Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)cc1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.1) (0.22 g, 0.5 mmol) and commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a brown solid (0.032 g, 14%). MS (ISP) 450.1 [(M+H)+]; mp 270° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([NH:5][C@H:6]([B:12]1[O:16][C@@H:15]2[CH2:17][C@@H:18]3[CH2:21][C@H:20]([C@:14]2([CH3:24])[O:13]1)[C:19]3([CH3:23])[CH3:22])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=[O:4].[CH3:32][C:33]([O:36][C:37]([NH:39][C@H:40]([C:49](O)=[O:50])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:25]([C@H:2]([NH:1][C:49]([C@@H:40]([NH:39][C:37](=[O:38])[O:36][C:33]([CH3:34])([CH3:32])[CH3:35])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:50])[C:3]([NH:5][C@H:6]([B:12]1[O:16][C@@H:15]2[CH2:17][C@@H:18]3[CH2:21][C@H:20]([C@:14]2([CH3:24])[O:13]1)[C:19]3([CH3:23])[CH3:22])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=[O:4])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@@H](N)Cc4ccccc4)O[C@@]3(C)[C@H]1C2
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Yield: 85 %

Procedure:
Into a 1-neck round-bottom flask was added (2S)-2-amino-N-{(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}-3-phenylpropanamide (217 mg, 0.511 mmol), Boc-homophe-OH (171 mg, 0.614 mmol), TBTU (246 mg, 0.767 mmol) and then N,N-dimethylformamide (14.5 mL, 0.187 mol) followed by N,N-diisopropylethylamine (0.187 mL, 1.07 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight The DMF was removed from the reaction mixture under vacuum and the resulting residue purified by preparative TLC in 40% EtOAc/Hexanes to give 298 mg (85% yield) of the desired product as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](O)=[O:12])=[N:2]1.CO>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1
Reactant: O=C(O)Cc1noc2ccccc12
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1noc2ccccc12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of benzo[d]isoxazol-3-yl-acetic acid (0.86 g, 4.85 mmol) in anhydrous THF (40 mL) was added dropwise borane dimethylsulfide complex (0.58 mL, 10 M, 5.8 mmol) at 0° C. The mixture was allowed to warm to room temperature and was stirred over night. MeOH (10 mL) was carefully added and when the gas evolution ceased, the mixture was heated under gentle reflux for 4 hours. The reaction mixture was concentrated in vacuo and the remainder was dissolved in dichloromethane (20 mL). An aqueous solution of Na2CO3 (20 mL) was added and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel which afforded 537 mg (67.8%) of the title compound.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:25])[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:24])[C@@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:5]2[S:4][CH2:3]1.[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C@@:2]1([CH3:25])[C@H:7]([C:8]([O:10][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[O:9])[N:6]2[C:11](=[O:24])[C@@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A solution of 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylic acid (2.74 g), p-nitrobenzyl bromide (1.52 g), and triethylamine (1 ml) in dimethylformamide (30 ml) is kept at room temperature for 3 hours. The reaction mixture is poured into ice water, and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated in vacuo to give p-nitrobenzyl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (3.45 g). Yield: 93%.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>>[ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[C:6]2[NH:9][C:20]3[CH2:21][CH2:22][NH:17][CH2:18][C:19]=3[C:7]=2[CH:8]=1
Reactant: Cc1ccc(NN)c(C(F)(F)F)c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CNCC3

Procedure:
A microwave-compatible sealable tube was charged with (4-methyl-2-trifluoromethyl-phenyl)-hydrazine hydrochloride (434 mg, 1.6 mmol), 4-piperidone monohydrate hydrochloride (300 mg, 1.6 mmol), and 2-PrOH (3 mL). The reaction was saturated with HCl gas and the tube was sealed. The reaction mixture was subjected to microwave irradiation at 120° C. for 12 min. The solids were filtered and washed with ether to provide crude 8-methyl-6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride. The resulting crude product was dissolved in THF (12 mL) and H2O (3 mL), then Na2CO3 (184 mg, 1.7 mmol) and Boc2O (374 mg, 1.7 mmol) were added consecutively. After 2 h, EtOAc (25 mL) and water (10 mL) were added. The aqueous layer was extracted with EtOAc (25 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1–2.5% MeOH/CH2Cl2) to provide 8-methyl-6-trifluoromethyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (200 mg, 29%).
Reaction SMILES: [C:1](Cl)(=[O:11])[O:2][CH:3]([O:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:4].C(Cl)(Cl)(Cl)Cl.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.CCOCC>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:11])[O:2][CH:3]([O:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:4])=[CH:21][CH:20]=1
Reactant: CCCC(=O)OC(C)OC(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(=O)OC(C)OC(=O)Nc1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A solution of 1-butanoyloxyethyl carbonochloridate (5 mmol) in CHCl3 (10 mL) prepared as above but substituting CHCl3 for CCl4 is added to a solution of 4-chloroaniline (1.3 g, 10 mmol) in Et2O (40 mL) at -70° C. Following stirring for 2 h at -70° C. and 3 h at -40° C. the mixture is kept at -20° C. for 3d. After filtration, treatment of the filtrate with charcoal, and evaporation of the filtrate the residue is triturated with ice-cold pentane (15 mL) and recrystallized from pentane (70 mL) to yield 0.4 g (28%) of the title compound with mp 52°-54° C. C13H16ClNO4 calc. C 54.65 H 5.64 Cl 12.41 N 4.90 (285.7) found 54.72 5.64 12.31 4.83 IR (10% CHCl3): ν=1750 cm-1. 1H-NMR (CDCl3 /TMS)45 : δ=0.95 (t, 3H, J=7 Hz, CH3 (CH2)2CO); 1.50 (d, 3H, J=5.5 Hz, CH3CH); 1.7 (m, 2H, CH3CH2CH2CO); 2.31 (t, 2H, J=7 Hz, CH2CO); 6.8 (bs, 1H, NH); 6.91 (q, 1H, J=5.5 Hz, CHCH3); 7.28 (m, 4H arom.)
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>C(#N)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[C:7]1([S:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: NCCN1CCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: O=S(=O)(CCNCCN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.78 %

Procedure:
A mixture of 40.94 g (0.20 mole) of [(2-chloroethyl)sulfonyl]benzene, 27.85 g (0.217 mole) of N-(2-aminoethyl)piperidine and 28.0 g (0.277 mole) of triethylamine in 800 ml of acetonitrile was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, a solution of 2 equivalents of maleic acid in methanol was added, and the product crystallized from the solution at room temperatue to give 64.35 g (60.78%) of title compound as a white crystalline solid, mp 154°-155.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C(C(=C)C(O)=O)(=O)C1C=CC=CC=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].[C:29]([CH:37]=[CH:38][C:39](NC1C(F)=C(F)C(F)=C(F)C=1F)=[O:40])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.FC1C(N)=C(F)C(F)=C(F)C=1F>>[C:29]([CH:37]=[CH:38][C:39]([NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])=[O:40])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(C=CC(=O)c1ccccc1)Nc1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1c(Cl)cccc1Cl
Agent: C=C(C(=O)O)C(=O)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Nc1c(F)c(F)c(F)c(F)c1F
Product: O=C(C=CC(=O)c1ccccc1)Nc1c(Cl)cccc1Cl

Procedure:
The following additional compounds are prepared by employing PCl5 reagent in accordance with the method of the above Example 6. An analogous quantity of the appropriate benzoylacrylic acid or a substituted benzoylacrylic acid is employed in the manner of the benzoylacrylic acid of Example 5. Likewise, an analogous quantity of the appropriately substituted aniline is employed in the manner of the 2,6-dichloroaniline. Thus, to prepare 3-(benzoyl)pentafluoroacrylanilide, an analogous amount of benzoylacrylic acid is employed and there is used an analogous quantity of pentafluoroaniline in place of the 2,6-dichloroaniline.
Reaction SMILES: [C:1]([C:9]1[CH:29]=[CH:28][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([C:24]([O:26]C)=[O:25])[O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.[OH-].[Na+]>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([C:24]([OH:26])=[O:25])[O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3cc(C(=O)O)oc3C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 126 mg (0.324 mmol) of methyl 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate in 10 ml of tetrahydrofuran, 1 ml of 2 N aqueous sodium hydroxide was added, followed by stirring at room temperature for 1 day. The reaction mixture was acidified with 10 ml of 1 N hydrochloric acid and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/methanol=4/1 to chloroform/methanol=1/1) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCCO
Temperature: 85 °C
Yield: 94.9 %

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (350 mg, 2.04 mmol) in CH3CN (5 mL), 3-bromo-propan-1-ol (268 μL, 3.06 mmol) and K2CO3 (844 mg, 6.12 mmol) were added. The mixture was heated at 85° C. overnight, concentrated and purified by silica gel column chromatography (DCM/MeOH=95/5) to afford 444 mg (S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester. MS: 230.2 (M+H)+, tR=0.99 min (method 1).
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])([CH3:3])[CH3:2].C(Cl)(Cl)=O.[C:14](=[O:17])(O)[O-:15].[Na+]>ClCCl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(N(CC)CC)C>[CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])([CH3:3])[CH3:2].[C:14](=[O:17])([O-:15])[NH2:4]
Reactant: O=C([O-])O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[O-]
Reaction time: 3 h

Procedure:
An alcohol was dissolved in dichloromethane or tetrahydrofunan under argon atmosphere, followed by addition of an appropriate amount of a base (triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine). To the reaction mixture, a solution of solid phosgene in dichloromethane or tetrahydrofunan was added dropwisely under ice bath, then the reaction was allowed to react for half an hour under ice bath and then for a few hours at room temperature to obtain a chlorofomate. After the addition of an appropriate amount of the base (triethylamine, diisopropylethylamine, pyridine or 4-(N,N-dimethyl)aminopyridine) under ice bath, a solution of the compound B in dichloromethane or tetrahydrofunan was slowly added dropwisely. The reaction was allowed to react for half an hour under ice bath and then for three hours at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added therein and the reaction mixture was extracted with dichloromethane. Then the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then treated with an anhydride or an acyl chloride in the presence of a base (triethylamine, diisopropylethylamine, pyridine or 4-(N,N-dimethyl)aminopyridine) to give carbamate derivative F.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CN(C=O)C.P(Cl)(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Yield: 95.9 %

Procedure:
3-Bromo-2-hydroxy-5-nitropyridine (8.5 g, 39 mmol) and N,N′-dimethylformamide (0.5 ml) in chloroform (75 ml) were treated dropwise with phosphorous oxychloride (7.3 ml, 80.2 mmol) and heated at reflux for 24 hrs. The mixture was then cooled and concentrated, before being partitioned between ethyl acetate (80 ml) and sodium hydrogen carbonate solution (50 ml). The organic phase was washed with brine (100 ml), dried Na2SO4) and concentrated to give the product as a yellow solid (8.88 g).
Reaction SMILES: C([NH:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.9 g of 4-(4-acetamidophenoxy)-3-n-butylamino-5-sulfamoylbenzoic acid and 19 ml of2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5, the precipitate formed filtered off, washed with water and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenoxy)-3-n-butylamino-5-sulfamoylbenzoic acid of the formula ##SPC9##
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[O:8]([NH2:10])[CH3:9].[C:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[C:36]4[C:31](=[CH:32][C:33]([O:43][CH3:44])=[C:34]([O:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:35]=4)[CH:30]=[CH:29]3)=[O:27])=[CH:22][CH:21]=2)=[C:16]([CH3:45])[CH:15]=1)(=O)[CH3:12]>CO>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][O:37][C:34]1[CH:35]=[C:36]2[C:31]([CH:30]=[CH:29][N:28]2[C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:11](=[N:10][O:8][CH3:9])[CH3:12])=[CH:15][C:16]=3[CH3:45])=[CH:25][CH:24]=2)=[O:27])=[CH:32][C:33]=1[O:43][CH3:44]
Reactant: CON
Reactant: COc1cc2ccn(C(=O)c3ccc(-c4ccc(C(C)=O)cc4C)cc3)c2cc1OCCN(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1ccc(-c2ccc(C(=O)n3ccc4cc(OC)c(OCCN(C)C)cc43)cc2)c(C)c1
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
Potassium t-butoxide (0.11 g, 1.0 mmole) was added to methanol (10 ml) with stirring under argon and after 20 minutes at room temp. the solution was treated with methoxylamine hydrochloride (0.11 g, 1.3 mmole). The resulting mixture was stirred at room temp. for 20 minutes, then treated with a solution of 1-(4'-acetyl-2'-methylbiphenyl-4-carbonyl)-6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (E5, 0.30 g, 0.63 mmole) in methanol (10 ml). The mixture was stirred for 18 h at room temp. followed by heating under reflux for 3 h, then concentrated in vacuo. The residue was treated with 10% Na2 CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 0-5% methanol/dichloromethane to afford the title compound (0.20 g, 63%), mp 120°-121° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Br-:10].C([NH+](CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:10][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:9])[CH3:1])=[N:4][CH:5]=1
Reactant: CN(C)c1ccccn1
Reactant: [Br-]
Agent: CCCC[NH+](CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(Br)cn1
Yield: 72 %

Procedure:
2-Dimethylaminopyridine (1.0 ml) was dissolved in chloroform (60 ml). After adding tributylammonium bromide (3.88 g) thereto, the resultant mixture was stirred for 7 min. Then the reaction solution was washed with an aqueous solution of sodium thiosulfate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-methanol system) to give the title compound (1.097 g) as yellow crystals (yield: 72.0%).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:21]/[N:22]=[C:23](/[C:54]2[N:55]=[C:56]([NH:59][C:60]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[S:57][CH:58]=2)\[C:24]([NH:26][CH:27]2[C:52](=[O:53])[N:29]3[C:30]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[C:31]([CH2:34][Cl:35])[CH2:32][S:33][C@H:28]23)=[O:25])[CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:87])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1([O:21]/[N:22]=[C:23](/[C:54]2[N:55]=[C:56]([NH:59][C:60]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[S:57][CH:58]=2)\[C:24]([NH:26][CH:27]2[C:52](=[O:53])[N:29]3[C:30]([C:36]([O:38][CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:37])=[C:31]([CH2:34][Cl:35])[CH2:32][S:33](=[O:87])[C@H:28]23)=[O:25])[CH2:18][CH2:19][CH2:20]1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.33 h

Procedure:
The residue obtained in (A) was dissolved in 50 ml of methylene chloride, and 620 mg (2.87 mmol) of m-chloroperbenzoic acid (purity: 80%) was added. The mixture was stirred for 20 minutes. To the reaction solution, 30 ml of methylene chloride and a 5% sodium bi-carbonate aqueous solution were added. Then, the organic layer was distributed and washed with water and with a saturated sodium chloride aqueous solution. Then, it was dried over anhydrous sodium sulfate, and concentrated to obtain a residue of the above-identified compound. The residue of the compound thus obtained was employed for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+].[Br:13]Br>C(O)(=O)C.[Zn]>[Br:13][C:6]1[C:2]([CH3:1])=[C:3]([C:7]([O:9][CH3:10])=[O:8])[S:4][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)c1sccc1C
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1C
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A solution of methyl 3-methylthiophene-2-carboxylate (20 g, 103 mmol, 1.0 eq) and sodium hydroxide (12.3 g, 307 mmol, 3 eq) in acetic acid (75 mL) was heated to 60° C. Bromine (46.9 g, 294 mmol, 2.85 eq) was added drop wise at such a rate so as to maintain the temperature of the reaction mixture at <85° C. The resulting mixture was stirred at 85° C. for 6 h. The solution was then allowed to cool to 50° C. and zinc dust (15.4 g, 236 mmol, 2.3 eq) was added in 3 gram portions to the reaction such that the exotherm was controlled to remain below 85° C. The resulting mixture was stirred at 85° C. for 1 h, and then filtered hot through a small bed of celite. Water (300 mL) was added and the mixture was extracted with hexane (300 mL). The organic phase was washed with water, then concentrated to dryness to give 27 g (89%) an off white oil which slowly crystallized upon standing at room temperature. 1HNMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 3.87 (s, 3H), 2.56 (s, 3H)