Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH2:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CO/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9]/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CO/C=C(/C=C/C(=O)OC)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/C(=C/Nc1c(Cl)cccc1Cl)C(=O)OC
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a solution of (2,6-dichlorophenyl)amine (12.8 g) in THF (73 mL) was added an 1 M THF solution of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (79.8 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To this solution was added a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (14.52 g) in THF (35 ml) at once, and the resulting mixture was stirred at 0° C. for 3 hr. The reaction mixture was diluted with EtOAc (150 mL) and washed with a mixture of 1 M HCl (200 mL) and brine (150 mL), saturated aqueous NaHCO3 (150 mL) and brine successively, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of EtOAc and hexane (1:2) and collected by filtration to give dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (9.28 g). The filtrate was evaporated in vacuo and the residue was purified by silica gel (200 g) column chromatography eluting with EtOAc-hexane (1:2) followed by triturating the isolated material with EtOAc-hexane (1:2) to afford dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (1.30 g).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine (10.54 g) in dry pyridine (105 ml) was added p-toluenesulfonyl chloride (14.35 g) at 0° C., followed by stirring at 25° C. for 23 hours. The reaction mixture was diluted with water and extracted with diethyl ether-dichloromethane (9:1). The extract was washed successively with saturated aqueous sodium chloride, 1N hydrochloric acid, saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, dried over anhydrous sodium suflate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Br:7].Br>>[Br:1][CH2:2][CH2:3][N:4]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Br:7]
Reactant: CCOC(=O)c1ccc(N(CCBr)CCBr)cc1
Agent: Br
Product: O=C(O)c1ccc(N(CCBr)CCBr)cc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Ethyl 4-[N,N-bis(2-bromoethyl)amino]benzoate (1.0 g; 2.6 mmol) was added to 10 ml of a 47% aqueous solution of hydrobromic acid, followed by stirring for 30 minutes under heating and reflux. The solvent was distilled out under reduced pressure, whereby 650 mg of white powder were obtained (yield: 70%).
Reaction SMILES: Cl.CS([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[O:29])(=[O:18])=[O:17]>>[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[O:29])(=[O:18])=[O:17].[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[N:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)NNc1ccccc1
Agent: CNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)cc1

Procedure:
1H-indole-2,3-dione-5-sulfonic acid methylamide was prepared from N-methylsulfonamidoaniline hydrochloride according to Procedure A: 1H NMR (DMSO-d6): δ 2.37 (d, J=4.7 Hz, 3H), 7.04 (d, J=8.4 Hz, 1H), 7.45 (q, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 11.38 (s, 1H); APCI−MS m/z 239 (M−H)−. The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid methylamide and 4-(N-methylsulfonamido)-phenylhydrazine according to Procedure G: mp>25° C.; 1H NMR (DMSO-d6): δ 2.38 (d, J=4.9 Hz, 6H), 7.08 (d, J=8.2 Hz, 1H), 7.33 (q, J=5.2 Hz, 1H), 7.35 (q, J=4.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.66 (dd, J=8.1, 1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.91 (d, J=1.5 Hz, 1H), 11.48 (s, 1H), 12.77 (s, 1H); APCI−MS m/z 422 (M−H)−. Anal. Calcd for C16H17N5O5S2: C, 45.38; H, 4.05; N, 16.54. Found: C, 45.46; H, 4.04; N, 16.45.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2-Chloro-3-trifluoromethyl-pyridine (4.43 g, 24.4 mmol) was dissolved in 42 ml 21% (wt.) sodium ethoxide in ethanol. The mixture was stirred at ambient temperature for 1.5 days. After this period of time, the solvent was evaporated and the residue was taken into water and extracted with dichloromethane three times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-ethoxy-3-trifluoromethyl-pyridine as a light liquid (3.42 g, 73% yield). The crude product was used directly for the next step. 1H-NMR (400 MHz, CDCl3): δ 1.42 (t, 3H, J=7.07), 4.49 (q, 2H, J=7.07), 6.94 (dd, 1H, J=7.45, J=5.05), 7.85 (dd, 1H, J=1.26, J=7.45), 8.30 (dd, 1H, J=1.26, J=5.06).
Reaction SMILES: [C:1]([C:6]1[CH:26]=[CH:25][C:9]([O:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]([O:14]CC)=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>>[C:1]([C:6]1[CH:26]=[CH:25][C:9]([O:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCC(Oc1ccc(C(=O)CCC)cc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCC(Oc1ccc(C(=O)CCC)cc1)C(=O)O
Yield: 29.2 %

Procedure:
1-[4-Hydroxyphenyl]-1-butanone (328 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Butyrylphenoxy]decanoate (616 mg, 85%) as a clear, colourless oil. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.64 (dd, J=5.7, 6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.85-1.99 (m, 2H), 1.65-1.75 (m, 2H), 1.39-1.44 (m, 2H), 1.22-1.34 (m, 10H), 1.20 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.04, 171.39, 161.80, 130.98, 130.48 (2C), 114.74 (2C), 76.68, 61.55, 40.37, 32.85, 32.01, 29.53, 29.37 (2C), 25.33, 22.84, 18.11, 14.34, 14.29, 14.10. The resulting ester (616 mg, 1.70 mmol) was saponified with lithium hydroxide (203 mg, 8.5 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Butyrylphenoxy]decanoic Acid (166 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 10.06 (br s, 1H), 7.91 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.70 (dd, J=5.9, 6.4 Hz, 1H), 2.87 (t, J=7.3 Hz, 2H), 1.96-2.02 (m, 2H), 1.68-1.77 (m, 2H), 1.44-1.59 (m, 2H), 1.24-1.37 (m, 10H), 0.97 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.95, 176.56, 161.74, 131.03, 130.73 (2C), 114.82 (2C), 76.16, 40.47, 32.79, 32.03, 29.53, 29.39, 29.37, 25.38, 22.86, 18.26, 14.31, 14.12. The acid (166 mg, 0.5 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Butyrylphenoxy]decanoate (149 mg, 85%) as a white solid. mp 262-278° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 4.70 (dd, J=6.1, 6.5 Hz, 1H), 2.90 (t, J=7.3 Hz, 2H), 1.88-1.93 (m, 2H), 1.67 (tq, J=7.4, 7.4 Hz, 2H), 1.41-1.57 (m, 2H), 1.20-1.35 (m, 10H), 0.95 (t, J=7.4 Hz, 3H), 0.83 (t, J=6.9 Hz, 3H); 13C NMR (101 MHz, CD3OD): δ201.82, 178.07, 163.36, 130.53 (2C), 129.54, 114.83 (2C), 79.46, 39.99, 33.11, 31.80, 29.40, 29.27, 29.15, 25.72, 22.54, 18.30, 14.46, 14.15; LRMS (ESI): m/z 713 (M2H+), 669 (2M-2Na++3H+), 335 (M-Na++2H+); HPLC: 3 min.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][S:11](O)(=[O:13])=[O:12].O=S(=O)=O.[Cl-].[Na+:20]>>[S:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([O-:9])=[O:8])([OH:13])(=[O:12])=[O:10].[Na+:20]
Reactant: O=C(O)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
122.1 g (1.0 mol) of benzoic acid are melted at 125° to 130° C. in a 1 l four-neck flask fitted with stirrer, internal thermometer and reflux condenser. Then 405 g of oleum are introduced over 30 minutes. Subsequently the reaction mixture is heated to 130° C. and stirred for a further 1 hour at this temperature. The reaction mixture is cooled and 1800 g (=1500 ml) of 26.4% strength sodium chloride solution are run in over 15 minutes. The reaction mixture is heated to 80° C. to 85° C. Then the mixture is allowed to cool to 50° C. while stirring. Subsequently it is cooled with an ice bath to <5° C. and stirred for a further 30 minutes at this temperature. The precipitated product is filtered off with suction and washed with 256 g (=250 ml) of 5% strength sodium chloride solution cooled to 5° C., in two portions. After drying, 204.4 g of sodium 3-sulfobenzoate are obtained with a purity of 96% and a sodium chloride content of 3% (corresponding to 196.3 g (0.88 mol) of 100% sodium 3-sulfobenzoate). 2342 g of effluent are produced.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:33][OH:34]>>[OH:34][NH:33][C:30]([C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])=[O:31]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 16 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 186.8 mg (0.4 mmol) of trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid with hydroxylamine provided 31.8 mg of trans-N-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxamide in 16% yield. MS: 470.1 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH:6](O)[N:5]([CH3:8])[C:4](=[O:9])[N:3]1[CH3:10]>O>[CH3:8][N:5]1[CH2:6][C:2](=[O:1])[N:3]([CH3:10])[C:4]1=[O:9]
Reactant: CN1C(=O)N(C)C(O)C1O
Solvent: O
Product: CN1CC(=O)N(C)C1=O
Yield: 78 %

Procedure:
In a 200 ml glass vessel equipped with a stirrer, thermometer, a dropping funnel and a distillation unit were charged 60 g (0.41 mol) of 4,5-dihydroxy-1,3-dimethyl-2-imidazolidinone and 60 ml of water. And then, the mixture was reacted at 100° C. to 200° C. for 2 hours while removing water under normal pressure by distillation. The obtained residue was evaporated under reduced pressure (109 to 117° C./0.53 to 0.67 kPa) to obtain 41 g (Isolation yield; 78%) of 1,3-dimethylimidazolidin-2,4-dione as a pale yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C:18]([CH2:29][OH:30])=[CH:17][N:16]=1>CO.C(Cl)Cl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:19]1[C:18]([CH2:29][OH:30])=[CH:17][N:16]=[C:15]([NH:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:20]=1
Reactant: NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(CO)c(-c3ccc(Cl)cc3Cl)n2)nc1
Yield: 51 %

Procedure:
The process of Example 140 is repeated using 2-chloro-5-nitro-pyridine and {2-[(2-aminoethyl)amino]-4-(2,4-dichlorophenyl)pyrimidin-5-yl}methan-1-ol. Chromatography of the residue (silica gel, 5% methanol/methylene chloride) afforded 200 mg (51%) of [4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]methan-1-ol as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:16]([N:15]([CH3:19])[CH3:14])=[O:17])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichloromethane and 1.5 mL of triethylamine at room temperature was added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-(1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2:dichloromethane/methanol=4/1 v/v.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:6][CH2:5]2.[N:34]1([CH2:39][CH2:40]O)[CH:38]=[CH:37][N:36]=[CH:35]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[N:34]1([CH2:39][CH2:40][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:6][CH2:5]3)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: OCCn1ccnc1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: COC(=O)C1c2ccc(OCCn3ccnc3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1

Procedure:
Methyl 6-hydroxy-2-[4-(4-methoxyphenoxy)benzenesulfonyl]-1,2,3,4-tetrahydroiso-quinoline-1-carboxylate (13B) is reacted with 2-imidazol-1-ylethanol in analogy to the method described under 3C.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[C:29]([N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (7.34 g, 25 mmol) and 4-dimethylaminopyridine (100 mg) in dichloromethane (25 ml) and triethylamine (3.9 ml, 27.5 mmol) is added benzoyl chloride (3.58 g, 25.5 mmol). The mixture is stirred 6 h at room temperature, diluted with hexane (200 ml), washed with water (4×20 ml), dried over MgSO4 and evaporated. The residue is chromatographed on silica gel (hexanes-ethyl acetate 4:1) and the pure fractions are recrystallized from hexane to afford 7.2 g of the title compound as white crystals, mp 74-78° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:36][N:35]=[N:34][N:24]=4)=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCC#N)cc3)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCc4nnn[nH]4)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenoxy]-acetonitrile (0.270 g, 0.630 mmol) was reacted with NaN3 (0.205 g, 3.150 mmol) and NH4Cl (0.168 g, 3.150 mmol) in DMF (5 ml) to give the product (0.211 g, 0.447 mmol, 71%) as a white solid, mp 174-177° C. 1H NMR (DMSO-d6) δ 1.71 (s, 3H), 5.30 (s, 2H), 5.52 (s, 2H), 6.84 (d, J=7.0 Hz, 1H), 6.88 (d, J=7.0 Hz, 2H), 7.10-7.13 (m, 3H), 7.16 (t, J=7.0 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.32-7.35 (m, 3H), 7.37-7.47 (m, 5H); IR (solid) 3020, 2910, 2860, 1605, 1510, 1480, 1440 and 1230 cm−1; [ESI(−)], m/z 470 (M−H)−; Anal. Calcd. for C30H25N5O: C, 76.41; H, 5.34; N, 14.85; Found: C, 76.42; H, 5.21; N, 14.95.
Reaction SMILES: [H-].[Na+].[C:3](=[N:16][OH:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=2[O:23][C:22]=1[CH3:36].C(O)(=O)C>CN(C=O)C.O>[C:4]1([C:3](=[N:16][O:17][CH2:19][CH2:20][C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=3[O:23][C:22]=2[CH3:36])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c(CCBr)c(C)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1cccc2c(CCON=C(c3ccccc3)c3ccccc3)c(C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Sodium hydride (60%, 30 mg) was suspended in DMF (1 ml) and a solution of benzophenoneoxime (157 mg) in DMF (2 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. To this solution, a solution of methyl (3-(2-bromoethyl)-2-methylbenzofuran-7-yloxy)acetate (201 mg) in DMF (3 ml) was added dropwise and the solution was stirred at room temperature for 30 minutes. Acetic acid was added to this reaction solution and the resulting solution was added to water layer (50 ml) followed by extraction of the resultant twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (177 mg, yield: 65%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:22]2\[C:23](=[O:28])[NH:24][C:25]3[C:21]\2=[CH:20][C:19]([F:18])=[CH:27][CH:26]=3)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCNCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: CCO
Product: CCNCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Yield: 95.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (99 g), ethanol (400 mL), 5-fluoro-2-oxindole (32 g) and pyrrolidine (1.5 g) were refluxed for 3 hours with stirring. The mixture was cooled to room temperature and the solids collected by vacuum filtration. The solids were stirred in ethanol at 60° C., cooled to room temperature and collected by vacuum filtration. The product was dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (75 g, 95% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.03 (t, 3H, CH3), 2.42, 2.44 (2×s, 6H, 2×CH3), 2.56 (q, 2H, CH2), 2.70, 3.30 (2×t, 4H, 2×CH2), 6.85, 6.92, 7.58, 7.72, 7.76 (5×m, 5H, aromatic, vinyl and CONH), 10.90 (br s, 1H, CONH), 13.65 (br s, 1H, pyrrole NH). MS m/z 369 [M−1].
Reaction SMILES: [C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c(C(=O)c2ccccc2)c1

Procedure:
Methyl 5-benzoylpyrrole-3-carboxylate (7.5 g.) was combined with 100 ml. of 1 N sodium hydroxide and 100 ml. of ethanol and boiled in an open flask for 1 hour, by which time most of the ethanol had evaporated. The aqueous residue was diluted with 100 ml. of water and acidified with conc. hydrochloric acid to precipitate crystalline 5-benzoylpyrrole-3-carboxylic acid [6.3 g., m.p. 289°-290° C. (dec.), m/e 215].
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:22]([O:23][CH3:24])=[C:21]([F:25])[C:20]([I:26])=[C:19]([CH3:27])[C:15]=1[C:16]([OH:18])=[O:17]>O1CCCC1>[F:25][C:21]1[C:20]([I:26])=[C:19]([CH3:27])[C:15]2[C:16](=[O:18])[O:17][C:2](=[O:4])[NH:13][C:14]=2[C:22]=1[O:23][CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1c(N)c(C(=O)O)c(C)c(I)c1F
Solvent: C1CCOC1
Product: COc1c(F)c(I)c(C)c2c(=O)oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Under nitrogen atmosphere, triphosgene (1.5 g, 5.04 mmol) was added to a tetrahydrofuran (200 ml) solution of 2-amino-4-fluoro-5-iodo-3-methoxy-6-methylbenzoic acid (I-30) (4.1 g, 12.6 mmol), followed by stirring at 40° C. for 16 hours.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].[CH3:11][N:12]([CH2:14][C:15]1[O:19][C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1)[CH3:13]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:24][CH2:23][CH2:22][S:21][CH2:20][C:18]1[O:19][C:15]([CH2:14][N:12]([CH3:13])[CH3:11])=[CH:16][CH:17]=1)#[N:2]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: C#CCN=C(NC#N)SC
Product: C#CCNC(=NCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
The product of Step A is reacted with about an equimolar amount of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine in a non-reactive solvent to give, after workup and chromatography as in Example 3, the title product.