Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([C:25]([F:28])([F:27])[F:26])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:8]2[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].CCOCC.CCCCCC>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([C:25]([F:28])([F:26])[F:27])[CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:29])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC(c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc2c(c1)c(C(CC(=O)O)C(F)(F)F)c(C)n2Cc1ccc(Br)cc1
Yield: 92.5 %

Procedure:
To a mixture of the ester from Step 4 (4.6 g, 9.2 mmol) in 45 mL of EtOH was added 10N NaOH (2.3 mL, 23 mmol) and the mixture was heated to reflux for 2 h. The mixture was cooled and concentrated and the residue was partitioned between ether and 1M HCl. The organic layer was dried over MgSO4 and evaporated to give a white solid. This material was swished with 10% ether/hexane to give 4.0 g of the title compound.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Pb:21]=O.S(O)(O)(=O)=O.NO>>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Pb+2:21].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=[Pb]
Agent: NO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Pb+2]
Reaction time: 0.25 h

Procedure:
A 500-ml capacity beaker was charged with 147 g of stearic acid and it was molten at 160°±5° C. in an oil bath under agitation by a glass vane, and 57.74 g of the lead monoxide powder (Sample A-6) and 0.31 g of powdery hydroxylamine sulfate were gradually added to the melt to effect reaction. Then, aging was conducted for 15 minutes to obtain a melt of lead stearate. The melt was poured into a watch glass and naturally cooled. The resulting solid was pulverized by an atomizer to obtain a lead stearate powder (Sample 2-7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=1)[CH3:2].[S:21]1[CH:25]=[N:24][N:23]=[C:22]1[NH2:26].[CH2:27]([O:29]C(=O)C)C>>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:27]([NH:26][C:22]2[S:21][CH:25]=[N:24][N:23]=2)=[O:29])=[C:8]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: Nc1nncs1
Reactant: CCOC(=O)Cc1ccc(N)c(C(=O)C2CCCC2)c1
Reactant: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2nncs2)c(C(=O)C2CCCC2)c1

Procedure:
3-Cyclopentanecarbonyl-4-(3-[1,3,4]thiadiazol-2-yl-ureido)-phenyl]-acetic acid ethyl ester (147 mg, 73%) was prepared from (4-amino-3-cyclopentanecarbonyl-phenyl)-acetic acid ethyl ester (138 mg, 0.5 mmol) and [1,3,4]thiadiazol-2-ylamine (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])=[CH:15][CH:14]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=S)c1cc(Nc2ccc(Cl)cc2)c(C)s1
Yield: 12.4 %

Procedure:
Using a procedure similar to Example 208, step (a), 66.6 mg (0.32 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 100 mg (2 equiv, 0.64 mmol) of 4-chlorophenyl boronic acid to give 11.8 mg (11.7%) of methyl 4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate and 21 mg (31.5%) of unreacted starting material. 1H NMR (CDCl3, 400 MHz) δ2.41 (s, 3H), 3.89 (s, 3H), 6.09 (bs, 1H), 6.94 (d, 2H, J=8.6 Hz), 7.25 (d, 2H, J=8.6 Hz), 7.70 (s, 1H).
Reaction SMILES: C1C=C([N+]([O-])=O)C([O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])=CC=1.C(=O)(O)[O-].[Na+]>>[O:10]=[CH:11][C@@H:12]([C@H:13]([C@H:14]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:19])[OH:20])[OH:21]
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Temperature: 37 °C
Reaction time: 2 h

Procedure:
To a solution containing 30.12 g (100 mmol) o-nitrophenyl-β-D-galactoside in 1000 ml distilled water buffered at pH 6.8 with 0.5 M phosphate buffer and maintained at 37° C. is added 10 mg of monoclonal antibodies prepared according to Example 6. The reaction mixture is gently agitated for 2.0 hours. The monoclonal antibodies are then recovered from the reaction mixture by ultrafiltration. The filtrate is then cooled to 10° C. and treated with 9.2 g (110 mmol) sodium bicarbonate. The D-galactose is recovered by extracting the filtrate with three 100 ml portions of diethyl ether. The ether portions are combined, washed once with 1.0 N sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield D-galactose. The aqueous portion is then combined with the sodium bicarbonate wash and acidified to pH 3 by the addition of 5 N hydrochloric acid. The acidified aqueous portion is then extracted three times with ether. The etheral extracts are combined, dried over magnesium sulfate, filtered and concentrated at reduced pressure to yield o-nitrophenol. The o-nitrophenol and D-galactose may be further purified by HPLC or by recrystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]([Cl:16])([Cl:15])C(O)=O.[Na+].ClC(Cl)(Cl)C([O-])=O.O>CN(C)C=O>[Cl:10][C:11]([Cl:16])([Cl:15])[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:7]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Temperature: 32.5 °C

Procedure:
A mixture of 4-chloro-benzaldehyde (35.5 g) and trichloro acetic acid (61.5 g) in N,N-dimethylformamide (200 ml) is stirred at 30-35° C. Trichloro acetic acid sodium salt (71.5 g) is added in portions over 20 minutes. Occasionally cooling is necessary. The reaction mixture is stirred at 30° C. for 2 hours. Towards the end it becomes viscous and additional N,N-dimethylformamide (150 ml) is charged. The reaction mixture is poured into water (700 ml). The aqueous phase is extracted with ethyl acetate (600 ml). The organic phase is separated, washed with water (300 ml), dried (magnesium sulfate) and evaporated. 2,2,2-Trichloro-1-(4-chloro-phenyl)-ethanol is obtained as oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.CC[N+](CCCN(C)C)=C=N.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]1)=[O:33])=[CH:26]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-1H-indole-2-carboxylic acid (96.3 mg, 0.538 mmol), N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide (EDC)(124 mg, 0.645 mmol) and 1-Hydroxybenzotriazole hydrate (HOBT) (87 mg, 0.645 mmol) in dichloromethane/DMF (4:1, 10 mL) was stirred for 2.5 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in methanol, stirred for 45 minutes and then filtered to give title compound (161 mg).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)(=[O:14])=[O:13])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.CCO.[NH4+].[OH-].O>C(Cl)(Cl)Cl>[NH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][S:12]([NH:11][CH2:10][CH2:9][P:4]([OH:8])(=[O:3])[OH:5])(=[O:14])=[O:13])[CH2:31][CH2:32]1
Reactant: CCOP(=O)(CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: O=P(O)(O)CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCNCC1

Procedure:
A solution of 6-9 (0.63 g, 0.142 mmol) in CHCl3 (5 ml) at rt was treated with TMSBr (0.85 mmol) for 16 hrs. The solvent was removed and the residue was dissolved in 10% aqueous acetone and this stripped to dryness. The residue was mixed with toluene and the resulting gum was purified by flash chromatography on silica gel eluting with 4:1:1 EtOH/H2O/NH4OH to provide pure 6-11. Rf 0.38 (silica gel, 4:1:1 EtOH/NH4OH/H2O ##STR61##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[CH2:16]([Cl:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CC>CS(C)=O>[Cl-:23].[O:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[C:4]1[CH:3]=[CH:2][N+:1]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: c1ccc2oc(-c3ccncc3)nc2c1
Reactant: ClCc1ccccc1
Solvent: CCCO
Solvent: CS(C)=O
Product: [Cl-]
Product: c1ccc(C[n+]2ccc(-c3nc4ccccc4o3)cc2)cc1
Yield: 39.8 %

Procedure:
A solution of 117.0 g of 2-(4-pyridinyl)benzoxazole and 95.0 g of benzyl chloride in 1 liter of a 9:1 mixture of n-propanol and dimethylsulfoxide is heated at reflux for 72 hours. The solvent mixture is then removed and the residue suspended in 100 ml of water. The crystalline product which separates is filtered, washed with acetone, and dried to give 76.6 g of product. Concentration of the mother liquors gives an additional 27.8 g of product, melting point 194°-196° C., dec. Recrystallization from water and drying in a vacuum at 100° C. for 5 hours raises the melting point to 216°-217° C., dec.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]1([N:12]2[C:16](=O)[CH2:15][C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:27](=[O:30])([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:16]1[N:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:13]=[C:14]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[C:15]=1[CH:27]=[O:30]
Reactant: O=C([O-])[O-]
Reactant: O=C1CC(c2cc(F)c(F)cc2F)=NN1c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(-c2cc(F)c(F)cc2F)nn(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMF (0.257 mL, 3.32 mmol) was added to a stirred mixture of POCl3 (0.722 mL, 7.74 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 5 minutes. Then 2-phenyl-5-(2,4,5-trifluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (321 mg, 1.106 mmol) in DMF (1 mL) was added slowly to the reaction mixture at 0° C. and the reaction mixture was heated at 70° C. for 16 hours. It was then poured into a cooled saturated solution of potassium carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (Biotage 12M) eluting with EtOAc/hexanes to give the product as a colorless solid.
Reaction SMILES: OC1C=C(C=CC=1[C:13](=[O:24])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1)C=CC(O)=O.[OH:25]C1C=CC(C=CC(O)=O)=CC=1C(=O)C=CC1C=CC(O)=C(O)C=1>>[C:13]([OH:24])(=[O:25])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1
Reactant: O=C(O)C=Cc1ccc(O)c(C(=O)C=Cc2ccc(O)c(O)c2)c1
Reactant: O=C(O)C=Cc1ccc(C(=O)C=Cc2ccc(O)c(O)c2)c(O)c1
Product: O=C(O)/C=C/c1ccc(O)c(O)c1

Procedure:
Fraction 2a was chromatographed on #3 Whatman paper, eluting with butanol-acetic acid-water (6:1:4) to separate any remaining caffeic acid. The eluate was concentrated and chromatographed on #3 Whatman paper. Elution with ethyl formate-acetic acid-toluene (4:1:5) produced the two isomers of the dimer in the following amounts: 73 mg. of 3-hydroxy-4-(3',4'-dihydroxycinnamoyl)-cinnamic acid, decomp. 135°-140° C. and 68 mg. of 4-hydroxy-3-(3',4'-dihydroxycinnamoyl)-cinnamic acid, decomp. 135°-140° C. The structural identity of the compounds was confirmed using ultraviolet scanning and nuclear magnetic resonance (NMR).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[OH2:11].[Cl:12][C:13]1[C:18]([O-])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:14]=1[Cl:23].[Na+]>CO>[Cl:12][C:13]1[C:18]([CH:2]([O:11][CH:2]([CH:1]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13]([Cl:12])=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([Cl:21])[C:17]=2[Cl:20])[CH:1]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:14]=1[Cl:23]
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: C=CC(Cl)c1ccccc1
Reactant: O
Agent: [Na+]
Solvent: CO
Product: Clc1c(Cl)c(Cl)c(C(C=Cc2ccccc2)OC(C=Cc2ccccc2)c2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)c(Cl)c1Cl
Yield: 90 %

Procedure:
The title compounds are prepared in a process comprising contacting an alkali metal or alkaline earth metal salt of a tetra- or pentahalophenol with a vinylbenzyl chloride in a liquid, aqueous solvent containing from about 68 to about 90 weight percent of a C1 or C2 alkanol in a remaining amount of water. The contact of the aforementioned reactants occurs at a pH from about 7 to about 11 and at a temperature less than about 65° C. As an example, sodium pentachlorophenoxide can be reacted with vinylbenzyl chloride by this process in an aqueous methanol solvent (with about 20 weight percent water) to yield about 90 percent pentachlorophenylvinylbenzyl ether, based on vinylbenzyl chloride.
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C@H:14]2[OH:17])=[CH:10][CH:9]=1
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O[C@@H]1CCc2ccc(Cl)cc21
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
To a solution of borane-tetrahydrofuran (1.8 mL, 1.8 mmol, Aldrich, 1 M solution in THF) and (S)-MeCBS (0.3 mL, 0.3 mmol, Aldrich, 1 M solution in toluene) was added a solution of 6-chloro-1-indanone (0.5 g, 3.0 mmol) in anhydrous tetrahydrofuran slowly over 30 min at room temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched with 2N hydrochloric acid over 30 min. The reaction mixture was extracted with ether, dried, filtered and concentrated to afford 500 mg of (R)-6-chloroindan-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:16][CH:15]([CH2:17]O)[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].CCN(CC)CC.S(Cl)(C)(=O)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[C:42]([CH:47]2[CH:52]([CH3:53])[CH2:51][CH2:50][CH:49]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[NH:48]2)=[N:43][CH:44]=[CH:45][CH:46]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:40][C:41]1[C:42]([CH:47]2[CH:52]([CH3:53])[CH2:51][CH2:50][CH:49]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[N:48]2[CH2:17][CH:15]2[CH2:16][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:14]2)=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC(CO)C1
Reactant: Cc1cccnc1C1NC(c2ccccn2)CCC1C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccnc1C1C(C)CCC(c2ccccn2)N1CC1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a 0° C. solution of [1-(2-nitro-benzenesulfonyl)-azetidin-3-yl]-methanol (165 mg, 0.606 mmol) in EtOAc (15 mL) was added Et3N (0.101 mL, 0.727 mmol) then mesyl chloride (0.052 mL, 0.666 mmol). The reaction mixture was stirred for 1 hour at room temperature. The precipitate was filtered through a plug of Celite and was washed with EtOAc. The filtrate was concentrated and the crude mesylate was dissolved in DMF (5 mL). To this solution was added DIPEA (0.211 mL, 1.20 mmol) and 3,3′-dimethyl-1′,2′,3′4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (162 mg, 0.606 mmol) and the mixture was heated at 80° C. for 17 hour Saturated NaHCO3 (15 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by radial chromatography on silica gel (Et2O saturated with NH4OH) to give 3,3′-dimethyl-1′-[1-(2-nitro-benzenesulfonyl)-azetidin-3-ylmethyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (168 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].[CH3:32][O:33][C:34]([C:36]1[CH:37]=[CH:38][C:39]([N:42]([CH2:55][CH2:56][CH3:57])[S:43]([C:46]2[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=2)[C:49](O)=[O:50])(=[O:45])=[O:44])=[N:40][CH:41]=1)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[CH3:25][O:24][C:22]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]([C:6]3[C:5]4[CH2:28][CH2:29][CH2:30][CH2:31][C:4]=4[S:3][C:2]=3[NH:1][C:49]([C:48]3[CH:47]=[C:46]([S:43]([N:42]([CH2:55][CH2:56][CH3:57])[C:39]4[CH:38]=[CH:37][C:36]([C:34]([O:33][CH3:32])=[O:35])=[CH:41][N:40]=4)(=[O:45])=[O:44])[CH:54]=[CH:53][CH:52]=3)=[O:50])=[O:8])=[CH:15][CH:14]=2)=[CH:27][CH:26]=1)=[O:23]
Reactant: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
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
Solvent: O
Product: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
To a mixture of 100 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 2 mL of DMF were added 105 mg of 3-{[5-(methoxycarbonyl)pyridin-2-yl](propyl)sulfamoyl}benzoic acid, 110 mg of HATU, and 0.060 mL of N-ethyl diisopropylamine, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 110 mg of methyl 6-[{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}(propyl)amino]nicotinate as a pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](Cl)=[O:28]>CC(C)=O.O>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:28]
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(Cl)c1cc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ncccc1C(=O)O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminonicotinic acid (91.1 g, 8.0 mmol), triethylamine (2.7 mL, 19.1 mmol) and acetone/H2O (3:1, 100 mL) was added 1-benzothiophene-2-carbonyl chloride (2.04 g, 10.4 mmol) at 0° C. The resulting solution was allowed to warm to rt and stir overnight. The volatile solvent was removed under reduced pressure and the aqueous solution was acidified with HCl (conc.). The resulting precipitate was filtered and then washed with EtOAc and dried under reduced pressure to afford the product. (1.2 g, 52%). NMR (DMSO): 11.7(1H, broad), 8.60(1H, m); 8.36(1H, s); 8.25(1H, d); 8.07(1H, d); 8.02(1H, d); 7.51(2H, m); 7.36(1H, m).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[N:14][N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:11]2[CH2:12][CH2:13][N:9]([CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]2=[N:14][N+:15]([O-:17])=[O:16])=[CH:27][N:26]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(C=C(c2ccccc2)c2ccccc2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture comprising 15.4 g of 1-(2,2-diphenylvinyl)-2-nitroiminoimidazolidine, 8.1 g of 2-chloro-5-chloromethylpyridine, 6.9 g of potassium carbonate and 80 ml of dimethylsulfoxide was stirred at 60° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give a crude product. To this was added 100 ml of ethyl acetate for recrystallization, and 13 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2,2-diphenylvinyl)imidazolidine was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[H-].[Na+].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O.O>[CH:14]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 50 °C
Yield: 57 %

Procedure:
A stirred solution of 3-hydroxy-4-methoxybenzaldehyde (2.00 g) in dry dimethylformamide (20 mL) is treated portionwise with sodium hydride (60% dispersion in oil; 0.56 g) and the mixture is then heated for 1 hour at 50° C. It is then treated dropwise with cyclopentyl bromide (2.36 g) and is stirred and heated at 50° C. for 22 hours. The solution is diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The ethereal extracts are combined, dried over magnesium sulfate and concentrated, to give 3-cyclopentyloxy-4-methoxybenzaldehyde (1.65 g) in the form of a golden oil.