Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6C(OC(C)(C)C)=O)=[N:35][CH:36]=5)=[CH:31][C:26]=4[CH2:25][N:24]([CH3:49])[CH2:23][C:22]=3[CH:50]=2)=[CH:15][N:14]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][NH:38]6)=[N:35][CH:36]=5)=[CH:31][C:26]=4[CH2:25][N:24]([CH3:49])[CH2:23][C:22]=3[CH:50]=2)=[CH:15][N:14]=1
Reactant: CN1Cc2cc(-c3cnc(C4CCCN4C(=O)OC(C)(C)C)[nH]3)ccc2-c2ccc(-c3cnc(C4CCCN4C(=O)OC(C)(C)C)[nH]3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CN1Cc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2-c2ccc(-c3cnc(C4CCCN4)[nH]3)cc2C1
Temperature: 50 °C
Yield: 147.7 %

Procedure:
To the solution of 3,9-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (24 mg) in DCM/MeOH (1.6 ml/0.75 ml) was added hydrochloric acid in dioxane (0.44 ml, 1.7 mmol). The mixture was heated at 50° C. for 3 hours and the solvents were evaporated under reduced pressure. The mixture was diluted with water and acetonitrile, and was freezer-dried to give 3,9-bis-[2-(pyrrolidin-2-yl)-3H-imidazol-4-yl]-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine as brown powder (25 mg). m/z: 480.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17]C(C)C)[N:14]([CH3:21])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:21])[C:13](=[S:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(-c2cc(=O)n(C)c(OC(C)C)n2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)[nH]2)cc1OC
Yield: 12.3 %

Procedure:
A mixture of 6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4(3H)-pyrimidinone (2.5 g) and phosphorus pentasulfide (3.5 g) in pyridine (50 ml) was refluxed for 13 hours with stirring. The reaction mixture was evaporated under reduced pressure. The residue was washed with 1N-hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in ethanol and the resulting precipitate was triturated again in chloroform and collected by filtration to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.27 g).
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C1(C)C=CC=CC=1.[N:27]1([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C=O)C>[OH:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=3[S:6][C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[N:3]=2)[CH2:29][CH2:28]1
Reactant: OCCOCCN1CCNCC1
Reactant: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCN(CCOCCO)CC1
Temperature: 110 °C

Procedure:
To a solution of 11-chloro-dibenzo[b,f][1,4]thiazepine-3-carboxylic acid amide, prepared as described in the previous step, (0.40 g) in DMF (1.5 mL) and toluene (1.5 mL) was added 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.50 g, 2.9 mmol). The solution was heated in a 110° C. oil bath under nitrogen for 5 hours, concentrated, and purified (silica gel, 2-5% methanol-dichloromethane containing ammonia eluent) to give the title compound as an off white solid. LC-MS: m/z 427 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([N:6]3C(OC(C)(C)C)=O)[CH2:4]1)[CH2:10]2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]12[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([NH:6]3)[CH2:12]1)[CH2:10]2
Reactant: COC12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-methoxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-17 (0.1 g, 0.037 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0° C. and trifluoroacetic acid (0.22 g, 1.8 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-18 (0.09 g, yield=95%) as an oily mass.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[Cl:27])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:27].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:43])[NH2:26])=[CH:21][C:20]=4[Cl:27])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1Cl)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1Cl)n2C)c1ccccc1
Yield: 82 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 82% of theory, C28H29ClN6O3 (533.1) ##EQU101##
Reaction SMILES: [H-].[Na+].CN(C)[C:5](=O)[CH3:6].[CH2:9]([O:16][C:17]1[C:27]2[NH:26][C:25](=[O:28])[C:24]([CH3:30])([CH3:29])[C:23](=[O:31])[N:22]([CH3:32])[C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(I)C>C(OCC)(=O)C.O>[CH2:9]([O:16][C:17]1[C:27]2[N:26]([CH2:5][CH3:6])[C:25](=[O:28])[C:24]([CH3:29])([CH3:30])[C:23](=[O:31])[N:22]([CH3:32])[C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C(C)(C)C(=O)Nc2c(OCc3ccccc3)cccc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCI
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cccc(OCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 100 %

Procedure:
60% sodium hydride (0.37 g, 8.5 mmol) was added to a N,N-dimethylacetamide (12.5 mL) solution of 6-benzyloxy-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.5 g, 7.7 mmol) under ice cooling, and the mixture was stirred for 30 minutes. Ethyl iodide (0.68 mL, 8.5 mmol) was added dropwise thereto, followed by stirring at 10-20° C. for 2 hours. Water (17.5 mL) was added to the reaction solution, and ethyl acetate (20 mL) was added, followed by ethyl acetate extraction. The resulting organic layer was washed with water, and the solvent was distilled off. An aqueous solution of 70% methanol was added to the resulting residue, and the mixture was heated under reflux for 1 hour, followed by stirring for 30 minutes under ice cooling. Crystals were collected by filtration, then washed with an aqueous solution of 70% methanol, and dried at 60° C., thereby obtaining 2.71 g of a white, powdery target compound (yield: 100%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[CH:12][CH:11]=1.O>C(Cl)Cl>[Br:1][C:20]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)=[N:17][NH:18][CH:19]=1
Reactant: Clc1ccc(-c2cc[nH]n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(-c2n[nH]cc2Br)cc1
Reaction time: 0.17 h

Procedure:
N-Bromosuccinimide (10.4 g, 56.0 mmol) was added portionwise to a solution of 3-(4-chlorophenyl)-1H-pyrazole (10.0 g, 56.0 mmol) in CH2Cl2 (140 mL). The mixture was stirred for 10 min, water and an additional portion of CH2Cl2 were added and the mixture was stirred for 5 min. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to yield 15.0 g of Ex 3-Step 1 product as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.6, 2H), 7.59 (s, 1H), 7.35-7.39 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>COCCOC>[C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:24](=[S:25])[N:11]3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1
Solvent: COCCOC
Product: S=C1Nc2ccccc2N2CCN(Cc3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-(phenylmethyl)-1H-1,2,5-triazepine (10.0 g) was hydrogenated in 1,2-dimethoxyethane (250 ml) as in example 11 and the volume reduced to approximately 150 ml. 1,1'-Thiocarbonyldiimidazole (20 g) was added and the solution refluxed with protection from moisture overnight. The solution was evaporated to dryness and the residue, dissolved in chloroform, was applied to a column (72×6.3 cm) of dry column grade neutral alumina prepacked in chloroform. Elution with chloroform provided a major component. Evaporation of appropriate fractions gave a product which was difficult to crystallize. This material was subjected to further fractionation on a column (67.5×4.2 cm) of the same absorbent with chloroform as eluting solvent. Fractions were monitored by t.l.c. on Alox-25 uv254 plates with ethyl acetate as developer. Evaporation of homogenous fractions provided material which was crystallized from chloroform-heptane; wt. 5.35 (51%), mp=124°-126°. Recrystallization (with decolorization) from the same solvents gave pure titled product, mp=125°-127°.
Reaction SMILES: ClCCCC(C1C=[CH:9][C:10]2[N:11]([CH2:26][CH3:27])[C:12]3[C:17](C=2C=1)=CC(C(=O)CCCCl)=C[CH:13]=3)=O.CNC.Cl[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:39]=[CH:40][C:41]2[N:42]([CH3:58])[C:43]3[C:48]([C:49]=2[CH:50]=1)=[CH:47][C:46]([C:51](=[O:57])[CH2:52][CH2:53][CH2:54][CH2:55]Cl)=[CH:45][CH:44]=3)=[O:37].C[N:60]1[C:72]2C=CC=C[C:67]=2C2[C:61]1=[CH:62]C=CC=2.ClCCCCC(Cl)=O>>[CH2:10]([NH:11][CH2:12][CH3:13])[CH3:9].[CH2:26]([N:11]([CH2:12][CH3:17])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:39]=[CH:40][C:41]2[N:42]([CH3:58])[C:43]3[C:48]([C:49]=2[CH:50]=1)=[CH:47][C:46]([C:51](=[O:57])[CH2:52][CH2:53][CH2:54][CH2:55][N:60]([CH2:72][CH3:67])[CH2:61][CH3:62])=[CH:45][CH:44]=3)=[O:37])[CH3:27]
Reactant: Cn1c2ccc(C(=O)CCCCCl)cc2c2cc(C(=O)CCCCCl)ccc21
Reactant: Cn1c2ccccc2c2ccccc21
Reactant: CCn1c2ccc(C(=O)CCCCl)cc2c2cc(C(=O)CCCCl)ccc21
Agent: CNC
Agent: O=C(Cl)CCCCCl
Product: CCN(CC)CCCCC(=O)c1ccc2c(c1)c1cc(C(=O)CCCCN(CC)CC)ccc1n2C
Product: CCNCC

Procedure:
Following the procedure of Example 32, only substituting respectively for 3,6-bis(4-chlorobutyryl)-N-ethylcarbazole and dimethylamine the appropriate molar equivalent amount of 3,6-bis(5-chlorovaleryl)-N-methylcarbazole, prepared from N-methylcarbazole and 5-chlorovaleryl chloride, and an excess of diethylamine, 3,6-bis(5-diethylaminovaleryl)-N-methylcarbazole is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.[OH:21]C(C(C)=C)C(OCC)=O.Cl.[C:32]1([CH3:38])C=CC=C[CH:33]=1>C(N(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:21])[C:17](=[C:32]([CH3:38])[CH3:33])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: Cc1ccccc1
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (19.6 g, 65 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (15.1 g, 105 mmol), ferric chloride (105 mg, 0.65 mmol) and tributylamine (611 mg, 3.3 mmol) were introduced into a flask (200 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 5 hours. After the reaction solution was cooled to room temperature, toluene (100 mL) was added, and then the reaction solution was washed with 1N sodium hydroxide (100 mL×2) and 1N hydrochloric acid (100 mL×2). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, acidic methanol (15 mL) was added to form a homogeneous solution. Then, 6N hydrochloric acid (2 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, washed with a mixed solvent consisting of methanol (20 mL) and 6N hydrochloric acid (5 mL) and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (16.7 g, yield 72.5%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH:25]=O)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH2:3]C.[S:31]([NH2:41])(=[O:40])([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH2:25][NH:39][C:36]4[CH:35]=[CH:34][C:33]([S:31](=[O:40])(=[O:32])[NH2:41])=[CH:38][CH:37]=4)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: CCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(CNc3ccc(S(N)(=O)=O)cc3)c(O)cc(C)c1C(=O)O2

Procedure:
This compound was prepared from the compound from Example 8 by means of a procedure similar to that used for Example 18 except replacing ethanolamine with sulphanilic amide.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][Cl:24])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[ClH:24].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16])[CH3:2])[CH3:19]
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Reactant: CCOc1c(C)c(C)c(O)c(C)c1CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)c(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
N-Methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (10.4 g), 2-ethoxy-5-hydroxy-3,4,6-trimethylbenzyl chloride (9.15 g) and triethylamine (8.10 g) were dissolved in N,N-dimethylformamide (80 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting liquid (1.0 g) was dissolved in methanol and conc. hydrochloric acid (0.2 ml) was added. The mixture was concentrated to dryness under reduced pressure. Recrystallization from ethanol-diethyl ether gave 910 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[CH3:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>O>[CH3:54][N:55]1[CH2:60][CH2:59][N:58]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)=[O:27])[CH2:57][CH2:56]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Reaction time: 0.08 h
Yield: 18.4 %

Procedure:
To a solution of example 8 (0.100 g, 0.262 mmol) in DMF (1 ml) HOBT (0.042 g, 0.314 mmol), EDC-HCl (0.125 g, 0.655 mmol) and triethylamine (0.1 ml, 0.786 mmol) were added and stirred for 5 min. 4-Methylpiperazine (0.023 g, 0.235 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.020 g, 1.7%). M.P.: 156-158° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.02 (dd, J=5.1, 3.6 Hz, 2H), 7.83 (dd, J=8.8, 1.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.63 (s, 2H), 3.30 (s, 2H), 2.36 (s, 4H), 2.19 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH2:10]([C:14]1[S:18][C:17]([S:19]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])=[O:20])=[C:16](B(O)O)[CH:15]=1)[CH:11]([CH3:13])[CH3:12].[OH-].[Na+].CCO>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.O.C1(C)C=CC=CC=1>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[C:14]([CH2:10][CH:11]([CH3:12])[CH3:13])[S:18][C:17]=2[S:19]([NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])(=[O:21])=[O:20])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: OCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)Cc1cc(-c2cccc(CO)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A mixture of m-bromobenzyl alcohol (1.05 g, 5.80 mmol), 5-iso-butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (2.41 g, 7.55 mmol; see step (c)), Pd(PPh3)4 (270 mg, 0.235 mmol), NaOH (19.1 mL, 1.5 M aq, 28.6 mmol), EtOH (5.0 mL) and toluene (30 mL) was stirred under N2 at 90° C. for about 4 h. After cooling, water (10 mL) was added to the reaction mixture and this was then extracted with ethyl acetate. The combined organic phase was dried and concentrated in vacuo. The crude product was purified on column chromatography (EtOAc/hexane, 30:70) to give sub-title compound as a colourless syrup in 57% yield (1.26 g, 3.31 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[C:17]([CH3:25])=[CH:18][N:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2.O.ClCCl>ClCCCl>[CH3:14][O:15][C:16]1[C:17]([CH3:25])=[C:18]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[N:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)cn2ccccc12
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: COc1c(C)c(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)n2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
690 mg (3.1 mmol) of 4-nitrobenzenesulphonyl chloride in solution in 4 ml of 1,2-dichloroethane are added to 500 mg (3.1 mmol) of 1-methoxy-2-methylindolizine dissolved in 8 ml of 1,2-dichloroethane, and the medium is stirred at room temperature for 20 hours. The reaction medium is poured over water and dichloromethane. The organic phase is separated after settling out, washed with water, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6])#N.[OH-:17].[Na+].[OH2:19].C>CO>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:12]=[C:3]([C:1]([OH:19])=[O:17])[C:4](=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O

Procedure:
Methyl 2-cyano-4-trifluoromethyl-benzoate (102.3 g.), sodium hydroxide pellets (108 g.), water (900 cc.) and methanol (1,900 cc.) are heated to the reflux temperature for 12 hours. The solution is decolorised by means of animal charcoal (0.6 g.). After filtration, hydrochloric acid (d = 1.19) (100 cc.) is added. The mixture is extracted with ethyl ether (2.25 liters). The organic layer is dried over anhydrous magnesium sulphate (40 g.). After filtering, and concentrating the filtrate, 4-trifluoromethyl-phthalic acid (99.1 g.) melting at 178° C is obtained.
Reaction SMILES: C(OCC[C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)(=O)C.[OH-].[Na+].Cl.[CH2:23]([OH:25])[CH3:24]>>[OH:25][CH2:23][CH2:24][C:13]1[C:9]2[CH:8]=[CH:7][CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: CC(=O)OCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1sc2ccccc2c1CCO
Reaction time: 4.5 h
Yield: 97 %

Procedure:
A solution of 5-(2-acetoxyethyl)-2-sulfamoyl benzo[b]thiophene (1.8 g, 0.006 mol), ethanol (50 ml) and 10% NaOH (50 ml) was heated at reflux. After 4.5 h, the mixture was poured into 3N HCl (150 ml) and extracted with ethyl acetate (3X). The organic extracts were washed with saturated Na2CO3, dried, filtered and concentrated to dryness to yield 1.5 g (97%) of product, m.p. 162°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][O:12][CH3:13])=[C:7]([CH:9]=1)[NH2:8].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:22]([O:21][C:19]([C:18]1[C:17](=[O:16])[C:9]2[C:7](=[C:6]([O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[NH:8][CH:24]=1)=[O:20])[CH3:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COCOc1ccc(OC)cc1N
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(OCOC)ccc(OC)c2c1=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
5-Methoxy-2-methoxymethoxyaniline (3.6 g) and diethyl ethoxymethylenemalonate (4.5 g) were heated at a temperature of 100°-120° C. for 1 hour. Eighty milliliter of diphenyl ether was added to the mixture, and the resulting mixture was further heated at 250°-260° C. for 1.5 hours. After the mixture was left to cool down to room temperature, it was purified by silica gel column chromatography (Wako Gel C-200, 140 g). Elution with a mixed solvent of chloroform (97 parts) and methanol (3 parts) gave 3.0 g of 3-ethoxycarbonyl-5-methoxy-8-methoxymethoxy-4(1H)-quinolone (compound 5).