Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[Br:16].[N:17]([O-])=O.[Na+]>Cl.O>[Br:16][C:3]1[CH:4]=[C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][NH2:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(NN)c(Br)c1
Reaction time: 0.5 h

Procedure:
A solution of 0.091 g of ethyl 2-(4-amino-3-bromophenyl)-2-methylpropionate in 0.32 mL of concentrated hydrochloric acid was stirred at −10 to −5° C. in an ice-acetone bath as a solution of 0.023 g of sodium nitrite in 0.20 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. Next, the supernatant was removed by syringe and added dropwise over 10 minutes to a solution of 0.36 g of stannous chloride dihydrate in 0.25 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about −5° C. A gummy material separated during the addition. After completion of the addition, strrring was continued at −10 to −5° C. for 1 hour. The mixture was then diluted with 60 mL ethyl acetate and washed with sodium carbonate. The organic layer was washed with water and brine then dried over magnesium sulfate. Concentration in vacuo gave the crude title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20]CC)=O)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][NH2:24].ClCCl.CO>O1CCCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([NH:24][CH3:23])=[O:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reactant: CN
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 2.35 g (6.32 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.4. of Example 7, and 15.80 ml (31.61 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 97/3 mixture of dichloromethane and methanol, 1.779 g of product are obtained in the form of a white solid.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21]>>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][N:21]1[C:3](=[O:11])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:12]
Reactant: CN(CCCN)CCCN
Reactant: O=C1Cc2ccccc2C(=O)O1
Product: CN(CCCN1C(=O)Cc2ccccc2C1=O)CCCN1C(=O)Cc2ccccc2C1=O

Procedure:
N,N-Bis-[3-(3,4-dihydro-1,3-dioxo-2-(1H)-isoquinolyl)-propyl]-methylamine was prepared analogous to Example 30 from 15 gm of isochroman-1,3-dione and N,N-bis-(3-amino-propyl)-methylamine. The hydrochloride was precipitated from acetone with ethereal hydrochloric acid and recrystallized from ethanol. M.p. of the hydrochloride: 202° -205° C; yield: 13.8 gm (32% of theory).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:15][CH:14]=2)[CH:6]=[C:7]([CH2:9][CH2:10][NH2:11])[N:8]=1)[CH2:2][CH3:3].O.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[O:35]>O1CCCC1>[C:33]([OH:37])(=[O:36])[C:34]([OH:26])=[O:35].[CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[CH:15][CH:14]=2)[C:6]2[CH:34]([C:33]([O:37][CH2:38][CH3:39])=[O:36])[NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Product: O=C(O)C(=O)O
Reaction time: 8 h
Yield: 119.4 %

Procedure:
To a mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole (10.0 g) and tetrahydrofuran (100 ml) is added a solution of ethyl glyoxylate hydrate (2.90 g) in tetrahydrofuran at room temperature. The reaction mixture is stirred overnight, refluxed for 30 minutes, and evaporated. The residue is dissolved in chloroform and the solution is washed with 2% hydrochloric acid solution, a saturated sodium hydrogen carbonate solution and brine. The organic layer is dried and evaporated. The crude product is crystallized with oxalic acid from ethanol-ether to give ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate oxalate (8.45 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>O1CCCC1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: Cn1nnnc1CCCC(O)=S
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=S)CCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)methylthiopropionic acid (2 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at the same temperature, and the mixture is further stirred for 3 hours. After distilling off the solvent, the resulting residue is subjected to column chromatography (Kieselgel 60, made by Merck & Co., eluting solvent, chloroform:methanol=50:1, V/V) to isolate N,N-diethyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (1.5 g), colorless liquid, nD25 =1.5200.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>O>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:2]3[CH:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:3]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
2.52 g (10 mmol) of 4-chloro-2,6-di-pyrrolidin-1-yl-pyrimidine (J. Med. Chem. (1990) 33 (4), 1145-1151) and 2.07 g (10 mmol) of 4-nitrophenylpiperazine are dissolved in a 250 ml flask containing 20 ml of anhydrous pyridine, under an argon atmosphere. The reaction mixture is heated at 100° C. for 48 hours. After cooling down, the contents of the flask are poured into 250 ml of water and the product is extracted using twice 50 ml of CH2Cl2. The organic phase is then washed with 50 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: Heptane/AcOEt: 2/1). An orange solid is obtained with a yield of 49%. Melting point: 200-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[N:14])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]([N+:35]([O-])=O)=[C:19]([NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=3)=O)[CH:20]=2)[CH:9]=1>C1COCC1.O.[Fe].CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[N:14])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]3[N:35]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=4)[CH2:23][C:22](=[O:34])[NH:21][C:19]=3[CH:20]=2)[CH:9]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4Cl)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C2=Nc3ccc(-n4cc(C#N)c(-c5ccccc5Cl)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from N-{5-[3-(2-chloro-phenyl)-4-cyano-pyrrol-1-yl]-2-nitro-phenyl}-3-(3-cyano-phenyl)-3-oxo-propionamide (Example M6) by reductive cyclization with Fe/HOAc in THF/H2O at 80° C. according to the general procedure J (method d). Obtained as a brown solid (164 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[N:27][C:5]2[NH:6][C:7]3[C:8](OC)([OH:24])[CH2:9][CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:28]=[N:27][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24]
Reactant: CCS(=O)(=O)c1cccc(C2=CCC(O)(OC)c3[nH]c4ncc(Cl)cc4c32)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 217 by using an analogous procedure to that outlined in the preparation of Compound 157. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1 H) 8.15(m, 1 H) 8.07 (m, 1 H) 7.97 (m, 1 H) 7.88 (t, J=8.0 Hz, 1 H) 7.66 (s, 1 H) 7.23 (d, J=8.36 Hz, 1 H) 7.16 (d, J=8.36 Hz, 1 H) 4.44 (t, J=5.8 Hz, 2 H) 3.72 (t, J=8.0 Hz, 2 H) 3.43 (q, J=7.32 Hz, 2 H) 3.03 (s, 6 H) 2.41 (m, 2 H) 1.34 (t, J=7.32 Hz, 3 H) [M+H] calc'd for C24H27ClN3O3S, 472; found, 472.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(OCC)(=O)C>CN(C=O)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:11]2[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][N:12]=2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (7 g, 62 mmol) is added to a solution of 5-bromo-2-chloro-pyridine (10 g, 52 mmol) and 4-benzyloxy-phenol (10.4 g, 52 mmol) in DMF (104 mL). The mixture is heated to 110° C. for 3.5 hours then cooled. The solution is then poured into water/ethyl acetate, and the organic layer is collected. The aqueous layer is extracted twice with EtOAc, and the combined organic layers are washed with brine. The organic layer is then dried over Na2SO4, filtered and concentrated. The resulting residue is purified on SiO2 (EtOAc/heptanes) to provide Intermediate D.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=[O:26])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:27][Mg]I>O1CCCC1.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]([OH:26])[CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]I
Reactant: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccc(O)cc1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(C(C)O)cccc2c1Nc1ccc(O)cc1C
Temperature: 25 °C

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.0 g, 6 mmol) was stirred in dry tetrahydrofuran (200 ml) at j-30° C. and treated with a solution of methylmagnesium iodide in ether. Cooling was removed and the mixture was allowed to warm to room temperature. The mixture was washed with saturated ammonium chloride solution (×2) and the aqueous extracted with dichloromethane. The combined organics were dried and evaporated to afford a brown oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to return aldehyde starting material (0.16 g ) and give 3-butyryl-4-(4-hydroxy-2-methyl-phenylamino)-8-(1-hydroxyethyl)quinoline as yellow crystals from ether-petrol (0.45 g, 21.5%), m.p. 182°-4° C.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH3:15][O:16][C:17](=[O:32])[CH:18]([NH:27][C:28](=[O:31])CO)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[CH:33]1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([NH:27][C:28]([CH:4]([O:5][C:6](=[O:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[C:1]([O:3][CH3:33])=[O:2])=[O:31])[C:17]([O:16][CH3:15])=[O:32])=[CH:21][CH:22]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)COC(=O)c1ccc(O)cc1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)C(OC(=O)c1ccc(O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 4-hydroxy-benzoic acid carboxymethyl ester 16 (11.8 grams, 60.20 mmol) and 2-(2-hydroxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester 3 (15.23 grams, 60.19 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL) drop wise. The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 17 which can be purified in an appropriate solvent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1cc(Br)ccc1NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1NC(C)=O
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a degassed solution of N-(4-bromo-2-ethylphenyl)acetamide (20 g, 0.082 mol) in toluene (1200 ml) and ethanol (400 ml), 4-chlorobenzene boronic acid (15.5 g, 0.099 mol) is added under an atmosphere of nitrogen, and the reaction mixture is heated to 80° C. Tetrakis(triphenylphosphine)palladium(0) (2.0 g, 0.0017 mol) is added followed by 2M aqueous potassium carbonate solution (160 ml). The reaction mixture is refluxed for 4 hours then cooled to room temperature. The reaction mass is filtered through diatomaceous earth, and the filtrate is evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3×500 ml) and the organic solutions are combined and concentrated under reduced pressure to give N-(4′-chloro-3-ethylbiphen-4-yl)acetamide (20.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:13][CH:14]=3)[C:9]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:41])=[C:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:31][CH:32]=1
Reactant: CC(C)(C)c1ccc2c(c1)c(Sc1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)c(S(=O)c1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (-10°) solution of 1-(p-chlorobenzyl) -5-(t-butyl)-3-phenylthioindole-2-acetic acid (67 mg) from Example 12 in 1.45 mL dry methylene chloride, under nitrogen, was added 34 mg of m-chloroperbenzoic acid. The reaction mixture was stirred at -10° for 1 h and room temperature for 30 min. The reaction mixture was then diluted with ether and washed with water (2×) and brine and dried over MgSO4. Filtration and concentration gave a solid which was passed through a short column of silica gel. Elution with ethyl acetate gave the title compound, mp 160°-161° (dec.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:12]#[N:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:12]#[N:13]
Reactant: Cc1ccc(C#N)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C#N)cc1O
Reaction time: 8 h
Yield: 93.3 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [CH2:1]([C:3]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[C:36](=[O:37])[C:35](=[O:38])[C:34]=3[O:39][CH:40]([CH3:42])C)=[CH:23][CH:22]=2)[C:6]2=[N:7][C:8]([CH3:18])=[C:9]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=[O:45])C>O>[CH2:34]([O:39][C:40](=[O:45])[CH3:42])[CH3:33].[CH2:1]([C:3]1[N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[C:34](=[O:39])[C:35](=[O:38])[C:36]=3[OH:37])=[CH:25][CH:26]=2)[C:6]2=[N:7][C:8]([CH3:18])=[C:9]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)c(S(=O)(=O)N(C)C)c(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CC(=O)O
Solvent: O
Product: CCOC(C)=O
Product: CCc1nc2c(C)c(S(=O)(=O)N(C)C)c(C)nc2n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1

Procedure:
A solution of the final product of Example 10 (0.19 g) in a mixture of acetic acid (8.3 ml) and water (3.7 mi) was heated at 95°-100° C. for 15 hours. The solvent was removed by evaporation under reduced pressure and the resulting residue was triturated with ethyl acetate (5 ml). The solid obtained was collected and dried in vacuo at 70° C. to give 2-ethyl-3-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-5,7, N,N-tetramethyl-3H-imidazo[4,5-b]pyridine-6-sulphonamide mono-ethyl acetate solvate (0.15 g; m.p. 195°-197° C. (with decomposition)), an active compound of the present invention.
Reaction SMILES: [CH3:1][C:2]12[CH2:18][CH2:17][C:16]3[CH:7]([O:8][CH2:9][C:10]4[C:15]=3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[CH:6]1[CH2:5][CH2:4][C:3]2=[O:20].[CH2:21](O)[CH2:22][OH:23].Cl.[NH+]1C=CC=CC=1.C(OCC)(=[O:34])C>C1C=CC=CC=1>[CH3:1][C:2]12[C:3](=[O:20])[CH2:4][CH2:5][CH:6]1[CH:7]1[C:16]([CH2:17][CH2:18]2)=[C:15]([CH2:14][CH2:13][C:12]2([CH3:11])[O:23][CH2:22][CH2:21][O:19]2)[C:10](=[O:34])[CH2:9][O:8]1
Reactant: OCCO
Reactant: CCOC(C)=O
Reactant: CC12CCC3=C4CCC(=O)C=C4COC3C1CCC2=O
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(CCC2=C3CCC4(C)C(=O)CCC4C3OCC2=O)OCCO1

Procedure:
A solution of 13-methyl-1,8,11,12,13,14,15,16-octahydro-2H,6H-7-oxa-cyclopenta[a]phenanthrene-3,17-dione (1.55 g, 5.7 mmol), ethylene glycol (0.32 mL, 5.7 mmol) and pyridinium hydrochloride (0.66 g, 5.7 mmol) in benzene (28.5 mL) was refluxed with a Dean-Stark apparatus for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bisulfate solution, and dried with magnesium sulfate. Flash chromatography using 15% ethyl acetate in hexane yielded the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[H][H].[CH:20](I)([CH3:22])[CH3:21]>CN(C=O)C.O>[CH:20]([N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2)([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)I
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Yield: 78.9 %

Procedure:
7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (500 mg, 2.42 mmol) was dissolved in 10 ml anhydrous DMF and the reaction cooled to 0° C. Sodium hydride (140 mg, 3.6 mmol) was charged and the reaction allowed to stir at 0° C. until hydrogen evolution ceases. Isopropyl iodide (1.45 ml, 14.50 mmol) was charged and the reaction allowed to warm to room temperature over night. In the morning, a new peak matching the desired mass was determined by LC/MS. The reaction was poured into 50 ml water and extracted with 3×25 ml portions of methylene chloride. The combined organic was washed with 2×10 ml portions water and 10 ml brine, dried over magnesium sulfate, filtered and evaporated. The resulting crude product was purified via silica gel chromatography on a 40 g Isco cartridge using a gradient of 0-70% ethyl acetate in hexanes to yield 1-Isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (474 mg, 79% yield) as a white solid. 1H-NMR (CDCl3) δ 8.16 (d, J=8.8 Hz, 1H), 8.11 (s, 1H), 7.34 (d, J=8.7 Hz, 1H), 4.78 (m, 1H), 2.78 (m, 1H), 2.78 (br s 2H), 2.32 (br s, 2H), 2.16 (br s, 1H), 1.98 (br s, 1H), 1.48 (br s, 2H), 1.14 (br s, 2H). LC/MS (ESI+)=249 (M+H).