Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]([OH:17])=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Oc1cc2cccnc2nc1-c1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 5.5 h
Yield: 68.4 %

Procedure:
2-Phenyl-[1,8]naphthyridin-3-ol (23 mg), 4-chloro-6,7-dimethoxyquinoline (69 mg), and 4-dimethylaminopyridine (38 mg) were suspended in o-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 5.5 hr. The reaction solution was cooled to room temperature. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)=[O:20])=[CH:17][CH:16]=1>>[CH:32]1[C:23]2[CH2:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:37][CH:36]=3)=[O:20])[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl

Procedure:
As described for Example 9, 3-chlorobenzo[b]thiophene-2-carbonyl chloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloromethane-hexane gives crystals, m.p. 252°-254° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)C(=O)OC(C)(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:28][N:29]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[N:38]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH:12][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:28][NH:29][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[N:38]=1
Reactant: Cc1cc(C)nc(N(Cc2ccc3cc(CN(C(=O)OC(C)(C)C)c4cc(C)cc(C)n4)ccc3c2)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(NCc2ccc3cc(CNc4cc(C)cc(C)n4)ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 6a (590 mg, 1.0 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (TFA, 8 mL). The reaction mixture was allowed to stir at room temperature for 8 h then was concentrated. The crude product was purified by flash column chromatography (2-5% MeOH in CH2Cl2) to yield 3a (355 mg, 90%) as a white solid: 1H NMR (500 MHz, CD3OD/CDCl3) δ 2.28 (s, 6H), 2.48 (s, 6H), 4.60 (s, 4H), 6.46 (s, 4H), 7.45-7.47 (d, J=8.5, 2H), 7.78 (s, 2H), 7.84-7.86 (d, J=8.5, 2H); 13C NMR (125 MHz, CD3OD/CDCl3) δ 18.6, 22.0, 45.9, 106.8, 114.5, 125.6, 129.0, 133.1, 134.3, 147.6, 153.8, 158.0; ESI (M+H+) calcd for C26H29N4 397.23922, found 397.23999.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([CH:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:28]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Product: CCOC(=O)c1ccccc1N1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
Step (c) of Example 75 was repeated, except that ethyl 2-bromobenzoate and 4-(3,3-diphenyl-1-propyl)piperazine were used. Thus, ethyl 2-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzoate was prepared.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:12][C:13](OCC)=[O:14])(=O)[CH3:10].C(O)C>S(=O)(=O)(O)O>[CH3:10][C:9]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(=O)oc2cc(O)ccc12
Yield: 71 %

Procedure:
0.1 mole resorcinol and 0.1 mole ethyl acetylacetate in solution in 100 ml concentrated sulphuric acid are maintained at 5° C. for 3 hours. After recyrstallisation of the solid formed from ethanol, there are obtained 12.5 grams 4-methyl-7-hydroxy-coumarin, melting at 185° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([CH2:27][C:28](Cl)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and t-butylacetyl chloride (0.40 g, 3.00 mmol) in CH2Cl2 (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 18 h, solution was washed with dil. aq. HCl (2×50 mL), water (2×50 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and triturated in EtOAc for 18 h. The product was dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3,3-dimethyl-butyramide as a white solid (0.39 g, 34% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.13 min (95.97%); mp: 232-234° C.; 1H NMR (DMSO-d6) δ 0.97 (s, 9H, CH3, CH3, CH3), 1.97-2.17 (m, 3H, CHH, CH2), 2.53-2.69 (m, 2H, CHH, CHH), 2.77-3.01 (m, 1H, CHH), 4.43 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.71-7.83 (m, 2H, Ar), 7.89 (d, J=7.6 Hz, 1H, Ar), 8.46 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 29.68, 30.52, 30.93, 41.87, 48.66, 48.99, 121.91, 123.45, 129.69, 131.57, 133.41, 147.87, 166.97, 167.10, 169.83, 171.11, 172.73; LCMS: MH=386; Anal Calcd for C20H23N3O5: C, 62.33; H, 6.02; N, 10.90. Found: C, 61.96; H, 5.95; N, 10.75.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[Cl:21]CCCl>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][N:10]=1)[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCl
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Agent: CN
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(tert-Butoxycarbonyl-methyl-amino)-nicotinic acid (12.5 g, 47.0 mmol) (prepared analogously to A-08 using methyl amine instead of ethylamine) is taken up in 300 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (10.0 mL, 74.8 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][C:14]2=[O:24])[CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+].CO>O1CCCC1>[CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][C:14]2=[O:24])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(N2CC(c3ccccc3)CC2=O)cc(N(C)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cc(C(=O)O)cc(N2CC(c3ccccc3)CC2=O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
A mixture of methyl 3-[methyl(methylsulfonyl)amino]-5-(2-oxo-4-phenylpyrrolidin-1-yl)benzoate obtained in Reference Example 18 329 mg (0.32 mmol), 2N aqueous sodium hydroxide solution (0.5 mL), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was stirred at room temperature for 15 hours. The solvent was concentrated and the mixture was adjusted by adding 1N hydrochloric acid to pH=3 and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 113 mg (0.291 mmol) of the title compound (yield: 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][CH:31]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[F:24])[CH2:36]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: Fc1ccccc1C1CNCCN1
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccccc5F)C4)c(F)cc3cc2c1=O

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-8-[3-(2-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.59 g) and (RS)-2-(2-fluorophenyl)piperazine (1.08 g). After recrystallization in dimethylformamide (60 cc) containing ethanol (50%), the expected product (1.3 g) is obtained in the form of a yellow solid, m.p. 228° C.
Reaction SMILES: [Si:1]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Mg]Br.CCCCC>C1COCC1>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Si:1]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CCO[Si](OCC)(OCC)OCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1c(C)cc(C)cc1C
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To tetraethyl orthosilicate (3.30 mL, 15.0 mmol, 3.00 equiv) in 10 mL of THF at −30° C. was added 2,4,6-trimethylphenylmagnesium bromide solution (1.0 M in THF, 5.0 mL, 5.0 mmol, 1.0 equiv) dropwise over 10 min. After stiffing at −30° C. for 1 h, the reaction mixture was warmed to 23° C. and was further stirred for 12 h. The reaction mixture was poured into 100 mL of pentane, and was washed three times with water (3×20 mL) and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. Bulb-to-bulb distillation (125° C., 0.5 Torr) afforded 0.87 g of the title compound as a colorless oil (62% yield). Rf=0.14 (hexanes). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 6.80 (s, 2H), 3.83 (q, J=7.0 Hz, 6H), 2.51 (s, 6H), 2.26 (s, 3H), 1.24 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 145.92, 139.79, 128.81, 124.99, 58.10, 23.73, 21.08, 18.15.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:16]N(C=O)C>>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][C:11]=3[N:12]2[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2[nH]c3cc(F)ccc3c21
Reactant: CN(C)C=O
Product: Cn1c2c(c3ccc(F)cc31)C(=O)CCC2
Reaction time: 1.5 h

Procedure:
A solution of 7-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (1.0 g) in dry DMF (8 ml) was added dropwise to a stirred, ice-cooled suspension of pre-washed (hexane: 2×10 ml) sodium hydride (78% dispersion in oil; 175 mg) in dry DMF (5 ml) under nitrogen and stirring was continued at room temperature for 1.5 h. The solution was cooled to 0°, iodomethane (0.35 ml) was added dropwise and stirring was continued at 0° for 2 h. The suspension was poured into 8% aqueous sodium bicarbonate (30 ml) extracted with dichloromethane (2×30 ml) and the combined, dried organic extracts were evaporated and dried in vacuo at 100° for 18 h to give the title compound (1.03 g) as a solide, m.p. 174°-175°.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>CS(C)=O.O>[CH:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)cc1
Yield: 36.5 %

Procedure:
A solution of ethyl 4-fluorobenzoate (0.293 mL, 2 mmol) and 1-isopropyl-1,4-diazepane (0.539 mL, 4.00 mmol) in dimethylsulfoxide (10 mL), was heated at 120° C. for 18 h. The reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with saturated sodium chloride solution (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate (0.212 g, 36.5%) as a yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[OH-].[NH4+:15]>>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To ice-cold solution of ammonium hydroxide (25%, 250 ml) is added 3-(chlorosulfonyl)benzoic acid (25 g, commercially available, Aldrich) portionwise and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum to about 50 ml and the mixture is acidified with conc. HCl. The precipitate is collected by filtration and dried under vacuum to afford 22 g (96%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 13.44 (br s, 1H), 8.38 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.49 (s, 2H), HPLC (max plot) 97%; Rt 0.68 min. LC/MS: (ES−): 199.8.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[C:25]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH:30]5[CH2:34][O:35]C)=[O:28])[S:26][C:19]=34)=[CH:16][C:11]=2[O:10][C:9]=1[CH3:37])=[O:7])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[C:25]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH:30]5[CH2:34][OH:35])=[O:28])[S:26][C:19]=34)=[CH:16][C:11]=2[O:10][C:9]=1[CH3:37])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COCC1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCC(C)C)c(C)oc4c3)c2s1
Agent: BrB(Br)Br
Product: Cc1oc2cc(Oc3ccnc4cc(C(=O)N5CCCC5CO)sc34)ccc2c1C(=O)NCC(C)C

Procedure:
This material was prepared from 2-methyl-6-[2-(2-methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-benzofuran-3-carboxylic acid isobutyl amide 85 by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (CD3CN) δ 8.52 (1H, d, J=5.5 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.5 Hz), 7.42 (1H, d, J=2.1 Hz), 7.20 (1H, dd, J=8.5, 2.1 Hz), 6.78 (1H, m), 6.71 (1H, d, J=5.3 Hz), 4.29 (1H, m), 3.94–3.63 (4H, m), 3.22 (2H, t, J=6.4 Hz), 2.65 (3H, s), 2.22–1.95 (4H, m), 0.98 (6H, d, J=6.8 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12].[H-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C#N)cc1OC1COCC1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OC1COCC1OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
2.5 g (11.0 mmol) of 3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A 15) in 12 ml of dimethylformamide are added dropwise under a nitrogen atmosphere to a solution of 350 mg (12.0 mmol) of sodium hydride in 12 ml of dimethylformamide and the mixture is heated at 40° C. for 1 h. 1.6 ml (13.0 mmol) of benzyl chloride, dissolved in 6 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 4 h. concentrated, treated with 50 ml of water and acidified with 2 N hydrochloric acid. After extraction with 3×40 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. For further purification, the product is chromatographed on silica gel [toluene/ethyl acetate=4:1]. The product-containing fractions are concentrated and the residue is crystallized from isopropanol. 3.05 g of the title compound of m.p. 72-75° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].S(Cl)(Cl)=O>>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)CNc1cccc(Cl)c1Cl
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(Cl)c2Cl)c1
Yield: 12.9 %

Procedure:
Using a procedure similar to that described in Example 17, but starting with 2-[3-(3-methylphenyl)ureido]acetic acid (1.04 g), tert-butyl 2-[(2,3-dichlorophenyl)amino]acetate (1.4 g) and sulphinyl chloride (0.6 g), and after recrystallisation in acetonitrile, tert-butyl 2-{N-(2,3-dichlorophenyl)-2-[3 -(3-methylphenyl)ureido]acetamido}acetate (0.3 g), m.p. 135° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23](=[O:24])[C:22]4[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=4[C:20]3=[O:30])=[C:15]([CH3:31])[CH:14]=2)=S)=O)=[CH:4][CH:3]=1.Cl.Cl.[NH2:34][NH2:35]>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:21]2[C:20](=[O:30])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:10]4[NH:9][C:7]([C:5]5[S:6][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:35][N:34]=4)=[CH:14][C:15]=3[CH3:31])[C:23](=[O:24])[C:22]=2[CH:25]=1
Reactant: NN
Reactant: Cc1cc(NC(=S)NC(=O)c2ccc(Cl)s2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nnc(-c3ccc(Cl)s3)[nH]2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 14.2 %

Procedure:
To a suspension of (5-chloro(2-thienyl))-N-({[4-(5-chloro-1,3-dioxobenzo[c]azolin-2-yl)-3-methylphenyl]amino}thioxomethyl)carboxamide (15 mg, 0.030 mmol) and hydrazine dihydrochloride (4 mg, 0.038 mmol) in DMF (0.3 mL) was added HgO (7 mg, 0.032 mmol). The reaction was stirred at room temp for 17 hr, and HPLC purified to give the desired product 5-chloro-2-(4-{[5-(5-chloro(2-thienyl))(4H-1,2,4-triazol-3-yl)]amino}-2-methylphenyl)benzo[c]azoline-1,3-dione (2 mg) (ES-MS (M+H)+=470, 472) and the aminoguanidine intermediate N-((1E)-2-aza-1-{[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]amino}-2-aminovinyl)(5-chloro(2-thienyl))carboxamide (2 mg) ES-MS (M+H)+=488, 490 (2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:55]1[C:63]2[C:58](=[C:59]([CH2:64][NH2:65])[CH:60]=[CH:61][CH:62]=2)[CH:57]=[N:56]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:65][CH2:64][C:59]2[CH:60]=[CH:61][CH:62]=[C:63]3[C:58]=2[CH:57]=[N:56][NH:55]3)=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1Cl
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.9 %

Procedure:
To a solution of 3-Chloro-thiophene-2,5-dicarboxylic acid 2-methyl ester (200 mg, 0.91 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.38 mL, 2.73 mmol), HBTU (0.52 g, 1.37 mmol), HOBT (0.147 mg, 1.09 mmol), and C-(1H-Indazol-4-yl)-methylamine (146 mg, 1.0 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-70% EtOAc in hexane to afford the desired product (0.073 g, 23% yield).