Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC=C[C:5]=1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)(O)=O.[CH:28]1[N:32]2C3CC4C=CC=CC=4C=3NC(=O)[C:31]2=[N:30][CH:29]=1.CN1C=CN=C1C=O.[H-].[Na+]>CS(C)=O>[CH3:31][N:30]1[CH:29]=[CH:28][N:32]=[C:5]1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: O=C(O)c1ccccc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: Cn1ccnc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ccnc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12

Procedure:
The process is performed as in Example 3 for the preparation of 10-(2-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one but starting with 4.46 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one, 80 ml of dimethyl sulphoxide, 2.6 g of 1-methyl-2-formylimidazole and 1.44 g of 80% sodium hydride. After treatment of the reaction mixture with 80 ml of water and 3 ml of acetic acid, the suspension is filtered and the red solid obtained is washed with methanol and air-dried to give 5 g of 10-[(1-methylimidazol-2-yl)methylene]-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one. The dihydrochloride is formed by adding 3 ml of 3N hydrochloric acid solution in-ethyl ether to a suspension of 1.5 g of crude base in 50 ml of methanol. The yellow precipitate formed is filtered off and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 1.75 g of 10-[(1-methylimidazol-2-yl)methylene]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one dihydrochloride are obtained, melting above 260° C. (Analysis, % calculated C: 55.68, H: 3.89, ° Cl: 18.26, N: 18.04, O: 4.12, % found C: 55.8, H: 3.9, N: 17.9).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15](OC(C)=O)=O>>[CH3:14][C:15]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(C(=O)O)cccc1C(=O)O
Product: Cc1nc2c(C(=O)O)cccc2c(=O)o1
Temperature: 140 °C
Yield: 89 %

Procedure:
2-Aminoisophthalic acid (50.0 g; 276.0 mmol) and Ac2O (250.0 ml; 5.00 V) were combined and heated to 140° C. for 4 h. The reaction mixture was cooled to room temperature and distilled under high vacuum on the rotary evaporator. The remaining AcOH was removed by azeotropic distillation with toluene. The residue was slurried with ethyl ether, filtered, and the solid was dried under vacuum to provide the desired intermediate (50.3 g, 89% yield).
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:19]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:17][O:16][C:11]1[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:29][C:25]4[CH:24]=[C:23]5[C:28](=[CH:27][CH:26]=4)[N:19]=[CH:20][CH:21]=[CH:22]5)[N:18]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: COc1ncccc1-c1cccn2nc(Cl)nc12
Product: COc1ncccc1-c1cccn2nc(Nc3ccc4ncccc4c3)nc12

Procedure:
[8-(2-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-quinolin-6-yl-amine was prepared from 2-chloro-8-(2-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and quinolin-6-ylamine in a manner analogous to Example 2d (0.12 g, 65%). MP=247-249° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (s, 1H), 8.88 (d, J=6.58 Hz, 1H), 8.75 (d, 1H), 8.45 (d, 1H), 8.25 (d, 1H), 8.15 (t, 1H), 7.85-7.90 (m, 2H), 7.55 (m, 1H), 7.42 (m, 1H), 7.10 (m, 1H), 3.90 (s, 3H). MS=369 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2].Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:31].[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(O)cc4)cc3)ccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(OCCN5CCOCC5)cc4)cc3)ccn2c1=O
Yield: 70 %

Procedure:
A solution of 6-ethyl-1-[4-(4-hydroxybenzoyl)-benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (136 mg), 4-(2-chloroethyl)morpholine hydrochloride (154 mg) and potassium carbonate (205 mg) in DMF (7 ml) was stirred at 100° C. for 6 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (132 mg).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15](=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=1.[O:29]1CCC[CH2:30]1>CN1CCCN(C)C1=O.[Au]>[CH3:13][O:14][C:15](=[O:28])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:25])[F:26])[CH:18]=1)[CH2:11][C@H:10]1[CH2:9][CH2:8][CH2:30][O:29]1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: [Au]
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C[C@H]1CCCO1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of diisopropylamine (1.86 mL, 13.29 mmol) in dry tetrahydrofuran (45 mL) cooled to −78° C. under argon was treated with a 2.5M solution of n-butyllithium in hexanes (5.10 mL, 12.75 mmol). The reaction mixture was stirred at −78° C. for 30 min and then was treated dropwise with a solution of (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid methyl ester (2.51 g, 10.63 mmol) in dry tetrahydrofuran (15 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (6.5 mL). The reaction mixture turned gold in color and was allowed to stir at −78° C. for 1 h. At this time, the reaction was treated with a solution of trifluoromethanesulfonic acid (R)-tetrahydro-furan-2-yl methyl ester (prepared as in Example 3, 3.23 g, 13.81 mmol) in dry tetrahydrofuran (15 mL). The reaction mixture was allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (30 mL) and was then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 85/15 hexanes/ethyl acetate) afforded 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (2.50 g, 39%) as a colorless oil: [α]23589=−18.62° (c=0.29, chloroform); EI-HRMS m/e calcd for C15H20O3S (M+Na)+ 343.0928, found 343.0927.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCCNCC(=O)O
Yield: 77 %

Procedure:
To a solution of 13.0 g. (5.46×10-2 moles) of N-(o-nitrobenzyl)ethyl glycine in 200 ml. of absolute ethyl alcohol was added slowly 0.76 g. (5% by weight) of 10% Pd/C catalyst and the mixture placed on a Paar hydrogenator. The mixture was shaken until theoretical hydrogen (16.4×10-2 moles) had been absorbed, removed from the Paar and the mixture filtered under suction. The catalyst was washed with ethyl alcohol and the solvent removed in vacuo affording a yellow oil. Purification of the oil was effected by distillation yielding 8.8 g. (77% yield) of a colorless oil; b.p. 124°-126° C. (0.03 mm).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:18]1[C:26]2[O:25][CH2:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:28][CH3:29]>C(N(CC)CC)C.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.[Cu]I>[CH3:29][O:28][C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:27])[CH2:24][O:25][C:26]=2[C:18]=1[C:3]#[C:2][CH2:1][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A solution of tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (0.449 g, 2.00 mmol) in triethylamine (12 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.580 g, 2.00 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.141 g, 0.200 mmol) and copper(I) iodide (0.0381 g, 0.200 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated, then the solid was suspended in a mixed solvent of 50% ethyl acetate in hexane, and the suspension was filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.473 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[S:14])[C:11]#[N:12])=[CH:5][CH:4]=1.I[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C>C(#N)C>[C:11]([C:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:14][C:13]=1[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)#[N:12]
Reactant: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Reactant: CCOC(=O)CI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1SC(N2CCOCC2)=C(C#N)C1c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile (from step 1), ethyl iodoacetate (0.25 mL, 2.1 mmol) and DIPEA (0.5 mL, 2.9 mmol) was dissolved in ACN (2 mL) and subjected to MWI at 150° C. for 10 min. The mixture was allowed to cool and was concentrated. The residue was diluted with 5% sodium bisulfite solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-yl-2,3-dihydrothiophene-2-carboxylate (0.168 g, 63% over two steps). LCMS: (AA) ES+ 375, ES− 373.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][C:27]=1[Cl:28])/[CH:17]=[N:18]/S(C(C)(C)C)=O.Cl>CCOCC.CO.C1COCC1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[NH2:18])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: Ic1ccccn1
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(c1ccc(Cl)c(Cl)c1)c1ccccn1
Temperature: -100 °C
Reaction time: 0.25 h

Procedure:
A 250-mL round-bottomed flask was charged with 2-iodopyridine (1.0 g, 4.88 mmol) and 50 mL of THF. The resulting mixture was cooled to −100° C. and then n-BuLi (2.5 M in hexanes, 5.3 mL, 13 mmol) was added at such a rate that the internal temp did not rise above −97° C. After 15 min at −100° C., (E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide (1.36 g, 4.88 mmol) was added and stirring was continued for 1 h at −100° C. 30 mL of 1M HCl in ether was added, and the mixture was allowed to warm to rt. Once at rt, 5 mL of MeOH was added and the mixture was stirred for an additional 1 h. The resulting precipitate was collected by filtration to give (3,4-dichlorophenyl)(pyridin-2-yl)-methanamine hydrochloride as a white solid.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[Br:17][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(O)c1cccc(-c2ccccc2)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CC(Br)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Yield: 0 %

Procedure:
To a solution of 3.97 g (20 mmol) of 3-(1-hydroxyethyl)biphenyl in 60 ml of dry diethyl ether was added dropwise 2.70 g (9.0 mmol) of phosphorous tribromide with ice-cooling, and the mixture was further stirred with ice-cooling for 3 hours. To the reaction solution were added ice water and tert-butyl methyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, dried and concentrated to obtain 3.73 g (14.28 nmol) of 3-(1-bromoethyl)biphenyl as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])=[CH:18][CH:17]=2)=[C:4]([O:32]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:24][CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:32])=[CH:17][CH:18]=1)[CH3:23]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CC(N)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 103.1 %

Procedure:
Following General Procedure F, tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (50 mg, 0.10 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 2 mL, 2 mmol) to afford the desired product (21 mg, 58%) as a light yellow solid (21 mg, 58%): 1H NMR (500 MHz, CD4OD) δ 7.65 (dt, J=5.2, 3.4 Hz, 2H), 7.59 (d, J=5.4 Hz, 1H), 7.41 (dt, J=4.0, 2.6 Hz, 2H), 7.30 (s, 1H), 6.07 (d, J=: 5.4 Hz, 1H), 4.62 (q, J=6.8 Hz, 1H), 1.76 (d, J=6.9 Hz, 3H); ESI MS m/z 371 [C19H15ClN1O2S+H]+; HPLC 97.8% (AUC), tR=9.72 min.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C([O-])([O-])=O.[Cs+].[Cs+].C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C.Cl>CN(C=O)C.O>[OH:17][C:18]1[CH:19]=[CH:20][N:6]2[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]2[N:1]=1
Reactant: N#Cc1cn[nH]c1N
Reactant: CCOC=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnn2ccc(O)nc12
Temperature: 100 °C
Yield: 96.7 %

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (2.70 g, 25.0 mmol) and Cs2CO3 (16.3 g, 50.0 mmol) in dry DMF (70 mL) was added ethyl 3-ethoxyacrylate (5.41 g, 37.5 mmol) and the mixture was heated at 100° C. for 4 hours. The mixture was cooled to ambient temperature and the resultant slurry was poured into deionized H2O (150 mL). The resulting aqueous solution was cooled on an ice bath and concentrated HCl was added slowly with mixing to pH=3.5. The resulting precipitate was collected, washed with H2O followed by Et2O. The solid was dried in vacuum to afford the product as a light beige powder (3.87 g, 97%). MS (apci) m/z=159.0 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[I:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([I:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(I)cc1
Yield: 92.2 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 4-iodobenzenesulfonyl chloride (Acros, 155 mg, 0.52 mmol) in THF. 254 mg (93%) of 101 was obtained as a pale yellow solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1)[CH3:13].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])=[O:27]>CN(C)C=O>[NH2:4][C:3]1[C:2]([C:1]#[N:5])=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[CH:16][CH:17]=2)[S:23][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37]
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: N#CCC#N
Reactant: CCOc1ccc(N=C=S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Nc2sc(C(=O)c3ccc(OC)cc3OC)c(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a stirred solution of malononitrile (0.40 g, 6.1 mmol) in dimethylformamide (DMF) (5 mL) was added potassium carbonate (1.68 g, 12.2 mmol, 2 eq.). The mixture was stirred at room temperature for 15 minutes, and 4-ethoxyphenyl isothiocyanate (1.07 g, 6.1 mmol) was added. After stirring for an additional 30 minutes, 2-bromo-2′,4′-dimethoxy-acetophenone (1.57 g, 6.1 mmol, 1 eq.) was added, and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure, and water (20 mL) was added to the residue. The resulting solid was collected by filtration and dried under vacuum to give 2.80 g of crude product as a yellow solid. This crude product was combined with two similar batches (altogether totaling 7.7 g of crude product) and purified by silica gel column chromatography, eluting with hexane/ethyl acetate (2:1 then 1:1) to give 4-amino-5-(2,4-dimethoxybenzoyl)-2-[(4-ethoxyphenyl)amino]thiophene-3-carbonitrile (2.2 g) as a yellow-brown solid. 1H NMR (DMSO-d6): δ 10.24 (1H, s), 7.79 (2H, br.s), 7.21 (2H, d, J=8.6 Hz), 7.09 (1H, d, J=8.6 Hz), 6.91 (2H, d, J=9.0 Hz), 6.56 (1H, d, J=2.0 Hz), 6.49 (1H, dd, J=8.4 Hz, J=2.2 Hz), 4.02-3.96 (2H, q, J=7.0 Hz), 3.76 (3H, s), 1.92-1.57 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[Br:18][C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[Br:18][C:19]1[N:24]=[C:23]([CH:25]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[OH:26])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2cc(-c3ccccc3)[nH]c2c1
Reactant: O=Cc1cccc(Br)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc2c(C(O)c3cccc(Br)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 87.4 %

Procedure:
To a suspension of 6-methoxy-2-phenyl-1H-indole (893 mg) and 6-bromopyridine-2-carboaldehyde (744 mg) in dichloromethane (13.3 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.060 mL), and the mixture was stirred at room temperature for 13 hours under an argon atmosphere. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.43 g). 1H-NMR (CDCl3) δ ppm: 3.81 (3H, s), 4.71 (1H, d, J=2.6 Hz), 6.09 (1H, d, J=2.6 Hz), 6.65 (1H, dd, J=2.3, 8.7 Hz), 6.86 (1H, d, J=2.3 Hz), 7.02-7.13 (2H, m), 7.33-7.54 (5H, m), 7.64-7.72 (2H, m), 8.10 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-benzenesulfonamide was synthesized (76%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (br s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.70-7.65 (m, 2H), 7.54 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.20 (s, 2H), 4.48 (s, 2H). MS (EI): m/z 509 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH2:14][CH:15]([CH3:17])[CH3:16].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Cn1ccc2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-bromo-1H-indole (1 g) in DMF (dry) (10 mL) was added NaH (60%, 0.612 g) at room temperature. The mixture was stirred at 80° C. for 10 min. 1-Iodo-2-methylpropane (0.587 mL) was added at room temperature and the mixture was stirred at 80° C. for 1 hr. Another 1-iodo-2-methylpropane (0.587 mL) was added and the mixture was stirred at 80° C. for 1 hr. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (554 mg) as colorless oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.[C:9]1([N:15]2[C:19](=[O:20])[C:18]3=CC=CC=[C:17]3[C:16]2=[O:25])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:4]1(=[O:6])[O:7][C:1](=[O:8])[C:2]2=[CH:14][CH:9]=[CH:10][CH:11]=[C:3]12.[C:9]1([N:15]2[C:19](=[O:20])[CH:18]=[CH:17][C:16]2=[O:25])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1
Reactant: O=C(O)/C=C\C(=O)O
Solvent: O
Product: O=C1C=CC(=O)N1c1ccccc1
Product: O=C1OC(=O)c2ccccc21
Temperature: 180 °C

Procedure:
A mixture of 2.32 parts of maleic acid, 2.23 parts of N-phenyl phthalimide and 20 parts of water is heated under sealed conditions for 2 hours at 180° C. The reaction mixture is then allowed to cool to ambient conditions and distilled under vacuum. Maleic anhydride is initially recovered followed by phthalic anhydride and N-phtnyl maleimide. There is obtained a yield of 16% by weight of phthalic anhydride and 14.1% by weight of N-phenylmaleimide.