Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:5](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:15]
Reactant: CCNCC
Reactant: O=C(O)c1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of thionyl chloride (6 mL) and the benzoic acid was heated at reflux until the starting benzoic acid dissolved. Excess thionyl chloride was removed under reduced pressure leaving the crude acid chloride as a low melting solid which was used without further purification. The crude acid chloride was dissolved in CH2Cl2 (20 mL) and cooled to −10° C. To this stirred solution was added triethylamine (4 mL), followed by the dropwise addition of diethylamine (1.4 equivalents). The heterogeneous reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was transferred to a separatory funnel containing H2O (20 mL). The organic layer was separated and washed with 5% HCl (2×25 mL), H2O (25 ml), and dried over Na2SO4. The solvent was removed under reduced pressure to afford the product N,N-diethyl benzamide.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)propanamide (74 mg, 0.222 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (63 mg). MS 352.3 (M+H); UV 206.6, 223.0, 245.6, 295.3, 351.1 nm; t 0.360 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.CO[CH:12](OC)[CH2:13][CH:14](OC)OC>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[CH:14]=[CH:13][CH:12]=[N:9][C:4]=2[N:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: COC(CC(OC)OC)OC
Product: Nc1nc(Cl)c2cccnc2n1

Procedure:
Starting from 2,6-diamino-4-chloropyrimidine and 1,1,3,3-tetramethoxypropane and using a procedure analogous to that of Example 71, the above compound is isolated after chromatographic purification on silica gel with methanol/diisopropylether (1:1) as a yellow oil which can be used in the following reactions without any further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:22][C@H:23]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]>ClCCl>[NH:22]([C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[C@H:23]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
Phenylacetyl chloride (5.7 ml) was added dropwise to a mixture of TsOH.H-L-Leu-OBzl (14.15 g) and TEA (12 ml) in dichloromethane (300 ml) under ice-bath cooling. After being stirred for 10 minutes at the same temperature, the mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate (300 ml). The solution was washed with 1N HCl (100 ml), water (100 ml), 1M aqueous sodium bicarbonate (100 ml), and brine (100 ml×2), dried over magnesium sulfate and evaporated to give N-phenylacetyl-L-Leu-OBzl (14 g). This product was used in a next step without further purification.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:24]([OH:28])[CH:25]([OH:27])[CH3:26]>C(OC)(C)(C)C>[C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([O:28][CH2:24][CH:25]([OH:27])[CH3:26])=[O:12]
Reactant: CC(O)CO
Reactant: CC(C)(C)OOC(=O)c1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CC(O)COC(=O)c1ccccc1C(=O)OOC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A 300 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 100 mL of methyl t-butyl ether, 16.7 g (0.06 mole) of 91.3% of 2-(t-butylperoxycarbonyl)benzoyl chloride and 5.5 g (0.07 mole) of pyridine. To this vigorously stirred solution at 20° C. was added 22.8 g (0.30 mole) of 1,2-propanediol over a period of 20 minutes. During the addition there was a slight exotherm and a white precipitate formed. The reaction mass was warmed to 25° C. and stirred at 25° C. for 240 minutes. The precipitate was separated by filtration and the white solid was washed with about 25 mL of methyl t-butyl ether. The methyl t-butyl ether washings were combined with the filtrate and the filtrate was washed twice with 50 mL portions of 5% aqueous HCl solution, then twice with 50 mL portions of 3% aqueous NaHCO3 solution. The methyl t-butyl ether solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 17.4 g (98.3% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band at ca. 3500 cm-1 and two carbonyl bands at ca. 1720 cm-1 and 1770 cm-1. The product had a peroxyester Act[O] content of 5.02%. Based on a theoretical Act[O] of 5.40% for the desired title product, the assay was 93.0% and the corrected yield was 91.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(Nc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4-amino-4′-(trifluoromethoxy)biphenyl (compound of Example 3(2); 112 mg, 0.442 mmol), 4-(tert-butyl)phenylboronic acid (87 mg, 0.486 mmol), copper(II) acetate (40 mg, 0.221 mmol), triethylamine (0.061 ml, 0.884 mmol) and pyridine (3.0 ml) was stirred at 50° for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with 1N hydrochloric acid (10 ml), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (50 mg, 29%) as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([C:11]1([Br:21])[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]1N)(C)C.[CH2:22](ON=O)[CH2:23][CH:24](C)C.O[PH2]=O>CCO>[CH:23]([C:16]1[CH:15]=[CH:14][C:13]([CH:17]([CH3:18])[CH3:19])=[CH:12][C:11]=1[Br:21])([CH3:24])[CH3:22]
Reactant: CC(C)C1=CC=CC(Br)(C(C)C)C1N
Reactant: CC(C)CCON=O
Agent: O=[PH2]O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (75 mL was added to a solution of Intermediate 34 in EtOH (100 mL) at 0° C. After stirring for 10 min, iso-amylnitrite (100 mL) was then added and the mixture was stirred for another 70 min. H3PO2 (70 mL) was added slowly and the mixture was warmed to ambient temperature over 5 hours. After dilution with ethyl acetate and sodium bicarbonate solution, the organic layer was separated, dried and concentrated to give the title compound in a crude form (17 g). Purification of the crude product by Kugelrohr distillation gave the title compound in pure form (13 g, 44% yield over 4 steps from 1,3-di-iso-propyl-benzene) as a colorless oil:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:59][C:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:66][S:63]([C:60]6([CH3:59])[CH2:62][CH2:61]6)(=[O:65])=[O:64])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: CC1(S(N)(=O)=O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of carboxylic acid 46 (240 mg, 0.38 mmol) and carbonyldiimidazole (2 eq) in dry THF (5 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 eq) and DBU (2 eq) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 170 mg (58%) of the title compound 48 as an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven: m/z=764 (M+H)+. 1H NMR (acetone-d6): 0.86 (m, 2H), 1.15-1.78 (m, 19H), 1.87 (m, 2H), 2.13-2.54 (m, 3H), 2.57-2.71 (m, 4H), 2.96-3.25 (m, 4H), 3.54 (m, 2H), 4.02 (s, 3H), 4.58 (t, J=13 Hz, 1H), 5.04 (m, 1H), 5.46 (m, 1H), 5.62 (m, 1H), 7.31 (s, 1H), 7.43 (d, J=9 Hz, 1H), 7.58 (s, 1H), 8.07 (d, J=13 Hz, 1H), 8.19 (broad s, 1H), 11.44 (broad s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[OH:20])[C:10]=1[CH3:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[CH2:57]([CH:59]([CH2:62][CH3:63])[CH2:60]O)[CH3:58]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:60][CH:59]([CH2:62][CH3:63])[CH2:57][CH3:58])[C:10]=1[CH3:11])[CH3:2]
Reactant: CCC(CC)CO
Reactant: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2O)c1C
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2OCC(CC)CC)c1C
Reaction time: 0.33 h

Procedure:
A solution of [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acid ethyl ester, 2, (0.18 g g 0.51 mmol), triphenylphosphine (0.26 g, 1.02 mmol), di-tert-butylazodicarboxylate (0.23 g, 1.02 mmol) and 2-ethylbutan-1-ol (0.116 ml, 1.02 mmol) in a mixture of THF (1 mL) and toluene (2 ml) was at 120° C. on microwave for 20 min. The volatiles were removed in vacuo. The crude product was purified on silica to yield {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-acetic acid ethyl ester, 3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCn2ccc(-c3nc(C)c(C(=O)NCc4cccnc4)s3)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(2-bromo-ethyl)-4-methoxy-benzene as described in Example 49 and isolated as a white solid (0.030 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ 8.55-8.63 (bm, 2H), 7.72 (d, J=8 Hz, 1H), 7.28-7.33 (m, 1H), 7.15 (d, J=2 Hz, 1H), 6.97 (d, J=8 Hz, 2H), 6.80 (d, J=8 Hz, 2H), 6.72 (d, J=2 Hz, 1H), 6.12-6.19 (m, 1H), 4.64 (d, J=8 Hz, 2H), 4.33 (t, J=8 Hz, 2H), 3.77 (s, 3H), 3.12 (t, J=8 Hz, 3H), 2.76 (s, 3H); MS (M+H)+=433.9; Rt=1.25 min; HRMS (M+H)+=434.16.
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11](OP(C1C=CC=CC=1)(=O)O)([OH:14])(=[O:13])=[O:12].[Cl-].[Ba+2].[Cl-]>O>[S:11]([C:3]1[CH:2]=[C:1]([P:7](=[O:9])([OH:8])[OH:10])[CH:6]=[CH:5][CH:4]=1)([OH:14])(=[O:13])=[O:12]
Reactant: O=P(O)(O)c1ccccc1
Reactant: O=P(O)(OS(=O)(=O)O)c1ccccc1
Agent: [Ba+2]
Agent: [Cl-]
Solvent: O
Product: O=P(O)(O)c1cccc(S(=O)(=O)O)c1

Procedure:
20.2 g of phenylphosphonic acid and 8.56 g of sulfotrioxide were mechanically mixed at 180° C. for 24 hr to prepare nz-sulfophenylphosphonic acid. After diluting with excess water, the mixture was added with 15% barium chloride. The precipitate was removed by filtering and excess dimethylether was added to extract unreacted phenyl phosphonic acid and obtain a m-sulfophenylphosphonic acid solution.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][O:8][CH3:9].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([C:21](=[O:23])[CH3:22])[C:5](=[O:10])[CH2:6][CH2:7][O:8][CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCC(=O)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To an ice cooled solution of 5.28 g (32.96 mmol) 5-methoxy-3-oxo-pentanoic acid methyl ester and 3.14 g (32.96 mmol) anhydrous magnesium chloride in 50 ml dichloromethane was dropped within 3 min 5.3 ml (65.92 mmol) pyridine. 3.27 ml (34.61 mmol) of acetic anhydride was then added within 3 min. The reaction mixture was stirred over night at RT and after concentration under reduced pressure it was partitioned between ether, 1N HCl and water. The ether solution was concentrated under reduced pressure to give 5.87 g pure 2-acetyl-5-methoxy-3-oxo-pentanoic acid methyl ester.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=O.O1CCCC1.[CH:28]1([Na])[CH:32]=[CH:31][CH:30]=[CH:29]1.O1CCCC1.Cl>C(OCC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[C:31]1[CH:30]=[CH:29][CH:28]=[CH:32]1
Reactant: O=C(c1ccc2ccccc2c1)c1ccc2ccccc2c1
Reactant: [Na]C1C=CC=C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CC(=C(c2ccc3ccccc3c2)c2ccc3ccccc3c2)C=C1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A 200-ml two-necked flask equipped with a magnetic stirrer and a three-way cock was thoroughly purged with nitrogen, and sequentially charged with 1.55 g (5.48 mmol) of di-2-naphthyl ketone produced by the method described in Heterocycles, vol. 40, No. 1, 79-83 (1995) and 40 ml of tetrahydrofuran. Then, 5.50 ml (11.0 mmol) of a 2.0 mol/l cyclopentadienyl sodium/tetrahydrofuran solution was gradually added while cooling the mixture in an ice water bath, and then the mixture was stirred at room temperature for 65 hours under a nitrogen atmosphere. Subsequently, 100 ml of 3 N hydrochloric acid and 100 ml of diethyl ether were gradually added. The two-layered solution thus obtained was transferred to a 300-ml separatory funnel and the funnel was shaken several times. The aqueous layer was then removed. This aqueous layer was subjected to extraction with 30 ml of diethyl ether once, and the extract was combined with the organic layer obtained previously. Subsequently, the organic layer obtained was washed 3 times with 100 ml of water and once with 100 ml of saturated brine, and dried over anhydrous magnesium sulfate for 2 hours. The solids were separated by filtration, and the solvent was distilled off to obtain solids. The solids were purified by separation using silica gel chromatography to obtain a target product (yield 1.21 g (67%)). The target product was identified by 1H-NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:18]([NH:23][C:24](=[O:29])[O:25][CH:26]([CH3:28])[CH3:27])(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C(#N)C.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:21][CH:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1)[CH2:19][C:18]([NH:23][C:24]([O:25][CH:26]([CH3:27])[CH3:28])=[O:29])=[O:22]
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)C)cc2)cn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
A mixture of ethyl 1-(4-aminophenyl)-1H-imidazole-4-carboxylate (for a preparation see intermediate 85) (9.4 g, 40.6 mmol), 1-methylethyl (2E)-2-butenoylcarbamate (for a preparation see intermediate 49) (6.96 g, 40.6 mmol), and yttrium nitrate hexahydrate (1.56 g, 4.06 mmol) in dry acetonitrile (200 mL) was stirred at 60° C. for 48 h then cooled to room temperature and concentrated in vacuo. The residue was suspended in AcOEt (250 mL) and the organic phase was washed with water (×2) then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 60-100% AcOEt in Hexanes followed by 0 to 5% methanol in AcOEt) gave ethyl 1-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazole-4-carboxylate (5 g, 12.42 mmol, 31%) as a colourless gum.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:7]=[N:6][CH:5]=[N:4]1.CCN(CC)CC.[C:22]([O:26][C:27](ONC(C1C=CC=CC=1)C#N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[N:3]1([CH2:8][CH:9]2[NH:10][CH2:11][CH2:12][N:13]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:14]2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: CC(C)(C)OC(=O)ONC(C#N)c1ccccc1
Reactant: c1ncn(CC2CNCCN2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCNC(Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a suspension of 2-(1H-1,2,4-triazol-1-ylmethyl)piperazine dihydrochloride (104 mg, 0.39 mmol) and Et3N (157.7 mg, 1.56 mmol) in CH2Cl2 (3 ml) was added [{[(tert-butoxy-carbonyl)oxy]amino}(cyano)methyl]benzene (106.5 mg, 0.43 mmol). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (MeOH/CHCl3= 1/50- 1/10) to give tert-butyl 3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (50.9 mg, 48.9%): HPLC-MS (ESI): Calcd for C, H20N6O2 [M+H]+ 268, found: 268.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20](Cl)=[O:21])=[CH:14][CH:13]=1)([O-:11])=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]2=[O:8])=[O:21])=[CH:36][CH:37]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: O=C1CCCCCN1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1NCCCCC1C(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of ε-caprolactam (14.82 g, 0.131 mol) in 400 ml of benzene is added to the above reactor containing 0.131 mol of 3,5-bis(4-nitrophenoxy)benzoyl chloride. The mixture is heated to 80°-90° C., and after all the reactants are dissolved, 150 ml of pyridine is added. The solution is stirred at 90° C. for 3 hours and the pyridine/acid chloride salt removed by filtration, the filtrate being kept in a freezer. White crystals formed from the filtrate are collected by filtration and dried. In order to remove traces of the 3,5-bis(4-nitrophenoxy)benzoic acid, the product is further purified by chromatography using silica gel as filler and ethyl acetate as eluate to yield 65 percent of white crystals: mp 157°-158° C.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:11])=[O:10].O>C(C(C)=O)C>[CH3:15][N:14]([CH:13]=[N:12][S:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][I:1])(=[O:11])=[O:10])[CH3:16]
Reactant: [I-]
Reactant: CN(C)C=NS(=O)(=O)CCCCCCl
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CN(C)C=NS(=O)(=O)CCCCCI
Yield: 93.3 %

Procedure:
2.98 g of sodium iodide were added to a solution of 2.09 g of the product of Step B in 31.5 ml of methyl ethyl ketone (M.E.K.), and the mixture was refluxed for 4 hours. After cooling, water was added and extraction was carried out with ethyl acetate. The extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 2.69 g of the expected product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:17][C:16]=2[Cl:28])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].Cl>N1C=CC=CC=1>[CH2:30]([O:32][N:33]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:17][C:16]=2[Cl:28])=[N:8][CH:9]=1)[CH3:2])[CH3:31]
Reactant: CC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a mixture of 0.41 g of 5-acetyl-2-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)pyridine and 10 ml of pyridine was added 0.17 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 89%) of 5-(1-(N-ethoxyimino)ethyl)-2-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)pyridine, nD24.5 1.5701.