Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: CN(C)C=O
Product: CCCCNc1cc(F)cc(F)c1[N+](=O)[O-]
Yield: 130.3 %

Procedure:
To a stirred solution of 2,4,6-trifluoronitrobenzene (5.31 g, 30 mmol), TEA (8.37 mL, 60 mmol) and DMF (50 mL) was added dropwise a solution of n-butylamine (2.96 mL, 30 mmol) in DMF (20 mL) at rt following General Procedure G1 to obtain crude 2-butylamino-4,6-difluoronitrobenzene (9.0 g). This product was mixed with 3-diethylaminopropanol (11.1 mL, 75 mmol) and anhydrous THF (150 mL), and then powdered KOBut (8.5 g, 75 mmol) was added following General Procedure G2 to afford crude 2-butylamino-4,6-di(3-diethylaminopropoxy)nitrobenzene (15.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.06 (d, J=8.0 Hz, 2H), 7.36 (m, 3H), 7.40-7.44 (m, 2H), 7.49 & 7.62 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 9.81 (s, 1H). MS: m/z 456.0 (M++1).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]=[C:15](OC)[C:14]2=[O:21])=[CH:9][CH:8]=1>CN(C=O)C>[Cl:3][C:15]1[C:14](=[O:21])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COc1nccn(-c2ccc(F)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1c(Cl)nccn1-c1ccc(F)cc1
Temperature: 0 °C
Yield: 64 %

Procedure:
POCl3 (5.6 mL, 61.3 mmol) was added dropwise to a solution of 1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one in DMF (30 mL) with stirring at 0° C. followed by heating at 90° C. for 1.5 hours. The residue was cooled to 0° C., quenched by adding saturated sodium acetate solution, extracted with CH2Cl2, washed with water, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (0.7% MeOH in CH2Cl2) to afford 3.52 g (64%) of the desired product. LRMS (ESI pos) m/e 224.9, 227.0 (M+1, Cl pattern). 1H-NMR (400 MHz, CDCl3) δ 7.41 (m, 2H), 7.21 (m, 4H); 19F-NMR (376 MHz, CDCl3) δ −110.9.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C:11]#[C:12][CH2:13][OH:14])=[N:3]1>CO.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2/[CH:11]=[CH:12]\[CH2:13][OH:14])=[N:3]1
Reactant: Cn1cc2c(C#CCO)cccc2n1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: Cn1cc2c(/C=C\CO)cccc2n1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
Under hydrogen gas atmosphere, a mixture of 3-(2-methyl-2H-indazol-4-yl)prop-2-yn-1-ol (50.0 mg, 0.269 mmol) and 5% palladium-calcium carbonate (lead poisoned, Lindlar catalyst, 5 mg) in methanol (3 mL) was stirred at −10° C. for 90 min, and filtered. The solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (41.6 mg, yield 82%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)(O)[CH2:7][CH3:8])=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)=[CH:7][CH3:8])=[CH:2]1
Reactant: CCC(O)(c1ccoc1)c1ccoc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=C(c1ccoc1)c1ccoc1
Yield: 10.3 %

Procedure:
A mixture of 1,1-di(3-furyl)propanol (43 g) and 1 g of p-toluenesulfonic acid in 300 ml of toluene was allowed to react at room temperature and the resulting mixture was concentrated in vacuo. The residual red oil was purified by silica gel column chromatography (methylene chloride) and kugelrohr distillation (50°-80° C. at 0.25 mmHg) to afford 4 g of 1,1-di(3-furyl)-1-propene (Formula III: R3 =CH3 ; R4 =H; R5 =R6 =3-furyl) as an oil, b.p. 50°-80° C. (0.25 mm).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O>[Cu]>[C:24]1([N:21]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([N:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:2]4[CH:7]=[CH:6][C:5]([C:8]5[CH:9]=[CH:10][C:11]([N:21]([C:2]6[CH:7]=[CH:6][C:5]([C:8]7[CH:9]=[CH:10][C:11]([N:21]([C:2]8[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=8)[C:24]8[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=8)=[CH:12][CH:13]=7)=[CH:4][CH:3]=6)[C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)=[CH:12][CH:13]=5)=[CH:4][CH:3]=4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(-c5ccc(N(c6ccccc6)c6ccc(-c7ccc(N(c8ccccc8)c8ccccc8)cc7)cc6)cc5)cc4)cc3)cc2)cc1
Yield: 48.5 %

Procedure:
8.66 g (0.021 mol) of N,N,N'-triphenylbenzidine thus obtained, 4.06 g (0.01 mol) of 4,4'-diiodobiphenyl, 2.90 g (0.021 mol) of anhydrous potassium carbonate, 0.32 g (0.005 mol) of copper powder, and 10 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 195° C. to 210° C. for 20 hours. The reaction product was then extracted with 140 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated. To the concentrate was then added 120 ml of n-hexane to recover a crude crystal. The crude crystal thus recovered was then purified by column chromatography (carrier: silica gel; elute: 1/2 mixture of toluene and n-hexane) to obtain 4.73 g (yield: 48.5%) of N,N'-bis(4'-diphenylamino-4-biphenylyl)-N,N'-diphenylbenzidine. The melting point of the product was from 242.5° C. to 243.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:13]([S:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C>[ClH:41].[ClH:41].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)[N:13]([S:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a solution of tert-butyl methyl{[5-[4-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (275 mg) in ethyl acetate (2 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 4 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate and recrystallized from ethanol to give the title compound as white crystals (yield 157 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]#[N:23])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1)[CH2:21][C:22]1[NH:28][N:27]=[N:26][N:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(Oc2c(Cl)cc(CC#N)cc2Cl)cc1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)cc1C(C)C
Yield: 33.4 %

Procedure:
To a stirred solution of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-phenylacetonitrile (160 mg) in 3.0 ml of dimethyl formamide, ammonium chloride (500 mg) and sodium azide (600 mg) was added at reflux. After 2 hours the reaction-mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 96:4:1 chloroform/methanol/acetic acid) to give 60 mg (34%) of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzyltetrazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1.Cl.O1CCOCC1>CC(O)C.O1CCOCC1>[ClH:1].[Cl:29][C:27]1[CH:26]=[C:25]([OH:30])[CH:24]=[C:23]([NH:22][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=1
Reactant: Nc1cc(O)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (3.24 g, 9.95 mmol) was dissolved in 2-propanol (40 mL). 3-Amino-5-chlorophenol (1.50 g, 10.4 mmol) from Example 64A and a 4 M solution of gaseous hydrogen chloride in dioxane (124 μL, 0.50 mmol) were added, and the mixture was heated to 80° C. for 20 h. Subsequently, further hydrogen chloride in dioxane (5.0 mL, 20 mmol) was added, and the mixture was heated for additional 3 h. The resulting precipitate was collected by suction filtration to yield 3.63 g (99%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCn1cccc1
Product: N#Cc1c(OCCn2cccc2)cccc1[N+](=O)[O-]
Yield: 42.5 %

Procedure:
Prepared as in Example 166d from 2-(1H-pyrrol-1-yl)ethanol and 2,6-dinitrobenzonitrile, in 42.5% yield. MS 258 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)c(OC)c1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: COc1ccc(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c(OC)c1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 256 mg of 4'-(2,4-dimethoxyphenyl)acetophenone and 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 467 mg of the title compound, melting at 186°-188° C., were obtained.
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[K+:5].[CH3:6][S:7][CH2:8][CH2:9][CH:10]1[NH:14]C(=O)NC1=O.N.C(=O)=O>O>[NH2:14][C@H:10]([C:1]([O-:2])=[O:4])[CH2:9][CH2:8][S:7][CH3:6].[K+:5]
Reactant: O=C([O-])O
Reactant: CSCCC1NC(=O)NC1=O
Agent: N
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: CSCC[C@H](N)C(=O)[O-]
Temperature: 180 °C

Procedure:
Using pump pressure, a solution of 100 kg of potassium hydrogen carbonate in aqueous solution and 41 kg of 5-(2-methylmercaptoethyl)-hydantoin in 400 l of water is fed hourly into a continuously operating pressurised column 8 made of special steel (compare FIG. 2) operated with steam. The reaction mixture is heated to 180° C. and has an average residence time of about 15 minutes at about 8 bar. Ammonia and carbon dioxide liberated is drawn off at the top of the reactor column by means of a pressure-maintaining valve. The reaction solution is depressurised at the bottom of the pressurised reactor and cooled with the heat exchanger 9. A quantity of 41.9 kg per hour of potassium methioninate in solution is obtained (94.5% of the theoretical).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:6]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:6]=1
Reactant: COCOc1nn(-c2ccccc2C)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COCOc1nn(-c2ccccc2C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of [3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazol-4-yl]methanol (2.39 g), activated manganese dioxide (5.0 g) and toluene (30 mL) was stirred at room temperature for 8 hrs. Activated manganese dioxide (5.0 g) was added and the mixture was further stirred for 12 hrs. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:2, v/v) to give 3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carbaldehyde as an orange oil (1.65 g, yield 81%).
Reaction SMILES: Cl[O-:2].[Na+].[F:4][C:5]([F:26])([F:25])[C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11]([S:13][CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=3)=[N:12][C:8]=2[CH:7]=1>C(OCC)(=O)C>[F:26][C:5]([F:4])([F:25])[C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11]([S:13]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=3)=[O:2])=[N:12][C:8]=2[CH:7]=1
Reactant: COc1ccnc(CSc2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccnc(CS(=O)c2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Reaction time: 0.03 h

Procedure:
600 ml of a 1.5% strength aqueous sodium hypochlorite solution are added within 3 minutes at 10° C. with vigorous stirring to a solution of 16.2 g (0.048 mole) of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole in 960 ml of ethyl acetate. The mixture is then stirred for a further 2 minutes. The organic phase is separated off and is washed with 100 ml of distilled water. The aqueous phase is adjusted to pH 7-8 by addition of glacial acetic acid and is then extracted three times with ethyl acetate. The extracts are washed with water and the combined organic phases are then concentrated to a volume of 100 ml and cooled in an ice bath. The precipitate which has separated out is filtered off with suction and washed with cold ethyl acetate. Yield: 13.2 g of m.p. 166° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10])[CH3:3]>Cl>[CH3:3][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10])[CH3:1]
Reactant: COC(=O)c1ccccc1OCCN(C)C
Agent: Cl
Product: CN(C)CCOc1ccccc1C(=O)O

Procedure:
4.4 g of methyl 2-[2-(N,N-dimethylamino)ethyl]oxy-benzoate are heated in the microwave for 15 minutes at 300 W with 30 ml of 5N hydrochloric acid. The mixture is extracted with ethyl acetate, the aqueous phase is concentrated by evaporation and recrystallised from acetonitrile/ether. Yield: 4.2 g (86% of theory).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)C.[CH3:8][N:9]([CH3:32])[CH2:10][CH2:11][N:12]1[C:28](=[O:29])[C:27]2[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:30]C)[CH:24]=4)[NH:19][C:18]=3[CH:17]=[CH:16][C:15]=2[C:13]1=[O:14]>C(Cl)(Cl)Cl>[CH3:8][N:9]([CH3:32])[CH2:10][CH2:11][N:12]1[C:28](=[O:29])[C:27]2[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:30])[CH:24]=4)[NH:19][C:18]=3[CH:17]=[CH:16][C:15]=2[C:13]1=[O:14]
Reactant: COc1ccc2[nH]c3ccc4c(c3c2c1)C(=O)N(CCN(C)C)C4=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClC(Cl)Cl
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(O)cc4c3c2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
1.52 g of anhydrous aluminum chloride was suspended in 30 ml of chloroform. Thereto was added 1.69 ml of ethanethiol, and the mixture was stirred at room temperature for 10 minutes. Thereto was dropwise added, in 1 minute, a solution of 770 mg of N-(2-dimethylaminoethyl)-6-methoxycarbazole-3,4-dicarboximide dissolved in 100 ml of chloroform. The mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was mixed with 200 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The mixture was stirred at room temperature for 30 minutes. The resulting insoluble material was removed by filtration. The separated insoluble material was washed with 50 ml of ethyl acetate. The washings were combined with the previously separated filtrate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 0.49 g (yield: 66%) of N-(2-dimethylaminoethyl)-6-hydroxycarbazole-3,4-dicarboximide as orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:21])=[CH:7][N:8]2[S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:22]([NH:24][NH2:25])=[O:23].C1COCC1.[N:31]([CH:34]([CH3:36])[CH3:35])=[C:32]=S.CCN=C=NCCCN(C)C.Cl>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:21])=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:4][C:3]=1[C:22]1[O:23][C:32]([NH:31][CH:34]([CH3:36])[CH3:35])=[N:25][N:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)c(F)cc32)cc1
Reactant: CC(C)N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Temperature: 60 °C
Yield: 40.3 %

Procedure:
In a 250 mL round bottomed flask, 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (880 mg, 1.86 mmol) was treated with THF (10 mL) and 2-isothiocyanatopropane (0.56 mL, 5.58 mmol) and heated to 60° C. for 1 h. The THF was removed under reduced pressure (rotary evaporator) and replaced with DMF (5.0 mL) and the solution was treated with EDC HCl (Aldrich, St. Louis, Mo., 535 mg, 2.79 mmol) and heated at 90° C. for 30 min. The reaction mixture was cooled to RT and treated with water and extracted with EtOAc (2×50 mL), washed with brine (2×50 mL) and dried over MgSO4, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (40 g Redisep column, using a gradient of 0-100% EtOAc in hexanes) afforded 5-(6-fluoro-3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (407 mg, 0.75 mmol, 40.5% yield) as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 540.8 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, s), 8.03 (2H, m, J=8.4 Hz), 7.95 (1H, d, J=11.2 Hz), 7.81 (1H, d, J=7.4 Hz), 7.71 (1H, d, J=6.7 Hz), 7.44 (2H, m, J=8.2 Hz), 3.74 (1H, dq, J=13.4, 6.6 Hz), 2.35 (3H, s), 1.21 (6H, d, J=6.5 Hz).
Reaction SMILES: C(O)C.[Na].[CH2:5]([N:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25](OCC)(=[O:31])[C:26](OCC)=[O:27]>C(O)(=O)C>[CH2:5]([N:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:26]([OH:27])[C:25]([OH:31])=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Into a 20L three-necked flask, 2.7L of ethanol was put, and 139.2 g (6.05 moles) of small cuts of metallic sodium were gradually added thereto with stirring at room temperature. After the addition was completed, the mixture was stirred under reflux until the metallic sodium became dissolved completely. The mixture formed was cooled to room temperature, and 770.7 g (2.760 moles) of the diethyl N-benzyliminodiacetate and 405.8 g (2.775 moles) of diethyl oxalate were added thereto, which were then stirred under reflux for 8 hours. After the reaction was completed, the reaction product was left to cool, and its pH was adjusted to 5.5 by adding 4.5L of acetic acid. The precipitate formed was collected by filtration and washed with water. This precipitate was washed with acetone to obtain 532.8 g of diethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (yield: 57.9%), having a melting point of 143.5 to 145.0° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]([Cl:22])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.CCO.[OH-].[K+]>O>[Cl:22][C:13]1[C:12]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:11][C:10]([CH:4]([CH2:5][CH:6]2[CH2:9][CH2:8][CH2:7]2)[C:3]([OH:33])=[O:2])=[CH:15][C:14]=1[O:16][CH2:17][C:18]([F:19])([F:20])[F:21]
Reactant: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 100.4 %

Procedure:
To a solution of the 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (8.0 g, 14.5 mmol) in a mixture of the EtOH (100 mL) and H2O (15 mL) was added potassium hydroxide (10 g, 178.5 mmol). The reaction mixture was refluxed for 3 h and the solvent evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid as a white solid (7.0 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 6.98 (s, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.49 (t, J=7.7 Hz, 1H), 2.27-2.13 (m, 2H), 2.06-1.73 (m, 5H), 1.71-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 153.6, 142.1, 141.2, 138.0, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.9, 124.0 (q, 1JCF=262.5 Hz), 123.0 (q, 1JCF=277.6 Hz), 121.8, 114.3, 67.3 (q, 1JCF=36.0 Hz), 49.3, 40.3, 33.9, 28.3, 28.0, 18.5.