Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:18][CH2:19][CH3:20])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([S:18][CH2:19][CH3:20])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[OH:16]
Reactant: CCOC(=O)c1c(SCC)nc2c(Cl)cccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1nc2c(Cl)cccc2c(O)c1C(=O)O
Yield: 95.3 %

Procedure:
To a solution of 8-chloro-2-ethylsulfanyl-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (19.81 g, 63.5 mmol) in THF:MeOH (1:1, 150 mL) at room temperature was added 1N NaOH. The reaction was allowed to stir at reflux for 24 hours, monitoring by HPLC. Upon the completion of the reaction, the mixture was acidified with 4N HCl and extracted 3 times with dichloromethane. The organic phases were combined, dried over Mg2SO4, and concentrated in vacuo to afford 8-chloro-2-ethylsulfanyl-4-hydroxy-quinoline-3-carboxylic acid (17.17 g, 95% yield). LCMS found 383.88 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8](=[O:17])(=[O:16])[N:7]=1)C.C(Cl)(Cl)Cl>C1COCC1.Cl>[O:17]=[S:8]1(=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][C:6]([CH2:5][C:4]([OH:18])=[O:3])=[N:7]1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
A solution of 4c (1.98 g, 7.36 mmol) in THF (10 mL) and 6 N HCl (20 mL) was stirred for 2 days at room temperature. Chloroform (20 mL) was added to the solution to induce precipitation upon vigorous stirring 15 min. The precipitate was collected by vacuum filtration to give 10b (1.50 g, 85%) as a yellow solid. 1H NMR (400 MHz, D6-DMSO) δ 12.25 (s, 1 H), 7.78 (d, J=8 Hz, 1 H), 7.66 (td, J=8, 1 Hz, 1 H), 7.44 (td, J=8, 1 Hz, 1 H), 7.32 (d, J=8 Hz, 1 H), 3.70 (br s, 1 H), 3.58 (s, 2 H).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.[ClH:26]>>[ClH:26].[CH3:24][C:10]1([CH3:25])[C:11]2[CH:12]=[N:13][C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Nc3ccccc3)cc21
Agent: Cl
Product: CC1(C)CNc2cc(Nc3ccccc3)ncc21
Reaction time: 4 h

Procedure:
3,3-Dimethyl-6-phenylamino-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (60 mg, 0.18 mmol) was treated with HCl (saturated solution in EtOAc) and stirred for 4 h. The mixture was then evaporated to dryness in vacuo to give a colourless gum which was used without further purification. MS: [M+H]+=240.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([OH:4])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (105 mg, 0.23 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 105 mg of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid as a light orange solid, which was immediately used in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:15]([N:13]1[CH2:14][C:10]2([CH2:11][NH:8][CH2:9]2)[CH2:12]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC2(CN(C(=O)NCc3ccc(Cl)cc3Cl)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CNC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-(2,4-Dichloro-benzylcarbamoyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (20 mg, 50 μmol) and trifluoroacetic acid (740 mg, 6.49 mmol) were dissolved in dichloromethane (2 mL) and the reaction mixture was stirred for 30 min at ambient temperature. Concentration of the reaction mixture in vacuo afforded the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33])[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]1[CH:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:33])[CH3:24]
Reactant: CCc1ccccc1N=C=O
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: CCc1ccccc1NC(=O)NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]1([O:7][C:8]2[C:12]([F:14])([F:13])[C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[C:9]=2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[H][H]>[Pd]>[CH:1]1([O:7][CH:8]2[CH2:9][C:10]([F:17])([F:18])[C:11]([F:15])([F:16])[C:12]2([F:13])[F:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: FC1(F)C(Cl)=C(Oc2ccccc2)C(F)(F)C1(F)F
Agent: [Pd]
Agent: Cl
Product: FC1(F)CC(OC2CCCCC2)C(F)(F)C1(F)F

Procedure:
In a 1.3 l autoclave, 605 g (2 mol) of 2-chloro-3,3,4,4,5,5-hexafluorocyclopentenyl phenyl ether (from Step 1) are suspended in 500 ml of pH 9 buffer (bora/HCl), and the mixture is hydrogenated at 70°-80° C. with 80 bar hydrogen, using 50 g of palladium/charcoal. The catalyst is filtered off, and the filtrate is extracted with dichloromethane. Distillation gives 2,2,3,3,4,4-hexafluorocyclopentyl cyclohexyl ether.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:30]3([OH:33])[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCOCC1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine (1 g, 2.92 mmol) in THF (10 mL) at room temperature was added isopropylmagnesium chloride (5.11 mL, 10.23 mmol). After 1 h stirring at room temperature, another equal amount of isopropylmagnesium chloride was added and the resulting mixture was stirred at room temperature overnight. To the solution was added dropwise dihydro-2H-pyran-4(3H)-one (0.540 mL, 5.84 mmol) and stirring was continued for 1 h. Reaction was quenched with saturated NH4Cl and extracted with DCM. Purification by Biotage produced the product. MS (ESI, pos. ion) m/z: 364.0. IC50 (uM) 0.04172.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:28](N(CC)CC)[CH3:29].ClC(OCC)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:28][CH3:29])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A stirred solution of 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid (Example 1c) (10 g, 0.026 mol) and triethylamine (3.0 g, 0.03 mol.) in dichloromethane (100 ml, dried over 4 A molecular sieves) at -50° C. was treated dropwise with ethyl chloroformate (3.2 g, 0.029 mol.). The solution was allowed to warm up to 0° C. over 0.5 hours, cooled back to -50° C. and treated with ethanol (6 ml, 0.1 mol). The solution was allowed to warm up and then stirred for 15 hours at 18° C. The mixture was then shaken with an aqueous solution of saturated sodium carbonate (500 ml). The organic layer was separated, dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 5% ethanol in chloroform) to give ethyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate as a pale-yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([CH3:13])[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:14])=[C:2]=[S:3].[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1(C)C=CC=CC=1>[NH2:17][CH2:16][CH2:15][NH:18][C:2](=[S:3])[NH:1][C:4]1[CH:12]=[C:11]([CH3:13])[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:14]
Reactant: NCCN
Reactant: Cc1cc(N=C=S)c(C)c2c1OCO2
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=S)NCCN)c(C)c2c1OCO2
Yield: 96.9 %

Procedure:
A solution of 1.6 g of 5-isothiocyanato-4,7-dimethyl-1,3-benzodioxole in 35 mL of toluene at 25° C. is added to a solution of 1.89 g of ethylenediamine in 65 mL of toluene. The reaction gradually turns cloudy as a solid precipitates from solution. This solid is collected and dried under vacuum to give 2.0 g of 5-[N'-(2-aminoethyl)thioureido]-4,7-dimethyl-1,3-benzodioxole as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[C:8]([C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:10])[CH3:9]>C1COCC1>[Cl:16][C:13]1[S:12][C:11]([C:8]([OH:10])([CH3:9])[CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])=[CH:15][CH:14]=1
Reactant: CCOS(C)(=O)=O
Reactant: CC(=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Product: CCOS(=O)(=O)CC(C)(O)c1ccc(Cl)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A solution of ethyl methanesulphonate (4.97 g) in THF (20 ml) was added dropwise to a solution of lithium hexamethyldisilylamide (42.0 ml of 1M solution in THF plus 20 ml of THF) at −78° C. under nitrogen, and the solution was stirred for 30 min. A solution of 2-acetyl-5-chlorothiophene (6.75 g) in THF (70 ml) was added to this over 15 min and the temperature maintained at −78° C. for 90 min. The reaction was quenched with saturated aqueous ammonium chloride and the mixture extracted with ethyl acetate. The combined organic fractions were washed with brine; dried (over magnesium sulphate) and concentrated under reduced pressure to afford a crude oil that was purified by Biotage™ chromatography (silica, eluting with ether-cyclohexane 1:3) to give the title compound (10.9 g) as a colourless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:23][CH2:24][CH3:25])[C:9]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13](=[O:22])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=1.O.[C:32](O)(=[O:34])[CH3:33]>C(OC(=O)C)(=O)C>[CH3:1][N:2]([C:3]1[C:12]2[C:7](=[C:8]([CH2:23][CH2:24][CH3:25])[C:9]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13](=[O:22])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)O
Reactant: CCCc1c2nc(C(=O)OCC)cc(NC)c2cc2c(=O)cc(C(=O)OCC)oc12
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c2nc(C(=O)OCC)cc(N(C)C(C)=O)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
A solution of diethyl 6-(N-methylamino)-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (1.25 g) in acetic acid (25 ml) and acetic anhydride (25 ml) was refluxed for 12 hours, then the solution was poured into water, extracted with ethyl acetate and the extract washed with sodium bicarbonate solution, dried and evaporated to give an oil. The oil crystallised from ethanol to give the required amide, 0.56 g (41%) mp 164°-5° C.
Reaction SMILES: N=C=N.[CH:4]([C:7]1[N:8]=[N:9][S:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)[CH:20]=1)[C:15](O)=[O:16])([CH3:6])[CH3:5].[CH3:28][C:29]1[N:30]=[CH:31][C:32]([CH2:35][NH2:36])=[N:33][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[CH:4]([C:7]1[N:8]=[N:9][S:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)[CH:20]=1)[C:15]([NH:36][CH2:35][C:32]1[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][N:33]=1)=[O:16])([CH3:6])[CH3:5]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3snnc3C(C)C)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3snnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(4-Isopropyl-[1,2,3]thiadiazol-5-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide was prepared using the carbodiimide-based amide synthesis procedure of example 7 in published patent application US2008004442. Briefly, 3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid, C-(5-methyl-pyrazin-2-yl)-methylamine, EDCI, HOBt and Et3N were added to methylene chloride, and the mixture was stirred at room temperature for 16 hours, then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography to give3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=445.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:27][S:28]SC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([S:28][CH3:27])=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSSC
Reactant: Cc1cccc2c(OCCNC(=O)OC(C)(C)C)noc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C)c2onc(OCCNC(=O)OC(C)(C)C)c12
Temperature: -70 °C
Yield: 86.4 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15 g) in tetrahydrofuran (20 ml) was added butyl lithium (0.75 ml, 1.6M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, and the mixture was stirred at the same temperature for 15 minutes, then followed by addition of dimethyldisulphide (0.11 g). The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.15 g, 88%) as a colorless powder.
Reaction SMILES: [CH3:1][C: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])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([N:3]1[C:2]([CH3:1])=[CH: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])=[C:18]([CH3:25])[CH:17]=2)=[N:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C1)OCO3
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C=C1C)OCO3
Yield: 69 %

Procedure:
A mixture of 3.37 g (10.0 millimoles) of 8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine and 25 ml acetyl chloride is stirred under boiling for 3 hours, whereupon the acid chloride is distilled off in vacuo. The residue is taken up in 100 ml of dichloro methane, washed with 50 ml of a saturated sodium carbonate solution and 50 ml of water. The organic phase is dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is recrystallized from 50 ml of acetonitrile. Thus 2.62 g of the desired compound are obtained, yield 69%, mp.: 115–116° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)(=O)OCC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:11]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOP(=O)(Cc1cccc(OCc2ccccc2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(OCc3ccccc3)c2)CC1
Yield: 56.3 %

Procedure:
Following the procedure in Example 1, Step 4, (3-benzyloxy-benzyl)-phosphonic acid diethyl ester (1.0 g, 3.0 mmol, from Step 1) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) were used to give the title compound (534 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([SH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:27][CH2:28][CH2:29][CH2:30]Br>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([S:17][CH2:30][CH2:29][CH2:28][OH:27])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: OCCCBr
Reactant: CCOC(=O)c1cc2c(S)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(SCCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 15.3 %

Procedure:
Sodium hydride (20 mg) was added to a stirred solution of ethyl N-(3,4-dichlorobenzyl)-4-mercaptoindole-2-carboxylate (170 mg) in DMF (7.5 ml). After 1 hour, 3-hydroxyprop-1-yl bromide (89 mg) was added and stirring continued for 16 hours. The reaction mixture was partitioned between water and ethyl acetate and combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using dichloromethane as eluent to give the product as a yellow gum (30 mg, 14%); M/z (+) 480.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4C)CC3)c(OC)nc2c1
Yield: 93 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.99-3.02 (m, 4H), 3.73-3.76 (m, 4H), 3.91 (s, 3H), 4.15 (s, 3H), 7.00-7.22 (m, 7H), 7.76-7.79 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[C:19]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[C:19]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=C(Cn2ccnc2)c2nccs2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C=C(Cn2ccnc2)c2nccs2)cc1-c1ccc(F)cc1
Yield: 80 %

Procedure:
A solution of methyl 2-(4-fluorophenyl)-4-[2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-en-1-yl]benzoate (E and Z isomers) (1.99 g; 5 mmol) in methanol (20 ml) was refluxed with 2N aqueous sodium hydroxide solution (5 ml; 10 mmol) for 2 hours. Methanol was then evaporated and the solution acidified to pH 5.5 with 6N HCl. The resulting precipitate was filtered, washed with water and dried to give 2-(4-fluorophenyl)-4-[2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-en-1-yl]benzoic acid as a mixture of E and Z isomers. Yield=80%.
Reaction SMILES: C(O)(=O)C.CO[CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:36]=[CH:37][CH:38]=1)[C:18]([NH:20][C:21]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])=[O:19].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:30]1([C:28]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:20][C:18](=[O:19])[C:17]3[CH:36]=[CH:37][CH:38]=[C:15]([N:14]4[CH:7]=[CH:11][CH:10]=[CH:9]4)[CH:16]=3)[CH:29]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc(-n2cccc2)c1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
0.25 mL of acetic acid and 4.3 μL of 2,5-dimethoxytetrahydrofuran were added sequentially to 10 mg of 2-(3-aminobenzamido)-4-phenylbenzoic acid at room temperature and stirred at 90° C. for 5 minutes. Ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure to obtain 8.3 mg of 4-phenyl-2-(3-(1H-pyrrol-1-yl)benzamido) benzoic acid as brown solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:21]=[CH:22][C:23]=1[CH3:24]>C(O)(C)C>[ClH:2].[CH3:24][C:23]1[CH:22]=[CH:21][C:20]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[CH:19][C:18]=1[NH:17][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(N)c2)cc1OC
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(C(=O)Nc2ccc(C)c(Nc3ccnc4cc(OC)c(OC)cc34)c2)cc1OC
Temperature: 85 °C
Yield: 23.6 %

Procedure:
Hydrochloric acid (0.15 ml) was added to a mixture of 4-chloro-6,7-dimethoxy quinoline (335 mg) and N-(3-amino-4-methylphenyl)-3,4-dimethoxybenzamide (472 mg) in isopropanol (8 ml) and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane to yield the title compound as a solid (180 mg, 24%); NMR: 2.31 (s, 3H), 3.82 (s, 6H), 3.97 (s, 3H), 3.99 (s, 3H), 6.75 (m, 1H), 7.06 (m, 1H), 7.25 (m, 1H), 7.42 (m, 2H), 7.51 (m, 1H), 7.55 (m, 1H), 7.64 (m, 1H), 8.1 (s, 1H), 8.36 (m, 1H), 9.84 (s, 1H), 10.61 (s, 1H); m/s: M+H+ 474.