Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+].[O:15]=[C:16]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:30]2[CH2:29][CH2:28][C@@:26]2([CH3:27])[C@:22]3(O)[CH2:23][CH2:24][C@@H:25]2[CH:35]=O)[CH2:17]1>C(O)(=O)C.O1CCOCC1>[C:10]([O:13][C@@:22]12[C@H:21]3[C@@H:30]([C@:31]4([CH3:34])[C@H:18]([CH2:19][CH2:20]3)[CH2:17][C:16](=[O:15])[CH2:33][CH2:32]4)[CH2:29][CH2:28][C@:26]1([CH3:27])[C@@H:25](/[CH:35]=[N:5]/[NH:6][C:7]([NH2:9])=[NH:8])[CH2:24][CH2:23]2)(=[O:12])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: N=C(N)NN
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: O=C(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)O[C@]12CC[C@H](/C=N/NC(=N)N)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2CC(=O)CC[C@@]21C
Yield: 76.4 %

Procedure:
To a solution of 0.13 g of aminoguanidine hydrogencarbonate, 2.00 g of sodium acetate in 25 ml of 0.2M acetic acid a solution of 0.30 g 3-oxo-14β-hydroxy-5β-androstane-17β-carboxaldehyde (Prepn. 5) in 40 ml of dioxane was added dropwise. After 2 hrs the mixture was evaporated to dryness under reduced pressure and the crude product was extracted three times with iso-propanol. Evaporation of the solvent gave 0.30 g of (E)-3-oxo-17β-guanidinoiminomethyl-5β-androstane-14β-ol acetate as a white foam.
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21][CH2:22][O:23]C(C3CCCOC3)=O)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.CC1C=CC(S(CCCO[CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)(=O)=O)=CC=1.C1C(C=O)=C[C:56]2[O:61]C[O:63][C:55]=2C=1>ClCCl.C(OCC)(=O)C>[CH2:56]1[CH2:55][O:63][C:3]2[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH2:20][CH2:21][CH2:22][O:23][CH:50]4[CH2:51][CH2:52][CH2:47][O:48][CH2:49]4)(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[CH:5][C:4]=2[O:61]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Reactant: CN(C)c1ccc(C=Cc2ccc(S(=O)(=O)CCCOC(=O)C3CCCOC3)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(CCCOC1CCCOC1)c1ccc(C=Cc2ccc3c(c2)OCCO3)cc1

Procedure:
As in Example 3a 2.98 g (10 mmol) of 2a and 1.65 g (11 mol) of piperonal give, after column chromatography [silica gel; dichloromethane/ethyl acetate mixtures], 1.22 g (27%) of yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:6]1=[O:34])[CH:2](C)[CH3:3].[C:35](N1C(C)=C(CCCCC)N(CC2C=CC(C3C=NC=CC=3C3NN=NN=3)=CC=2)C1=O)(C)(C)C>>[CH:1]([N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:21][CH:22]=2)[C:6]1=[O:34])([CH2:2][CH3:3])[CH3:35]
Reactant: CCCCCc1c(C)n(CC(C)C)c(=O)n1Cc1ccc(-c2cnccc2-c2nnn[nH]2)cc1
Reactant: CCCCCc1c(C)n(C(C)(C)C)c(=O)n1Cc1ccc(-c2cnccc2-c2nnn[nH]2)cc1
Product: CCCCCc1c(C)n(C(C)CC)c(=O)n1Cc1ccc(-c2cnccc2-c2nnn[nH]2)cc1

Procedure:
1-isobutyl-4-pentyl-5-methyl-1,3-dihydro-3-[[4-[4-(1H-tetrazol-5-yl)-3-pyridinyl]phenyl]methyl]-2H-imidazol-2-one, 1-tertbutyl-4-pentyl-5-methyl-1,3-dihydro-3-[[4-[4-(1H-tetrazol-5-yl)-3-pyridinyl]phenyl]methyl]-2H-imidazol-2-one;
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:39])[CH:27]=3)[C:23](O)=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:43]=1[S:49]([NH2:52])(=[O:51])=[O:50].N12CCCN=C1CCCCC2>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:39])[CH:27]=3)[C:23]([NH:52][S:49]([C:43]3[CH:44]=[CH:45][C:46]([CH3:48])=[CH:47][C:42]=3[O:41][CH3:40])(=[O:50])=[O:51])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc2c(C(C(=O)O)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
1,1′-Carbonyldiimidazole (2.8 kg) was added to a stirred solution of 2-(1,3-benzodioxol-5-yl)-2-(6-methoxycarbonyl-1-methyl-1H-indol-3-yl)acetic acid (from step (a), 5.0 kg) in dry tetrahydrofuran (50 liters) at room temperature under a nitrogen atmosphere. The suspension was heated to reflux for 1.5 h, allowed to cool to room temperature, and treated sequentially with 2-methoxy-4-methylbenzenesulfonamide (see Preparation 11, International Patent Application WO 97/43260; 3.0 kg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 kg). The mixture was heated to reflux for 3.5 h, allowed to cool to room temperature and quenched by the addition of 2M hydrochloric acid (40 liters). The product was extracted from the acidic aqueous solution with dichloromethane (40 liters) and the organic phase was washed with 2M hydrochloric acid (40 liters) and water (40 liters). The organic phase was concentrated to low volume, diluted with acetonitrile (93 liters) and the resulting suspension heated to reflux. The mixture was allowed to cool and the precipitated product collected by filtration to give the subtitle compound as a white crystalline solid (5.34 kg, 71.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[C:19]([CH3:25])=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[C:19]([CH3:25])=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (25 mg, 0.06 mmol) in dioxane (3 mL) and water (3 mL) was treated with sodium borohydride (8 mg, 0.22 mmol). The mixture was stirred at rt for 30 min. Acetic acid (0.5 mL) was added and the mixture was stirred for 25 min. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a dry film, 13 mg (48%).
Reaction SMILES: [OH-:1].[Na+].[CH:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(=O)[CH3:14].Cl>O.C(O)C>[O:1]=[C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=[CH:3][CH:14]=[CH:13][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: [OH-]
Reactant: O=CC=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C=CC=CC(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
Sodium hydroxide (128.0 g, 3.2 mol) is dissolved in water (1400 mL) and ethanol (675 mL). Cinnamaldehyde (66.1 g, 0.5 mol) and 4-acetylbenzoic acid (82.1 g, 0.5 mol) are added and the mixture stirred for about 5 min. A thick precipitate is formed and the thick mixture is diluted with water (750 mL) and ethanol (750 mL). Stir at room temperature for 18 h. The reaction is cooled and acidified with concentrated HCl (270 mL). The mixture is extracted with ethyl acetate (3×). The combined organic portions are washed with water (2×), dried over Na2SO4, filtered and evaporated. The resulting solid is recrystallized from 2-methoxyethanol and washed with diethyl ether to obtain 36.1 g (26%) of yellow crystals. m.p.=210-214° C.; Anal. Calcd for C18H14O3: C, 77.68; H, 5.07. Found: C, 77.47; H, 5.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>C1(C)C=CC=CC=1.O.Cl.C(O)(=O)C.[Zn].[Hg](Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1c(CCCC(=O)O)ccc2c1CCCC2
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1c(CCCC(=O)O)ccc2ccccc12
Reaction time: 0.08 h

Procedure:
155.4 g of zinc turnings, 18.6 g of mercury(II) chloride, 231.2 ml of water and 7.7 ml of concentrated hydrochloric acid are combined and shaken well for 5 minutes. The aqueous phase is decanted off from the zinc amalgam and the latter is added to a solution of 78.45 g (0.31 mol) of the compound from Example 1 in 140 ml of toluene, 175 ml of water, 310 ml of concentrated hydrochloric acid and 15 ml of glacial acetic acid. The mixture is heated to reflux for 18 h, 81 ml of concentrated hydrochloric acid being added every 6 h. The solution is filtered, shaken 3 times with 300 ml of ethyl acetate each time and the combined ethyl acetate phases are washed with 500 ml of saturated sodium chloride solution. After drying over sodium sulphate, the solution is evaporated and the residue is flash chromatographed on silica gel using CH2Cl2 /acetone as the eluent.
Reaction SMILES: C[C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:18].[Ca+2].[Cl-].Cl.[CH:22]1C=CC=CC=1>>[Cl:18][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:2]=[C:3]([CH3:22])[C:4]=2[CH2:10]1
Reactant: c1ccccc1
Reactant: [Cl-]
Reactant: Cc1ccc2c(c1)CC(O)c1ccccc1S2
Agent: Cl
Agent: [Ca+2]
Product: Cc1cccc2c1CC(Cl)c1ccccc1S2
Reaction time: 20 h

Procedure:
10 g of 10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol, 100 ml of absolute benzene and 10 g of finely powdered calcium chloride are saturated at room temperature with dry hydrogen chloride gas (ca 2 hours) and then stirred for a further 20 hours. The calcium chloride is subsequently filtered off under a vacuum and washed with chloroform and the filtrate concentrated under reduced pressure. There is obtained 10-chloro-10,11-dihydro-methyl-dibenzo[b,f]thiepine as a yellow oil which crystallises on standing. 19.7 g of 10-chloro-10,11-dihydro-2-methyl-dibenzo-[b,f]thiepine dissolved in 100 ml of chloroform are heated under reflux for 24 hours together with 36.5 g of 1-carbethoxy-piperazine. Then the mixture is concentrated under reduced pressure and the residue crystallised from acetone/hexane. There is obtained 1-carbethoxy-4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 96°-98° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH2:24].N[C:30]1[CH:31]=C(C=[CH:37][C:38]=1N)C(N)=O>>[CH:15]1[C:16]2[C:2](=[CH:31][CH:30]=[CH:38][CH:37]=2)[CH:3]=[CH:4][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:24][C:23]3[CH:22]=[CH:21][C:20]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:19][C:18]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Product: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(Oc4ccc5ccccc5c4)cc3)nc2c1

Procedure:
This compound was prepared according to the methods described in Example 22 and Scheme 3, substituting 4-(naphthalen-2-yloxy)-benzaldehyde for 4-(4-fluoro-phenoxy)-benzaldehyde, and 3,4-diamino-benzenesulfonamide for 3,4-diaminobenzamide.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].Cl.[NH2:45][C:46]1([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:48][CH2:47]1.C(N(CC)CC)C>ClCCl>[CH2:52]([O:51][C:49]([C:46]1([NH:45][S:2]([C:5]2[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=3[C:15]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[O:17])=[O:9])(=[O:4])=[O:3])[CH2:48][CH2:47]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)C1(N)CC1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 600 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 390 mg of ethyl 1-aminocyclopropane carboxylate hydrochloride, 0.27 mL of triethylamine, and 6.0 mL of dichloromethane was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 523 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a pale yellow solid. ESI+: 730
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]1.[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[N:21]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of Example A1 (1.5 g, 5.96 mmol), N-methyl-4-(tributylstannyl)imidazole (3.32 g, 8.94 mmol) and Pd(PPh3)4 (0.344 g, 0.298 mmol) in toluene (30 mL) sparged with Ar and heated at 110° C. overnight. The mixture was cooled to RT, treated with 10% KF and EtOAc, stirred at RT for 2 h, the solids removed via filtration through diatomaceous earth and washed with 5% MeOH/DCM. The layers of the filtrate were separated and the organic layer was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was washed with a small amount of Et2O and dried to afford 2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61 g, 91%). MS (ESI) m/z: 298.1 (M+H+).
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)[C:11]=1[CH3:12]
Reactant: COc1ccnc(COC(C)=O)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 85.2 %

Procedure:
5.7 g of 2-acetoxymethyl-3-methyl-4-methoxy-pyridine was dissolved in chloroform, and 18 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 5.3 g (1 eq.) of 2-mercaptobenzimidazole, 45 mL of a 28% sodium methoxide solution, and 100 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, and ice and ethyl acetate were added to the residue, to wash the residue by suspending. Produced crystals were collected by filtration, and then were washed by suspending in water, to obtain 7.1 g of colorless crystals. Total yield 20.9% (purity by HPLC: 98.2%).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([O:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=5[F:41])=[CH:26][CH:27]=[N:28]4)=[CH:23][C:22]=3[O:42][CH3:43])[CH2:18][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.CCOC(C)=O>[F:41][C:33]1[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:32]=1[O:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:17]3[CH2:18][CH:13]4[CH2:12][NH:11][CH2:15][CH:14]4[CH2:16]3)=[C:22]([O:42][CH3:43])[CH:23]=2)[N:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (2.5 g, 4.1 mmol, 1.0 eq), 33% HBr in acetic acid (5 ml) and acetic acid (5 ml). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc to give a pale orange solid. The solid was filtered, washed with EtOAc and dried, giving 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). 1H NMR (400 MHz, CDCl3): 8.83 (d, 1H), 8.32 (m, 2H), 8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d, 1H), 5.3 (d, 2H), 4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m, 2H), 1.68 (m, 2H); MS (EI) for C24H24FN3O5: 454 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C@H:3]([NH:7][CH3:8])[C:4]([OH:6])=[O:5].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([N:7]([CH3:8])[C@@H:3]([CH:2]([CH3:9])[CH3:1])[C:4]([OH:6])=[O:5])=[O:20]
Reactant: CN[C@H](C(=O)O)C(C)C
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N(C)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
(2S)-3-Methyl-2-methylamino-butanoic acid (5 g, 38.12 mmol) is added to a stirring solution of sodium hydroxide (76.2 mL of 1 M, 76.24 mmol). After complete dissolution, sodium carbonate (2.1 g, 19.82 mmol) is added followed by methyl chloroformate (3.18 mL, 41.17 mmol) at 0° C. over 40 minutes. The reaction mixture is stirred at rt for 4 hours, and then washed with diethyl ether (2×75 ml). The aqueous layer is cooled to 0° C., acidified to pH 1-2 and extracted with CH2Cl2. The organic phase is dried over MgSO4, filtered and concentrated to dryness to give the title compound (2S)-2-[methoxycarbonyl(methyl)amino]-3-methyl-butanoic acid (5.12 g, 71%) as a clear oil.
Reaction SMILES: CN(C)C=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][C:23]=1[O:33][CH3:34]>O>[CH3:34][O:33][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:22]=1[O:21][CH3:20])[CH:28]=[CH:29][C:30]([NH:9][C:8]1[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:15])=[O:14])=[O:31]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 38.5 %

Procedure:
To 15 ml of dimethylformamide was dissolved 2.06 g (0.015 mol) of anthranilic acid. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g (0.01 mol) of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. The resulting mixture was added dropwise to the above solution, with stirring at room temperature. After the completion of the dropping, the reaction mixture was stirred for additional 1.5 hours, and then treated in the same manner as in Example 1. There was obtained 1.26 g (yield: 38.5%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14](=[O:30])[C:15]3[CH:20]=[C:19]([I:21])[C:18]([CH2:22][CH3:23])=[C:17]([I:24])[C:16]=3[O:25][CH2:26][C:27]([OH:29])=[O:28])[C:6]=2[CH:31]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C1COCC1>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[O:42])=[CH:31][C:6]=2[C:7]=1[C:14](=[O:30])[C:15]1[CH:20]=[C:19]([I:21])[C:18]([CH2:22][CH3:23])=[C:17]([I:24])[C:16]=1[O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Solvent: C1CCOC1
Product: CCCCc1oc2ccc(NC(=O)Nc3ccc(OC)cc3)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Yield: 75.3 %

Procedure:
A solution of 5-amino-2-n-butyl-3-(3,5-diiodo-4-ethylcarboxymethoxybenzoyl)-benzofuran (prepared as in Example 1(g), 320 mg, 0.5 mmol) and p-methoxyphenylisocyanate (75 mg, 0.5 mmol) in THF (10 mL) was stirred at room temperature for 3 h. The mixture was concentrated, ethyacetate was added and the organic layer was washed with water, 1M HCl, then NaHCO3 (sat) then brine, dried using MgSO2 and then concentrated. Purification by column chromathography on silica with a 95:5 mixture of methylenechloride--methanol as eluant produced 300 mg (75%) of 2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-(4-methoxyphenylureido)benzofuran.
Reaction SMILES: [C:1]([C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7](Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C(C#N)=C[CH:19]=[C:18]([C:24]([CH3:27])([CH3:26])[CH3:25])N=1>>[C:1]([C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:19]#[C:18][C:24]([CH3:27])([CH3:26])[CH3:25])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Reactant: Cc1cc(C#N)c(Cl)nc1C(C)(C)C
Product: Cc1cc(C#N)c(C#CC(C)(C)C)nc1C(C)(C)C

Procedure:
Procedure analogous to 31, using 62.6 g (300 mmol) of 6-tert-butyl-2-chloro-5-methylnicotinonitrile, S79, instead of 194.7 g (1 mol) of 2-chloro-3-cyano-6-tert-butylpyridine, S28, and scaling the remaining reagents correspondingly on a molar level. Yield: 68.9 g (271 mmol), 90%. Purity: >95% according to 1H-NMR.