Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[N:9]#[N:10].Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH:20]=[C:19]([S:26]([NH:29][C@H:30]([C:38]([N:40]([CH2:45][CH2:46][O:47][CH3:48])[CH2:41][C:42]([Cl:44])=[O:43])=[O:39])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:37])[NH2:36])(=[O:28])=[O:27])[CH:18]=[CH:17]2>>[N:9]#[N:10].[ClH:44].[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][C:42](=[O:43])[CH2:41][N:40]([C:38](=[O:39])[C@H:30]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:36])[NH2:37])[NH:29][S:26]([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[CH:20]=2)(=[O:28])=[O:27])[CH2:45][CH2:46][O:47][CH3:48])[CH:1]=1
Reactant: Cc1cccc(O)c1
Reactant: COCCN(CC(=O)Cl)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: Cl
Agent: N#N
Product: COCCN(CC(=O)Oc1cccc(C)c1)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 90 °C
Yield: 86 %

Procedure:
A mixture of 2.00 g of m-cresol and N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride obtained above was heated at 90° C for 50 minutes. At the end of this period, the reaction mixture was cooled, washed several times with dry ethyl ether, and then dissolved in 10 ml of dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed several times with dry ethyl ether to give 2.12 g (86 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine m-tolyl ester hydrochloride in the form of a powder.
Reaction SMILES: [OH-].[OH:2][P:3]([O:12][CH2:13][CH:14]1[CH2:18][CH:17]([S:19][C:20]2[CH:26]([CH3:27])[CH:25]3[N:22]([C:23](=[O:31])[CH:24]3[CH:28]([OH:30])[CH3:29])[C:21]=2[C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])[CH2:16][O:15]1)([O:5]C([N+](C)(C)C)C)=[O:4].C(=O)(O)[O-].[Na+].O.O1[CH2:56][CH2:55]OCC1>[Pd]>[OH-:2].[C:32]([C:21]1[N:22]2[CH:25]([CH:26]([CH3:27])[C:20]=1[S:19][CH:17]1[CH2:16][O:15][CH:14]([CH2:13][O:12][P:3]([OH:2])([O:5][CH2:55][CH2:56][N+:22]([CH3:25])([CH3:23])[CH3:21])=[O:4])[CH2:18]1)[CH:24]([CH:28]([OH:30])[CH3:29])[C:23]2=[O:31])([OH:34])=[O:33]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COP(=O)(O)OC(C)[N+](C)(C)C)C3)C(C)C12
Reactant: C1COCCO1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(COP(=O)(O)OCC[N+](C)(C)C)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.387 g of product from Example 91, 0.046 g of sodium bicarbonate, 4 ml of water, 19 ml of dioxane, and 0.050 g of 10% palladium/carbon to give 0.031 g of the desired product.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CN.[CH3:30][N:31](C=O)C>O>[CH3:30][NH:31][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CNc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.55 g of potassium carbonate, 0.14 g of methylamine hydrochloride, and 3 ml of DMF was stirred while heating at 60° C. for three hours. To the mixture, 0.55 g of potassium carbonate and 0.14 g of methylamine hydrochloride were added, and the reaction mixture was stirred while heating for further two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and resultant crystals were washed with diethyl ether to give 0.13 g of methyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]amine (hereinafter, referred to as “active compound 83”).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14](O)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14]([NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: NCCc1ccncc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)O)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
2,5-digeranyloxybenzoic acid(2.40 g) was dissolved in chloroform(40 ml) and triethylamine(1.58 ml), and then diphenylphosphinic chloride(1.08 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.69 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.90 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22](NC)=[N:21][CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.ClC1C=CC2C(C3C=CC(Cl)=CC=3)=[N:34][CH2:33]C3ON=C(C)C=3C=2N=1.ClC1C=CC(C2C3C(F)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:10]=[CH:19][C:20]([NH:34][CH3:33])=[N:21][C:22]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Reactant: CNc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Agent: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: CNc1ccc2c(n1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1

Procedure:
A procedure similar to 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine was followed, except that 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine was used as starting material instead of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine. LC/MS m/z 339 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.42 (td, J=2.30, 8.70 Hz, 2H), 7.39-7.35 (m, 3H), 7.22 (d, J=8.72 Hz, 1H), 6.41 (d, J=8.93 Hz, 1H), 4.63 (br. s, 2H), 2.91 (d, J=4.57 Hz, 3H), 2.58 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC(=O)O)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate (98 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 2M HCl was added until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoic acid as off-white solid. Yield: 90 mg, 95%.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8](O)[CH2:9][OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OCC(O)CC)(=O)C(C)=C.C(OCCCCO)(=O)C(C)=C.C(OCCC(O)CO)(=O)C(C)=C.C(OCCCCCO)(=O)C(C)=C.C(OCCCCCCO)(=O)C(C)=C.C(OC(C)CC(C)(O)C)(=O)C(C)=C.C(OCCCCC(O)CO)(=O)C(C)=C.C(OCCCCCCCO)(=O)C(C)=C>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC(O)CO
Agent: C=C(C)C(=O)OC(C)CC(C)(C)O
Agent: C=C(C)C(=O)OCC(O)CC
Agent: C=C(C)C(=O)OCCC(O)CO
Product: C=C(C)C(=O)OCCCO

Procedure:
2,3 dihydroxypropyl methacrylate; 2-hydroxybutyl methacrylate; 4-hydroxybutyl methacrylate; 3,4-dihydroxybutyl methacrylate; 5-hydroxypentyl methacrylate; 6-hydroxyhexyl methacrylate; 1,3-dimethyl-3-hydroxybutyl methacrylate; 5,6 dihydroxyhexyl methacrylate; and 7-hydroxyheptyl methacrylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.CCOCC.[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:12]2([OH:16])[C:10]3[CH:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][C:9]=3[CH2:15][CH2:14][CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C1CCCc2sc(-c3ccncc3)cc21
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC1(c2ccc(Cl)cc2)CCCc2sc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 250 mL round bottomed flask was placed 2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (1400 mg, 6.1 mmol) and then dissolved in tetrahydrofuran (50 mL). To the mixture was added 1 M of 4-chlorophenylmagnesium bromide in ether (10 mL, 10 mmol) and the mixture was stirred for 1.5 h at rt. To the mixture were added a 5% aqueous solution of NH4Cl (100 mL) and EtOAc (100 mL). The resulting bi-phasic mixture was vigorously stirred for 15 min and then the aqueous phase was discarded. The organic phase was washed with brine (50 mL), and then dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography eluted with a 20% to 80% EtOAc/hexane to obtain 4-(4-chlorophenyl)-2-pyridin-4-yl-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (2.9 g) as a colorless foam.
Reaction SMILES: C([O:5][C:6](=[O:37])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:36])[CH:13]([CH3:35])[CH2:14][S:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[SH:15][CH2:14][CH:13]([CH3:35])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:37])=[O:5])=[O:36]
Reactant: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester (5 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.). After one hour storage at room temperature, the solvents are removed in vacuo and the residue is applied to a column of silica gel equilibrated with benzene:acetic acid (75:25) and eluted with the same solvent. The fractions corresponding to the component with Rf 0.40 (TLC silica gel with same system) are pooled and concentrated to dryness to yield 1-[3-mercapto-2-methylpropanoyl]-L-proline. Rf 0.62 (silica gel, chloroform/methanol: acetic acid:water 50:40:10), identical to the compound of Example 34.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH:29]([CH3:35])[C:30](OCC)=[O:31].CN(C)C=O>O>[CH3:35][CH:29]1[S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26][C:30]1=[O:31]
Reactant: CCOC(=O)C(C)Br
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: O
Solvent: CN(C)C=O
Product: CC1SC(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)=NC1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 1.00 g (2.60 mmol) of the starting material I, 0.94 g (5.19 mmol) of ethyl 2-bromopropionate and 10 ml of dimethylformamide was stirred at 80-90° C. for 2 h. After diluting with water the obtained crude product was purified by refluxing in 15 ml of ethanol to yield 1.08 g (95%) of the title compound; Mp.: 213-214° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 110 °C
Yield: 63.3 %

Procedure:
649 mg (corresponding to 3.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 285 mg (corresponding to 3.0 mmol) of 2-aminopyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for one hour. After the reaction solution was cooled down to room temperature, 254 mg (corresponding to 5.4 mmol) of sodium hydrogencarbonate was added thereto. The resulting mixture was refluxed in an oil bath at 100° C. for one hour. After the completion of the reaction, the reaction solution was cooled to room temperature, and precipitates were filtered and recovered therefrom. The precipitates were washed with acetonitrile and water, and then dried under reduced pressure to obtain 405 mg (corresponding to 1.9 mmol) of 2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 4, Step 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([OH:11])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2cc(F)ccc2c1O

Procedure:
Prepared as in Example 1c from 3-fluoroaniline and diethyl 2-(ethoxymethylene)malonate as a brown solid (51%). MS 236 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC=CC=1.C(OCC)C>[CH2:30]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc(Cn2ccc3ccccc32)cc1
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of indole (1) (0.03 mole, 3.51 g), potassium hydroxide (0.03 mole, 1.97 g)) powdered in a mortar and 18-crown-6 ether (0.001 mole, 250 mg) in benzene (20 cm3) is heated under reflux with vigorous stirring for two hours. A solution of benzyl chloride (26) (0.04 mole, 5.06 g) in benzene (10 cm3) is added to the above mixture and reflux is maintained for an additional four hours. The reaction is monitored by TLC. The reaction mixture is filtered on Celite. Evaporation of the solvent gives an orange liquid which is purified by dry column chromatography eluted using a mixture of dichloromethane in 50% petroleum ether. Evaporation of the solvent gives a colourless thick liquid which is solidified in the presence of diethyl ether to give a white solid of 1-benzylindole (3b) (1.2 g, 0.007 mole, 25%), m.p. 48-51° C., shown to be pure by 1H nmr.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]1[CH2:16][NH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=2)=[N:13]1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:18]=2)[NH:15][CH:16]=1
Reactant: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c[nH]c(-c2ccnc(NC(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of oxalyl chloride (0.06 mL, 0.72 mmol) in anhydrous dichloromethane (1.0 mL) was added anhydrous dimethyl sulfoxide (0.09 mL, 1.20 mmol) dropwise at −78° C. under nitrogen atmosphere. The resulting solution was stirred for 10 minutes, followed by dropwise addition of a solution of N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide (0.17 g, 0.60 mmol) in anhydrous dichloromethane (1.5 mL). The reaction mixture was stirred for 40 minutes, followed by the addition of anhydrous triethyl amine (0.33 mL, 2.38 mmol), warmed to ambient temperature during 3 hours and partitioned between water (15 mL) and dichloromethane (25 mL). The aqueous layer was extracted with dichloromethane (2×25 mL). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with ethyl acetate followed by methanol in ethyl acetate (1:25 ratio) to give N-(4-(4-methyl-1H-imidazol-2-yl)pyridin-2-yl)benzamide as a colorless solid (0.05 g, 38%): mp 133-135° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.81 (s, 1H), 8.69 (s, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.08-8.03 (m, 2H), 7.64-7.49 (m, 4H), 6.95 (br s, 1H), 2.24 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 168.5, 154.1, 149.8, 144.5, 140.8, 135.6, 133.4, 129.8, 128.8, 116.9, 111.4, 11.6; MS (ES+) m/z 279.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Bromo-4-methanesulfonyl benzene (50.78 g, 213 mmol) was placed in a 3-necked round bottomed flask and purged with argon. Copper(I) iodide (2.05 g, 10.6 mmol) and bis(triphenylphosphine)palladium(II) chloride (PdCl2(PPh3)2) (7.55 g, 10.6 mmol) were added while purging with argon, followed by the addition of triethylamine (200 mL) and anhydrous dichloromethane (200 mL). (Trimethylsilyl)acetylene (61 mL, 425 mmol) was added and the reaction mixture was stirred at room temperature over 72 hours. The mixture was concentrated, then partitioned between ethyl acetate and water. The combined organic layers were washed with 1 N hydrochloric acid, water, and brine, dried over magnesium sulfate, filtered, and concentrated to afford crude (4-methanesulfonyl-phenylethynyl)-trimethyl-silane (54 g, 213 mmol), which was used in the next step without further purification. MS (ESI+) cald. for C12H16O2SSi [(M+H)+] 252, obsd. 253.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:21]([OH:23])[CH3:22].O>C(N(CC)CC)C>[N+:18](=[C:14]([C:15](=[O:17])[CH3:16])[C:13](=[O:20])[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([O:23][CH2:21][CH3:22])(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[N-:19]
Reactant: CCO
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)c1ccc(CCC(=O)C(=[N+]=[N-])C(C)=O)cc1

Procedure:
6-(4-Chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (2.0 g, 6.4 mmol) obtained in Example 3, (3) was stirred in triethylamine (1.5 ml) and ethanol (5 ml) for 16 h at room temperature, then the mixture was poured into H2O and extracted thrice with chloroform. The organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was chromatographed on silica gel (Wako Gel C-200) with chloroform as eluent to give the title compound as a pale yellow viscous oil; yield: 550 mg.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:12][CH2:11][S:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[C:7]1([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)O)[CH3:4].OO.C(OCC)(=[O:28])C.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]([CH3:4])[CH2:5][C:6]1[CH2:12][CH2:11][S:10](=[O:28])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[C:7]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: CN(C)CC1CCSc2ccccc2C1(O)c1cccnc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CC1=C(c2cccnc2)c2ccccc2S(=O)CC1
Reaction time: 24 h

Procedure:
0.5 g of 4-dimethylaminomethyl-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b]thiepin-5-ol hydrochloride was dissolved in 2.5 ml of glacial acetic acid; about 0.23 ml of 35% hydrogen peroxide solution was added dropwise at room temperature, with stirring, and stirring was continued for 24 hours. The reaction mixture was covered with a layer of ethyl acetate, while cooling with ice, rendered alkaline with 32% sodium hydroxide solution and extracted twice with ethyl acetate; the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. 0.38 g of crude product was obtained and was chromatographed on silica gel with ethyl acetate/25% ammonia solution (v/v=98:2). 0.15 g of a mixed fraction and 0.13 g of dimethyl-(1-oxo-5-pyridin-3-yl-2,3-dihydro-1H-1λ4-benzo[b]thiepin-4-ylmethyl)-amine were obtained. The latter was dissolved in 6 ml of 2-acetone p.a. and converted into the corresponding hydrochloride with about 0.004 ml of water and about 0.043 ml of chlorotrimethylsilane, while cooling with ice; the hydrochloride was dried in vacuo (about 50 mbar) (yield 0.09 g of white solid).