Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(NCC)C.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(Br)cn1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
Copper (I) iodide (10 mg) was added to a solution of 2,5-dibromopyridine (4.74 g), propargyl alcohol (1.34 g) and BTPC (75 mg) in diethylamine (50 ml) and the mixture stirred overnight (18 h), under nitrogen. The solution was evaporated in vacuo and the residue treated with 8% sodium bicarbonate (50 ml) and partitioned with dichloromethane (3×50 ml). The combined extracts were dried and evaporated and the residual semi-solid purified by FCC. Eluting with ether afforded the title compound (3.43 g) as fawn crystals m.p. 121°-122°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 69.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]=[C:15]=[S:16]>>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]=[C:15]1[NH:5][CH2:4][CH2:3][S:16]1
Reactant: [NH3+]CCCl
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cccc(N=C2NCCS2)c1Cl

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 2,3-dichlorophenyl isothiocyanate according to Method C1a to give 2-(2,3-dichlorophenylimino)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(2,3-dichlorophenylimino)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [IH:1].[NH2:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[NH:5].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=O>C(O)(=O)C>[IH:1].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=[N:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[NH:5]
Reactant: Cc1cccc(C)c1C=O
Reactant: N=C(NN)NCc1ccccn1
Agent: I
Solvent: CC(=O)O
Product: Cc1cccc(C)c1C=NNC(=N)NCc1ccccn1

Procedure:
A mixture of 2.93 g. of 1-amino-3-(2-pyridylmethyl)guanidine hydriodide and 1.34 g. of 2,6-dimethylbenzaldehyde [G. Lock and K. Schmidt, J. Prakt. Chem., 140, 229 (1934)] is dissolved in 5 ml. of glacial acetic acid at 100° C. After 2 hours the solidified reaction is triturated with water and filtered. Crystallization from absolute ethanol gives the desired product as colorless needles, m.p. 184°-186° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7](O)[CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1.P(Br)(Br)[Br:17]>C(Cl)Cl>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=1
Reactant: Oc1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Temperature: 0 °C

Procedure:
A mixture of 6 g 2,6-di(trifluoromethyl)-4-hydroxypyridine and 4.9 ml phosphorus tribromide was heated 15 min. at 140°-150° C. and 90 min. at 160°-170° C. The reaction mixture was cooled, 150 ml methylene dichloride added, and poured into ice-water. From the methylene dichloride layer there was isolated 3.5 g 4-bromo-2,6-di(trifluoromethyl)pyridine, colorless solid, m.p. 92°-95° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30]Br)[CH3:26]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([O:24][CH2:30][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:32])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(Cl)c2)C1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCOC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a slurry of NaH (0.835 g, 0.0348 mol) in DMF (50 mL) was added a solution of (R)-tert-butyl 3-((3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.8 g, 0.0116 mol) in DMF (30 mL) dropwise at −15˜−5° C. and the reaction mixture was stirred for about 1 h at rt. A solution of 3-bromopropionic acid ethyl ester (4.2 g, 0.0232 mol) in DMF (30 mL) was added to the reaction mixture dropwise while the temperature was maintained at −15˜−5° C. and the mixture was warmed slowly to rt and stirred overnight. The reaction was cooled in an ice bath and quenched with satd aq NH4Cl (80 mL). The product was extracted with EtOAc, washed with brine, dried over NaSO4 and purified by flash chromatography to afford (3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylate (2.0 g, 4.71 mmol, 41%). 1H NMR (400 MHz, CDCl3): 1.12-1.37 (m, 4H), 1.45 (s, 9H), 1.47-1.75 (m, 3H), 1.82-1.93 (m, 1H), 2.50-2.58 (m, 4H), 3.43-3.52 (m, 2H), 3.80-4.01 (m, 2H), 4.07-4.17 (m, 3H), 7.13-7.23 (m, 1H), 7.25-7.27 (m, 3H). MS (E/Z): 426 (M+H+).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.C(Cl)(Cl)Cl.C(OO)(=[O:24])C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:24])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)OO
Reactant: CCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
3.81 G. of 1-acetamido-2-nitro-4-n-propylthiobenzene in 35 ml. chloroform is treated at -20° to -15° C with a solution of 3.0 g. 40% peracetic acid in 3 ml. methanol. The mixture is allowed to warm to 20° C and stirred at 15°-25° C for four hours, then washed with sodium bisulfite solution and sodium bicarbonate solution. Removal of the chloroform leaves a gum which is treated on a steam bath, with 15 ml. 5N sodium hydroxide for one hour. The mixture is cooled, extracted with chloroform, separated and the solvent removed. The crude residue is recrystallized from benzene yielding 1-amino-2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].C[S+](C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16](C(=O)C)=[CH:15][CH:14]=1.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:24]2([CH3:23])[CH:26]([CH3:22])[O:25]2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CC1OC1(C)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture was poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:3]=1[C:29](=[O:31])[CH3:30].Br[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:27][CH2:28]2)[C:3]=1[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: BrCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1c(C2CCN(Cc3cccnc3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (0.049 mmol, 20 mg), 3-(bromomethyl)pyridine (0.049 mmol, 12 mg) and DIEA (0.29 mmol, 37 mg) in THF (2 mL) was stirred at room temperature overnight. Concentration and purification by prep-LC afforded 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(1-(pyridin-3-ylmethyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone: LCMS tR=2.71 Min (10 min run, UV254nm). Mass calculated for, M+ 503.24, observed LC/MS m/z 503.99 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.C1CCN2C(=NCCC2)CC1.[SH:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)(OCC)OCC.[O-]CC.[Na+].Cl>CN(C)C=O.C(O)C>[CH2:20]([O:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:2]3[S:34][CH2:35][CH2:36][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:4][C:3]=3[CH:6]=2)=[CH:11][CH:12]=1)[CH2:21][CH3:22]
Reactant: CCCOCCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Reactant: CCOC(=O)CCCS
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
Under a nitrogen flow, 533.2 g of crude 2-fluoro-5-(4-propoxyethoxyphenyl)benzaldehyde was dissolved in 894 ml of N,N-dimethylformamide and cooled to 10° C. or lower 1,8-Diazabicyclo[5.4.0]-7-undecene (450 g, 2.956 mol) was added while keeping the mixture at 0-10° C. After dropping ethyl 4-mercaptobutyrate (438 g, 2.956 mol) slowly, the mixture was heated to 20° C. and then stirred at 20-30° C. for 1 hour. At 20-30° C., 8940 ml of diethyl carbonate was added and subsequently a solution of 20% sodium ethoxide (2012 g and 5.912 mol) in ethanol was dropped. The mixture was stirring at 20-30° C. for 3 hours and then cooled to 5° C. After adding 4.35 L of a 2N hydrochloric acid while maintaining the temperature at 10° C. or lower, phase separation was conducted and the water layer was extracted with 3.75 L of ethyl-acetate. The organic layers were combined and washed with 4 L of water, 4 L of a 5% aqueous sodium hydrogencarbonate solution, and 4 L of a 5% brine. Activated carbon Shirasagi A (45 g) and then tri-n-butyl phosphine (51 ml) were added. The mixture was stirred at room temperature for 20 minutes and then filtered. The residue was washed with 1.2 L of ethyl acetate. The filtrate was concentrated under vacuum, 1.2 L of isopropanol was added and then vacuum concentration was conducted (twice). After addition of 1.2 L of isopropyl ether and vacuum concentration, 900 ml of isopropyl ether was added to the oily matter obtained. Crystals formed during stirring at room temperature were dissolved by heating under reflux. After cooling and stirring for 2.5 hours and stirring for 2 hours while cooling in ice, the mixture was filtered and the residue was washed with 900 ml of ice-cooled isopropyl ether. Through vacuum drying (40° C.), 344.8 g (Yield from 5-bromo-2-fluorobenzaldehyde: 57%) of ethyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([F:16])[CH:5]=1.[CH:17](OCC)=[O:18].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:17]=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([F:16])[CH:5]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1F
Reaction time: 0.5 h

Procedure:
Then, 3.6 g of sodium hydride (60% in oil) was suspended in 120 ml of tetrahydrofuran, and the mixture was cooled to 5° C., to which a solution of 17.8 g of ethyl 4-choro-2-fluorophenylacetate in 120 ml of tetrahydrofuran was slowly added drop-wise. The mixture was stirred for 30 minutes with a gradual temperature increase to room temperature, to which 20 ml of ethyl formate was added at room temperature, followed by stirring for 3 hours. Then, the reaction mixture was cooled with ice, to which diluted aqueous hydrochloric acid was added. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 19.1 g of ethyl 2-(4-chloro-2-fluorophenyl)-2-formylacetate.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.O>ClCCCl>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: O
Product: Fc1ccccc1CNc1ccc(I)cc1
Yield: 109.5 %

Procedure:
A solution of 4-iodoaniline (1 g, 4.5 mmol), 2-fluorobenzaldehyde (0.48 ml, 0.566 g, 4.5 mmol) and triacetoxyborohydride (1.9 g, 9.0 mmol) in 1,2-dichloroethane (20 ml) was stirred for 4 days at room temperature. After addition of water the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound (1.612 g, quant.). The crude material was used without further purification. MS: (ES/+) m/z: 328 [MH+], C13H11FIN requires 327; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.4-7.1 (m, 6H), 6.4 (d, 2H), 4.3 (m, 1H), 2.5 (m, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 42 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and ethyl chloroformate. Yield: 42% of theory, C28H29N7O5 (543.6) Rf value: 0.20 (silica gel; dichloromethane/ethanol=19:1) EKA mass spectrum: (M+H)+ =544
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:16]1([CH2:22][CH2:23]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(CC)=O>[CH:16]1([CH2:22][CH2:23][N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrCCC1CCCCC1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 42.8 %

Procedure:
A suspension of 24.1 g (0.12 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole, 28.3 g (0.15 mol) of 2-cyclohexylethyl bromide, 26.3 g (0.19 mol) of potassium carbonate and 6.22 g (0.04 mol) of sodium iodide in 550 ml of ethyl methyl ketone was boiled at reflux for 3 days. The solid was filtered off and the solvent was distilled in a vacuum. The residue was dissolved in ethyl acetate, whereupon the solution was washed with water and sodium chloride solution and concentrated. After chromatography over silica gel (ethyl acetate-methylene chloride 1:2) there were obtained 16.1 g (43%) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]indole as a beige oil. MS: m/e (% basis peak): 313 (M+,11), 217 (21), 216 (100), 108 (13), 44 (13).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([CH2:34][C:35]([OH:37])=[O:36])[CH:9]=[C:10]([Br:33])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[C:15](OC)[C:14]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>C(Cl)Cl>[Br:33][C:10]1[CH:9]=[C:8]([CH2:34][C:35]([OH:37])=[O:36])[CH:7]=[C:6]([Br:5])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:12][CH2:13][CH2:18][C:17]([CH3:19])=[CH2:16])=[CH:15][C:14]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1
Reactant: COc1cc(C(C)C)cc(Oc2c(Br)cc(CC(=O)O)cc2Br)c1C(=O)c1cccc(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Reaction time: 0.25 h

Procedure:
A 1M solution of BBr3 in CH2Cl2 (12 mL, 12 mmol) was added slowly with a syringe to a stirred solution of 3,5-dibromo-4-[5-isopropylmethoxy-2-(3-methylbenzoyl)phenoxy]-phenylacetic acid (2 g, 3.5 mmol) in 20 mL CH2Cl2 at −20° C. After 15 min at −20° C. the solution was allowed to reach room temperature. After an additional 1 h at room temperature, the solution was poured onto ice and extracted three times with EtOAc. The combined extracts were dried over MgSO4 and concentrated to give the title compound which was used in the next step without further purification. 1H NMR (CDCl3): δ 7.8–7.7 (m, 2H), 7.5 (s, 2H), 7.4−7.3 (m, 2H), 6.9 (s, 1H), 6.2 (s, 1H), 3.6 (s, 2H), 3.3–3.2 (m, 1H), 2.4 (s, 3H), 1.1 (d, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+]>[Pd].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(O)C.O>[CH3:9][O:12][C:2]1[CH:7]=[CH:6][C:5]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:2]3[CH:7]=[CH:6][C:5]([O:12][CH3:9])=[CH:4][CH:3]=3)[CH:3]=2)=[CH:4][CH:3]=1
Reactant: Ic1cccc(I)c1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cccc(-c3ccc(OC)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 277.3 %

Procedure:
A mixture of a mixed solvent (toluene/ethanol/water=5/5/1; 1,600 ml), the compound (T-6) (75.9 g, 499.4 mmol), 1,3-diiodobenzene (75.0 g, 227.3 mmol), 5% palladium on carbon (3.75 g), potassium carbonate (94.1 g, 681.0 mmol) and tetrabutylammonium bromide (18.29 g, 56.7 mmol) was refluxed with stirring for 15 hours under an atmosphere of nitrogen. The resulting reaction mixture was cooled to room temperature, and deposits were collected by filtration. The deposits were recrystallized from a mixed solvent of THF and ethyl acetate to give colorless crystals (61.0 g) of 4,4″-dimethoxy-(1,1′:3′,1″)-terphenyl (T-7).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=[O:11].[C:15](=O)([O-])[O-:16].[K+].[K+].C=O>C(O)C>[OH:16][CH2:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1[nH]c2ccccc2c1CO
Temperature: 25 °C

Procedure:
Ethyl indole-2-carboxylate (5.87 gm) in absolute ethanol (85 ml) was combined with potassium carbonate (4.3 gm) and 37% formaldehyde (2.6 gm) and heated to reflux for four days. The mixture was cooled to room temperature and the solvents removed on a rotary evaporator. The residue was dissolved in water (100 ml) and the water solution was washed with ether (2×50 ml). The aqueous solution was made acidic with 3.6 N sulfuric acid and the resulting mixture was extracted with methylene chloride (2×50 ml) and ether (2×50 ml). The combined organic layers were dried over magnesium sulfate and the solvent removed on a rotary evaporator. The residue was dissolved in acetone and purified by preparative centrifugally accelerated radial thin layer chromatography on silica gel using 10% methanol in methylene chloride as eluant. The product was obtained as an off-white solid. Physical data are reported in Table I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[CH:16][CH:17]=1)=[O:23])([CH3:39])[CH3:35]
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol) and TBTU (92 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (221 μL, 1.29 mmol). Then isopropylamine (25 μL, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (84 mg, 88%) as a light yellow solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.Cl.[C:17](Cl)(Cl)=[S:18]>CCOCC.C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([N:7]=[C:17]=[S:18])=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 77.9 %

Procedure:
Unless otherwise indicated, all thioureas, isothiocyanates, thioamides and amines were purchased from Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Transworld Chemical Co. (Rockville, Md.), or Aldrich Chemical Co., (Milwaukee, Wis.). (a) 4-Amino-4′-chlorodiphenylether (TCI America, Portland Oreg., 520 mg, 2.03 mmol) was slurried in 10 mL of ether and treated with ca. 1 mL of ether saturated with HCl gas. After 5 min. the solvent was removed in vacuo. To a stirring biphasic solution amine-HCl salt in 20 mL CHCl3-sat'd NaHCO3 (1:1, v/v) at ambient temperature was added thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of CHCl3 dropwise via an addition funnel. The reaction was vigorously stirred for 1 h (TLC, 50% ethyl acetate-hexanes indicates clean conversion to a higher Rf spot), at which time the layers were separated, the aqueous layer extracted with CHCl3 (1×20 mL), and the combined organic layers washed with brine (1×20 mL) and dried (Na2SO4). Concentration of the solvent in vacuo yielded the crude 4-(4-chlorophenoxy)-phenylisothiocyanate (414 mg). (b) The 4-(4-chlorophenoxy)-phenylisothiocyanate was transferred to an Ace Glass pressure tube equipped with a Teflon coated stir bar and treated with a 2.0 M solution of NH3 in 5 ml methanol (Aldrich Chemical Co., Milwaukee, Wis.)). The tube was sealed and immersed in a 80° C. oil bath. After 2 h, the reaction was cooled to 0° C. in an ice bath. The precipitates were filtered and dried under vacuum to yield amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (328 mg, 79%). 1H NMR (DMSO-d6, 300 MHz) 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C13H11ClN2OS, 278.8 (M+H), found 279.4.