Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10]2)(=[O:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2cc(S(=O)(=O)Cl)ccc12
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
5-(Acetylamino)naphthalene-2-sulfonyl chloride (280 mg, 0.987 mmol) was added to benzylamine (127 mg, 1.19 mmol) and triethylamine (0.17 ml, 1.22 mmol) dissolved in tetrahydrofuran (3.0 ml), and the mixture was stirred at room temperature for 1 hour. Water (10 ml) was added to the reaction solution, and after the mixture was stirred for 10 minutes, the resulting solid was collected. The solid was washed with water and isopropyl ether to give the title compound as a light pink solid (296 mg, 84.6%).
Reaction SMILES: N[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:12][CH3:13])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH2:14]([N:16](CC)CC)C.Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[CH:35]=[CH:36][CH:37]=[C:28]([C:29]=23)[S:27]1(=[O:39])=[O:38].[Cl-].[Na+].Cl>CN(C)C=O.C1(C)C=CC=CC=1>[O:38]=[S:27]1(=[O:39])[C:28]2=[CH:37][CH:36]=[CH:35][C:34]3=[CH:33][CH:32]=[CH:31][C:30](=[C:29]23)[N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:16][CH2:14][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:12][CH3:13])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COc1cccc2c1CC(N)CC2
Reactant: CCN(CC)CC
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(CNCCCCN1c3cccc4cccc(c34)S1(=O)=O)CC2

Procedure:
1.6 g of 2-amino-8-methoxytetralin (8.4 mmol), 1.16 ml of triethylamine (8.4 mmol) and 1.59 g of 2-(4-bromobutyl)-2H-naphth[1,8-cd]isothiazole 1,1-dioxide are stirred for 48 h at 40° C. in 32 ml of dimethylformamide. The reaction solution is then stirred into a mixture of 320 ml of 5% strength sodium chloride solution, 100 ml of toluene, 8.4 ml of 1N hydrochloric acid and kieselguhr. The kieselguhr containing the hydrochloride of the final product attached thereto is filtered off with suction-- and introduced into a mixture of 300 ml of water and 100 ml of toluene. The final product is transferred to the organic phase by dropwise addition of 9 ml of 1N sodium hydroxide solution.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CS(=O)(=O)Oc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2OS(C)(=O)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-methanesulfonyloxybenzoic acid (0.30 g, 1.4 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (10 mL) was heated at 40° C. for 45 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.49 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.47 mmol) and triethylamine (98 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (55%) of the title compound as white crystals: mp 144-145° C.; [α]21D -7.1° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (10, M+).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O.[BrH:17]>>[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][Br:17]
Reactant: CC(C)CCCC(C)CCO
Reactant: Br
Agent: O=S(=O)(O)O
Product: CC(C)CCCC(C)CCBr
Temperature: 25 °C
Yield: 82.1 %

Procedure:
48% HBr (200 ml) and concentrated sulfuric acid (0.46 ml) were added to 3,7-dimethyl-1-octanol (21.0 g, 157.9 mmol), and the mixture was heated overnight. After allowing to cool to room temperature, and the mixture was extracted with hexane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated to give the title compound (28.7 g, 82.1%).
Reaction SMILES: [Na+].[CH:2]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([O-:24])(=O)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].P(Cl)(Cl)(Cl)(Cl)Cl.[Na+].[Cl-]>ClCCl.C1(C)C=CC=CC=1>[CH:2]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:33])(=[O:24])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)[O-])cc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 4′-isopropoxycarbonylaminobiphenyl-4-sulfonic acid sodium salt (283 g, 0.79 mol), toluene (700 ml) and pyridine (35 ml, 0.43 mol) was stirred vigorously at RT and POCl3 (215 ml) was slowly added dropwise such that the internal temperature was kept between 30° C. and 45° C. Subsequently, PCl5 (100 g) was added at 35° C. in about 6 portions and the mixture was heated to 60° C. within 30 min. Afterward, further PCl5 (100 g) was added at 70° C. within 15 min and the mixture was left to stir without further heating for 1 h. In this time, the internal temperature fell to about 30° C. The mixture was diluted with dichloromethane (500 ml) and then worked up. To this end, a mixture of ice-water (5 kg), saturated NaCl solution (1000 ml) and dichloromethane (1000 ml) was initially charged with vigorous stirring and the reaction mixture was slowly added dropwise. In this time, the temperature was kept at from 15° C. to 25° C. by adding ice (2 kg). Subsequently, stirring was continued for 1 h, in the course of which the temperature was allowed to rise up to 30° C. The phases were separated and the aqueous phase was extracted twice using dichloromethane (1500 ml). The combined organic phases were reextracted using water (8000 ml), dried over Na2SO4 and concentrated by evaporation under reduced pressure. About 360 g of crude product were obtained as beige crystals. These were taken up in dichloromethane and filtered through a silica gel layer (15×30 cm, 70–200 μm), the layer was rinsed using dichloromethane and the filtrate was concentrated by evaporation. 270 g (96%) of isopropyl(4′-chlorosulfonylbiphenyl-4-yl)carbamate were obtained as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH2:23])=O)=[CH:15][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]#[N:23])=[CH:15][CH:14]=3)[C:9]2=[O:24])=[CH:6][CH:7]=1
Reactant: NC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#CCCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Temperature: 0 °C

Procedure:
To 750 mg of 1-(4-bromophenyl)-3-[4-[2-(aminocarbonyl)ethyl]-phenyl]-imidazolidin-2-one and 320 mg of pyridine in 10 ml of tetrahydrofuran are added dropwise at -10° C., with stirring, 460 mg of trifluoroacetic acid anhydride in 1 ml of tetrahydrofuran. After stirring overnight at ambient temperature the reaction mixture is diluted with ice water and the precipitate obtained is suction filtered, washed and dried.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].C(N(CC)CC)C.Cl.[Cl:21][CH2:22][CH2:23][CH2:24][NH2:25]>C(Cl)Cl>[Cl:21][CH2:22][CH2:23][CH2:24][NH:25][S:7]([NH:10][C:11](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:9])=[O:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NCCCCl
Reactant: CC(C)(C)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCCCl
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
Tert-butyl alcohol (2.45 g, 33 mmol) was added to chlorosulfonyl isocyanate solution (4 g, 28.26 mmol) in CH2Cl2 (80 mL) at 0° C. and agitated for 30 min. Triethylamine (19.7 mL) and 3-chloropropylamine HCl (4.29 g, 33 mmol) were added to the mixture and agitated for 2 hr at room temperature, followed by extraction using CH2Cl2 and brine and drying over anhydrous MgSO4. The residue was purified by silica gel column chromatography to give tert-butyl N-(3-chloropropyl)sulfamoylcarbamate (2, 4.17 g, 54%). 1H NMR (300 MHz, CDCl3): δ 5.25 (br, 1H), 3.67-3.62 (m, 2H), 3.28-3.26 (m, 2H), 2.09-2.01 (m, 2H), 1.51 (S, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O.[C:12]([OH:16])(=[O:15])[CH:13]=O>C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])/[CH:9]=[CH:13]/[C:12]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)/C=C/C(=O)c1cccc(Cl)c1
Temperature: 130 °C
Yield: 39.2 %

Procedure:
A stirred mixture of 3'-Chloroacetophenone (15 mL, 97 mmol) and glyoxylic acid monohydrate (9 g, 97 mmol) was heated at 130° C. under reduced pressure (1,5 mmHg), over 8 hours. During this time the reduced pressure was maintained in order to remove the water formed during the reaction. After cooling, the crude reaction product was taken up in aqueous 10% potassium carbonate solution (100 mL) and the resulting solution was washed with diethyl ether (3×30 mL), the alkaline aqueous layer was cooled at 0° C. and then cautiously acidified with 6N HCl. The resulting suspension was extracted with ethyl acetate (3×50 mL), the collected organic extracts were washed with brine and dried (Na2SO4). Concentration of the solvent in vacuo afforded a yellow solid (8 g) which was chromatographed (SiO2 ;CH2Cl2 /MeOH 98:2) to provide the pure acid (6 g, 30%), lightly yellow solid melting at 158-59° C. (diisopropyl ether).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[S:25][C:24]3[CH:23]=[C:22]([CH2:26][CH3:27])[N:21]([CH2:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:20](=[O:37])[C:19]=3[C:18]=2[O:38][CH2:39][CH3:40])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1>[CH2:39]([O:38][C:18]1[C:19]2[C:20](=[O:37])[N:21]([CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([CH2:26][CH3:27])=[CH:23][C:24]=2[S:25][C:17]=1[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9][CH2:10]1)=[O:16])[CH3:40]
Reactant: CCOc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(C(=O)NC2CCN(C(=O)CO)CC2)sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c12
Yield: 67.6 %

Procedure:
A mixed solution of 2-[4-({[3-ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]pyridin-2-yl]carbonyl}amino)piperidin-1-yl]-2-oxoethyl acetate (90 mg, 0.18 mmol) and potassium carbonate (39 mg, 0.28 mmol) in THF (8 mL)-methanol (2 mL)-water (2 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (64 mg, 69%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:41][C:40]1[CH:11]=[C:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[O:12][C:37](=[O:38])[C:36]=1[S:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1c(C)cc(C)cc1C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c(C)c1

Procedure:
The title compound was prepared by Method A using 2',4',6'-trimethylacetophenone (1.86 g, 11.5 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.65 mmol), chlorotrimethylsilane (1.60 mL, 12.65 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (2.95 g, 10.4 mmol). m.p. 134-136° C.; 1H NMR (250 MHz, DMSO-d6) δ2.11 (s, 6 H), 2.26 (s, 3 H), 3.98 (s, 2 H), 6.03 (s, 1 H), 6.96 (s, 2 H), 7.25 (m, 5 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:40]([S:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:22]2[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=[C:19]([C:13]4[S:14][C:10]([CH2:9][NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:2]([CH3:3])[CH3:1])=[CH:11][CH:12]=4)[CH:20]=3)[NH:24][CH:23]=2)[CH2:36][CH2:35]1)(=[O:39])=[O:38])[CH3:41]
Reactant: CC(C)OCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCCOC(C)C)s4)cc23)CC1
Yield: 9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). After purification on an Agilent MDAP twice as shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, the impure title compound was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:17])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([OH:3])=[O:2].[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[C:32]([CH:47]=[CH:48][CH:49]=1)[C:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)C>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:32]3[CH:47]=[CH:48][CH:49]=[C:30]([O:29][CH3:28])[C:31]=3[O:50][CH3:51])=[O:17])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([OH:3])=[O:2]
Reactant: O=C(NCCN1C(=O)c2ccc(C(=O)O)cc2C1=O)OCCCCCCO
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cccc(C(OCCCCCCOC(=O)NCCN2C(=O)c3ccc(C(=O)O)cc3C2=O)(c2ccccc2)c2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an argon atmosphere, 1.02 g (2.70 mmol) of 1-[(4-carboxyphthalimidylethyl)aminocarbonyl]oxy-6-hexanol (compound 3a) was dissolved in 27 ml of pyridine. To the solution, 915 mg (2.70 mmol) of dimethoxytrityl chloride was added, and the mixture was stirred at room temperature. After 2 hours, 440 mg (1.30 mmol) of dimethoxytrityl chloride was further added to the reaction solution, and the mixture was stirred at room temperature for additional 2 hours. 5 ml of ethanol was added to the reaction solution, and the mixture was then concentrated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The solution was washed with 50 ml of water twice and 50 ml of saturated saline once and dried over sodium sulfate. The solution was concentrated under reduced pressure, followed by azeotropy with 5 ml of toluene. The residue was purified by silica gel column chromatography (elution solvent: ethanol-chloroform, containing 0.3% pyridine) to obtain 1.88 g (pyridine salt, yield: 92%) of the title compound (compound 4a) as a yellow foam.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:36]=[C:37]([O:39][CH2:40][C:41]4[N:42]=[C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[S:44][CH:45]=4)[CH:38]=3)[CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:36]=[C:37]([O:39][CH2:40][C:41]4[N:42]=[C:43]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[S:44][CH:45]=4)[CH:38]=3)[CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:19]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
After a mixture of ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (498 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (378 mg, yield: 79%). This was recrystallized from ethyl acetate-hexane. Melting point: 78–79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Cl:16][C:17]([Cl:31])=[CH:18][CH2:19][O:20][N:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:16][C:17]([Cl:31])=[CH:18][CH2:19][O:20][N:21]=[CH:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])=[CH:5][C:4]=2[Cl:14])=[CH:27][CH:28]=1
Reactant: OCc1ccc(C=NOCC=C(Cl)Cl)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCON=Cc1ccc(COc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a mixture of 0.35 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.32 g of 4-(hydroxymethyl)benzaldehyde O-(3,3-dichloro-2-propenyl)oxime, 0.32 g of triphenylphosphine, and 10 ml of dichloromethane was slowly added dropwise 0.25 g of diisopropyl azodicarboxylate. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 0.43 g (yield, 67%) of 4-((2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)methyl)benzaldehyde O-(3,3-dichloro-2-propenyl)oxime, m.p., 76.2° C.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[N:13][C:12]([CH:15]=CC2C=CC=CC=2)=[CH:11][N:10]=1)=CC1C=CC=CC=1.S(=O)(O)[O-:24].[OH2:27]>CO>[N:13]1[CH:14]=[C:9]([CH:1]=[O:27])[N:10]=[CH:11][C:12]=1[CH:15]=[O:24]
Reactant: O=S([O-])O
Reactant: C(=Cc1cnc(C=Cc2ccccc2)cn1)c1ccccc1
Reactant: O
Solvent: CO
Product: O=Cc1cnc(C=O)cn1

Procedure:
A solution of pyrazine-2,5-dicarboxaldehyde in water is prepared by ozonolysis of 2,5-distyrylpyrazine in methanol. The ozonide is decomposed with aqueous bisulfite and the reaction mixture evaporated under vacuum at 30°. The residual aqueous solution of the dialdehyde is purified by extraction with ether--first while acidic, then while basic. From 2 g. of starting material there is obtained 15 ml of asolution of the dialdehyde (theory 0.96 g.). The pH isadjusted to pH 10-11 and 5 ml. of 2% aqueous potassium cyanide is added with cooling and stirring to dissipate the heat of reaction. There is an instantaneous formation of a red-brown precipitate turning black. Up to this point all operations have been conducted under an inert atmosphere and below 30°. The reaction mixture is heated 5 minutes on a steam bath. The pH is adjusted to 6.5. The product is collected as a red-brown solid and is dried in vacuum at 55° to give 0.3 g. of a black solid, soluble in alkali to give a deep maroon solution and soluble in acid. Anal. Calcd. for the nonamer (Formula I, n=7, X and Y=COOK) as its dodecahydrate: C54H33N18O20K3.12H2O: C, 40.80; H, 3.27; N, 15.87. Found: C, 41.16; H, 3.26; N, 15.78. Acid-base titration establishes the isoelectric point at pH 6.5. In acid, K of the formula is replaced by H.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.Cl[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Nc1ccccc1F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCO
Product: Fc1ccccc1N1CCNCC1
Temperature: 100 °C
Yield: 30.8 %

Procedure:
2-Fluoroaniline (4.0 g, 36.0 mmol) and bis-(2-chloroethyl)-amine hydrochloride (6.4 g, 36.0 mmol) were dissolved in n-butanol (40 mL) and potassium carbonate (12.0 g, 86.8 mmol) was added. The reaction mixture was heated to 100° C. for 16 h, cooled to room temperature, and concentrated under reduced pressure. The crude reaction mixture was diluted with 10% MeOH in CHCl3 and filtered. The clear filtrate was concentrated under reduced pressure to get 1-(2-fluorophenyl)piperazine (2.0 g, yield 31%), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 9.95 (br s, 1H), 7.12-6.95 (m, 4H), 3.43 (br s, 8H). MS (ESI) m/z: Calculated for C10H13FN2: 180.11. found: 180.9 (M+H)+