the filtrate concentrated and the residue purified using dry silica gel column chromatography eluting with 30 mL portions of solvent system (2M NH3 in methanol:CH2Cl2, 5:95) to afford an orange oil 21 (35 mg, 27.8%); 1H NMR (DMSO-d6) δ 8.36 (d, 2H, J=8.6 Hz), 8.18 (s, 1H), 7.86 (d, 2H, J=8.8 Hz), 7.75 (d, 1H, J=3.2 Hz), 7.61 (d, 1H, J=5.3 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.14-7.05 (2×m, 2H), 6.85-6.80 (m, 1H), 6.69 (s, 1H), 4.29 (m, 2H), 2.91-2.84 (m, 1H), 2.08 and 2.06 (2×s, 3H), 2.03-1.93 (m, 1H), 1.90-1.78 (m, 1H), 1.72-1.63 (m, 1H), 1.61-1.43 (m, 3H), 1.37-1.20 (m, 2H); ESI-MS (m/z, %): 474 (M+1, 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][NH:41][CH3:42]>C1COCC1>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][N:41]([CH3:42])[CH3:40])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN(C)C)c2)cc1
Temperature: 70 °C

Procedure:
The product from Example 72D in anhydrous THF (1 mL) was treated with 2.0 M dimethylamine (1.0 mL, 1.97 mmoles) in THF and heated to 70° C. overnight. Reaction mixture concentrated under reduced pressure and the residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (m, 11 H), 6.86 (d, 2 H), 6.72 (s, 1 H), 6.50-6.70 (m, 2 H), 6.32 (t, 1 H), 4.39 (s, 2 H), 4.35 (s, 2 H), 3.98 (t, 2 H), 3.30 (m, 2 H), 2.91 (s, 3 H), 2.90 (s, 3 H), 2.83 (s, 3 H), 2.25 (m, 2 H), 2.13 (s, 3 H); MS (ESI+) m/z 574 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][NH:22][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)([CH3:21])[CH3:20])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNC(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzoyl chloride (0.2 g) in dichloromethane (3 ml) was added dropwise to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.4 g) in dichloromethane (7 ml) with stirring at 0° C. The mixture was treated in a similar manner to Example 55 to give N-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)-ethyl]benzamide as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.COC(OC)(C)C.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:13][C@H:12]1[O:14][C@@H:7]([N:6]2[C:5](=[O:16])[N:4]=[C:3]([NH2:17])[C:2]([F:1])=[CH:15]2)[C@@H:8]2[O:9][C:19]([CH3:24])([CH3:20])[O:11][C@H:10]12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)OC
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 5'-deoxy-5-fluorocytidine (490 mg), p-toluenesulfonic acid monohydrate (418 mg) and 2,2-dimethoxypropane (984 μl) in acetone (10 ml) was stirred for 1.5 hour at room temperature. To the solution was added sodium hydrogen carbonate (900 mg) and the mixture was stirred for 4 hours at room temperature. The precipitate was filtered off and washed with acetone. The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 5'-deoxy-5-fluoro-2',3'-O-isopropylidenecytidine (570 mg). MS 286 (MH+); mp of the picrate 169°~171° C.