Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:28](OCC)=[O:29].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:28]=[O:29])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -80 °C
Reaction time: 0.67 h
Yield: 71.5 %

Procedure:
To a finely divided suspension of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.0 g, 3.3 mmoles) [prepared in Step B] in tetrahydrofuran (10 mL) at -80° C. was added n-butyl lithium (1.54 mL of 2.14M solution), 3.3 mmoles) with the formation of a dark violet color. After stirring for 40 minutes at -80° C., ethyl formate (0.32 g, 4.3 mmoles) was added and the mixture stirred for 2.5 hours at -80° C. The mixture was hydrolyzed with 1N hydrochloric acid and extracted with methylene chloride. The extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give 0.77 g of yellow solid, m.p. 128°-131° C. The solid was crystallized from isopropyl acetate-hexane to give 0.55 g of the title compound; m.p.=130°-132° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=[O:51])[NH:33][C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=[C:36]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:35]=1[O:49][CH3:50].CCN(C(C)C)C(C)C>O1CCOCC1>[CH:32]([OH:51])=[O:31].[C:40]([C:38]1[CH:39]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[C:35]([O:49][CH3:50])=[C:36]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])[CH:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: O=CO
Temperature: 60 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
A mixture of Intermediate 5c (122 mg, 0.33 mmol), Intermediate 104a (150 mg, 0.33 mmol) and DIPEA (87 μL, 0.50 mmol) in dioxane (2 mL) was stirred at 60° C. for 18 h and then at 85° C. for 48 h. The volatiles were concentrated in vacuo and the resultant residue was purified by MDAP (Method 7) to afford the title compound (88 mg, 40%). LCMS (Method 5): Rt 3.41 min, m/z 662 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.24 (9H, s), 1.81-2.27 (10H, m), 2.28-2.40 (1H, m), 3.04 (3H, s), 3.11-3.18 (2H, m), 3.67 (3H, s), 3.99 (1H, t, J=8.3 Hz), 4.83-4.99 (1H, m), 5.43 (1H, t, J=4.5 Hz), 6.93 (1H, d, J=2.3 Hz), 7.25-7.44 (7H, m), 7.76 (1H, d, J=10.3 Hz), 8.05 (1H, s), 8.15 (1H, s), 8.18 (1H, d, J=2.8 Hz), 8.27 (1H, d, J=2.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>[I-].[Na+].CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:22][CH3:19])=[CH:28][CH:29]=1)[S:9]([N:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNS(=O)(=O)NC(=O)OC(C)(C)C
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)N(Cc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 66.5 %

Procedure:
Ethyl ({[(tert-butoxycarbonyl)amino]sulfonyl}amino)acetate (1.00 g, 4.0 mmol) was mixed with N,N-dimethylformamide (DMF, 6.0 mL) and stirred at room temperature. Sodium iodide (0.01 g, 0.1 mmol, 0.025 equiv.), potassium carbonate (2.40 g, 20 mmol, 5.0 equiv.) and para-methoxybenzyl chloride (2.64 mL, 19.5 mmol, 4.875 equiv.) were added to the mixture. This reaction was warmed to 80° C. and stirred at 80° C. for 2 h. LCMS indicated reaction completion. The reaction was cooled to room temperature and filtered through Celite. The Celite bed was washed with dichloromethane and the combined organic filtrates were concentrated. The concentrated residue was dissolved in dichloromethane (20 mL) and washed with sodium bicarbonate (5×12 mL) and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel (0-40% ethyl acetate/hexane gradient elution) to give the desired product (1.39 g, 80%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.22 (m, 2H), 7.14 (m, 2H), 6.88 (m, 4H), 4.64 (s, 2H), 4.33 (s, 2H), 4.03 (q, 2H, J=7.1 Hz), 3.92 (s, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 1.39 (s, 9H), 1.14 (t, 3H, J=7.1 Hz).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C1([SiH3])C=CC=CC=1>ClCCl.C(O)(=O)C.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>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of N-{4-[5-(1-Allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.0650 g, 0.138 mmol) in dichloromethane (1.0 mL) and acetic acid (0.34 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.00798 g, 0.00691 mmol) followed by phenylsilane (0.0870 mL, 0.706 mmol). The solution was stirred at 40° C. for 90 minutes. The solution was cooled to room temperature then concentrated in vacuo and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted 3 more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.0380 g, 64%). LCMS: (FA) ES+, 431. 1H NMR (400 MHz, d4-Methanol) δ: 8.75-8.70 (m, 1H), 8.44-8.39 (m, 1H), 7.70-7.44 (m, 4H), 7.13-7.07 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6])([OH:3])=[O:2].[CH3:12][NH:13][CH3:14].[CH2:15]=O>O>[C:5]([C:4]([CH2:12][N:13]([CH3:15])[CH3:14])([CH2:8][CH:9]([CH3:11])[CH3:10])[C:1]([OH:3])=[O:2])([OH:7])=[O:6]
Reactant: CNC
Reactant: C=O
Reactant: CC(C)CC(C(=O)O)C(=O)O
Solvent: O
Product: CC(C)CC(CN(C)C)(C(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
2-Carboxy-4-methylpentanoic acid (67 g) is suspended in 400 ml of water and cooled to 5° C. Aqueous 40% dimethylamine (50 g) is added to the suspension followed by aqueous 37% formaldehyde (35.7 g). The resulting solution is stirred for about 16 hours and solid product is filtered and dried in vacuo to yield 57.3 g of the title compound, melting point 134°-137° C. with carbon dioxide and dimethylamine given off.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[CH2:1]([N:3]1[C:7]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCn1nccc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCn1nccc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.1 %

Procedure:
To a solution of 1-ethyl-1H-pyrazole-5-amine (500 mg, 4.50 mmol) and pyridine (0.440 ml, 5.40 mmol) in tetrahydrofuran (15 ml) was added 2,2,2-trichloroethyl chloroformate (0.747 ml, 5.40 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 646 mg (50.1%) of the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[CH3:28][N:8]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[N:15][C:11]=2[CH:10]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]2[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:7]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C)c1ccccc1
Product: CC(Nc1nc2cc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)ccc2n1C)c1ccccc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(1-phenyl-ethyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (65 mg, 46%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.58 (s, 2H), 8.57 (s, 1H), 7.75-7.81 (m, 2H), 7.48-7.51 (m, 2H), 7.32-7.41 (m, 5H), 7.17-7.26 (m, 4H), 6.98-7.00 (m, 1H), 5.65 (d, J=6.3 Hz, 1H), 5.17 (m, 1H), 3.67 (s, 3H), 3.44 (s, 3H), 1.58 (d, J=6.9 Hz, 3H). MS (ESI) m/z=529 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]([OH:26])=[O:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(C(=O)O)c1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzaldehyde (1.5 g) in acetone (30 ml) was added Jones' reagent with ice-cooling, and the mixture was stirred for 2 hours. After addition of methanol (1.5 ml), the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to give 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzoic acid
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:18])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn].Cl.C(OCC)(=O)C>C(O)(C)C.CCCCCC>[CH2:1]([N:8]1[CH2:9][C:10]2[C:15](=[C:14]([CH3:18])[CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1C(=O)N(Cc1ccccc1)C2=O
Agent: Cl
Agent: [Sn]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1cccc2c1C(=O)N(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 4.2 %

Procedure:
A mixture of 2-benzyl-4-methyl-isoindole-1,3-dione (0.500 g, 2 mmol), tin (0.59 g, 5 mmol) and concentrated HCl (2 mL) in isopropanol (10 mL) was heated at reflux for 2.5 h. After this time, the reaction mixture was cooled to ambient temperature, the solids removed by filtration and the filtrate concentrated. The resulting material was dissolved in dichloromethane (20 mL) and the solution washed with brine (7 mL). The organic solution was separated, dried over anhydrous MgSO4, filtered, and concentrated to afford a mixture of regio isomers. Silica gel column chromatography of this mixture using 25% ethyl acetate in hexane afforded 2-benzyl-7-methyl-2,3-dihydro-isoindol-1-one (0.02 g, 9%); 1H NMR (300 MHz, CDCl3): δ ppm) 2.68 (s, 3H), 4.23 (s, 2H), 4.77 (s, 2H), 7.15-7.40 (m, 8H) and GC-MS: m/z 237 (M)+, 160 (M−77)+; and 2-benzyl-4-methyl-2,3-dihydro-isoindol-1-one (0.02 g, 9%); 1H NMR (300 MHz, CDCl3): δ (ppm) 2.68 (s, 3H), 4.23 (s, 2H), 4.77 (s, 2H), 7.15-7.40 (m, 8H) and GC-MS: m/z 237 (M)+, 160 (M−77)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=2)=[CH:6][C:5]=1[OH:22].[CH3:23][S:24][CH2:25]Cl.O>CN(C)C=O>[Cl:17][C:16]1[C:11]([C:7]2[CH:6]=[C:5]([O:22][CH2:23][S:24][CH3:25])[C:4]([Cl:3])=[CH:9][C:8]=2[F:10])=[N:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=1
Reactant: CSCCl
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.1 g (4.4 mmol) of sodium hydride was added to a solution of 1.3 g (4 mmol) of 2-chloro-5-(3-chloro-5-trifluoromethylpyrid-2-yl)-4-fluorophenol in 50 ml of dimethylformamide. After the mixture has been stirred for 1 hour, it was treated with 0.5 g (5.2 mmol) of methylthiomethyl chloride. Then, the mixture was stirred for another hour. For working-up, the reaction mixture was treated with 50 ml of water. The product was then extracted with 100 ml of methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 0.3 g.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[O:14][C:13]3=[O:22])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]=O>C(O)=O>[CH3:25][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[O:14][C:13]3=[O:22])=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: C=O
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(C2=CCNCC2)cc1
Solvent: O=CO
Product: CN1CC=C(c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
3-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one (31 mg, 0.095 mmol), formaldehyde (1.5 mL) and formic acid (1.5 mL) were mixed and heated at 100° C. for 2 hours. The reaction mixture was concentrated; the residue was dissolved in DCM (2 mL) and neutralized by adding saturated NaHCO3. The aqueous phase was extracted with DCM (2×3 mL). The combined organic phase was dried over sodium sulfate and concentrated in vacuo. The crude residue was purified on silica gel eluting with 2M NH3 in methanol/DCM (4: 96) to give the product as off-white solid (25 mg, 78%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.39 (d, 2H), 7.23 (d, 2H), 6.09 (br, 1H), 4.41 (s, 2H), 3.13 (br, 2H), 3.09 (s, 2H), 2.7 (m, 2H), 2.59 (br, 2H), 2.42 (s, 3H), 1.78 (m, 4H), 1.54 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[Cl-].[Cd+2:20].[Cl-]>CCOCC>[Cd:20].[Cl:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Cd+2]
Reactant: Clc1ccc(Br)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Clc1ccccc1
Product: [Cd]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 95 g of p-bromochlorobenzene in 250 cc of ether was added to 15 g of magnesium in 250 cc of ether while maintaining the reaction mixture at reflux. The mixture was stirred for 11/2 hours at room temperature to obtain a solution containing 0.78 mole per liter of p-chlorophenyl magnesium bromide. 17.9 g of cadmium chloride were added to 230 cc of the acid solution and after stirring for 10 minutes, the ether was distilled off while maintaining the volume constant by addition of benzene to obtain a benzene solution of bis-(p-chlorobenzene) cadmium compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-chloro-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8](OC2CCCCO2)[C:9]([C:11]2[O:12][C:13]3[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[NH:10])[CH:5]=[CH:6][CH:7]=1.C[OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][C:13]3[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[N:10][OH:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc2cc(C(=N)N(OC3CCCCO3)c3cccc(Cl)c3)oc12
Reactant: CO
Product: CC(=O)Nc1cccc2cc(C(=NO)Nc3cccc(Cl)c3)oc12
Yield: 73 %

Procedure:
To a methanol solution of N-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamide was added 200 mg of acidic Dowex resin. The resulted solution was stirred at reflux temperature for 1 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified using a chromatotron and eluting with hexane/ethyl acetate (8:2) to give 25 mg N-{2-[N-(3-chloro-phenyl)-N′-hydroxy-carbamimidoyl]-benzofuran-7-yl)-acetamide in 73% yield.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 60 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-nonyl chloroformate. Yield: 60% of theory, C36H45N7O5 (655.8); Rf value: 0.48 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=656; (M+H+Na)++=339.8; (M+Na)+=678.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6](C(O)=O)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[C:15]([O-:18])([O-])=[O:16].[K+].[K+].S(OC)(O[CH3:25])(=O)=O>CN(C)C=O.O>[CH3:25][O:18][C:15](=[O:16])[C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
9.8 g (50 mmol) of 4-methylamino-3-nitro-benzoic acid are treated in 50 ml of dimethyl formamide (DMF) with K2CO3 (14 g). 5 ml of dimethyl sulphate are added dropwise to this mixture over 10 minutes with stirring. It is stirred for 15 minutes and heated for 0.5 hours at 60° C. After cooling, it is diluted with water, the precipitated solids are filtered off, washed with water and dried. Yield: 9.8 g (93%); M.Pt.: 138-140° C.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:23][CH2:22][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]3)[C:15]2=O)=[CH:11][CH:10]=1>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:8][C:9]1[CH:17]=[C:16]2[C:12](=[CH:11][CH:10]=1)[CH2:13][C:14]1([CH2:19][CH2:20][CH:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]1)[C:15]2=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: O=C1c2cc(Br)ccc2CC12CCC(C(F)(F)F)CC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
Titanium ethoxide (2.03 mL, 9.85 mmol), 2-methyl-2-propanesulfinamide (0.895 g, 7.39 mmol) and 6′-bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 78, 1.71 g, 4.93 mmol) in dry 2-Me THF (30 mL) were heated to 100° C. to give an azeotrope at 74° C. The azeotropic distillation was continued for 5 h and then the mixture was refluxed for 2 days. The mixture was cooled to r.t. Water (10 mL) and EtOAc (20 mL) were added, under continuous stirring, while a solid formed. The reaction mixture was stirred at r.t. for 2 h, and then the formed solid was left to sediment for 1 h. The mixture was filtered, and the solid was washed with EtOAc. The filtrate was concentrated in vacuo to give a residue that was purified by flash chromatography (eluent heptane/EtOAc 65/35) to give the title compound (400 mg, 18% yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.34-1.37 (m, 9 H) 1.56 (s, 4 H) 1.73-1.82 (m, 2 H) 2.13 (br. s., 5 H) 2.89 (d, 2 H) 7.22 (d, 1 H) 7.60 (dd, 1 H) 8.53 (d, 1 H); MS (ES+) 451 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])O.O>C(O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:22]1[O:23][C@H:14]([CH2:13][OH:12])[C@@H:16]([OH:17])[C@H:18]([OH:19])[C@H:20]1[OH:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Fc1ccc2c(c1Cl)CCN2
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@@H](N2CCc3c2ccc(F)c3Cl)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 94.2 %

Procedure:
A mixture of 4-chloro-5-fluoroindoline (584 mg) and D-glucose (1.04 g) in ethyl alcohol (20 ml)-H2O (3 ml) was refluxed for 1.5 days. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15) to give 4-chloro-5-fluoro-1-(β-D-glucopyranosyl)indoline (1.07 g) as a colorless foam. APCI-Mass m/Z 334/336 (M+H). 1H-NMR (DMSO-d6) δ 3.02 (m, 3H), 3.20-3.45 (m, 4H), 3.57 (m, 2H), 3.71 (m, 1H), 4.35 (t, J=5.8 Hz, —H), 4.60 (d, J=8.3 Hz, 1H), 4.93 (d, J=5.1 Hz, 1H), 5.04 (d, J=4.0 Hz, 1H), 5.07 (d, J=4.3 Hz, 1H), 6.51 (dd, J=8.6, 3.6 Hz, 1H), 7.00 (t, J=9.1 Hz, 1H).
Reaction SMILES: C(O[Si:5]([CH3:8])([CH3:7])[CH3:6])(=O)C.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11]>CCCCCC>[C:9]([O:14][Si:5]([CH3:8])([CH3:7])[CH3:6])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: CC(=O)O[Si](C)(C)C
Reactant: C=C(C)C(=O)O
Solvent: CCCCCC
Product: C=C(C)C(=O)O[Si](C)(C)C

Procedure:
20 ml of acetoxytrimethylsilane and 11.4 ml of commercial methacrylic acid (ATOFINA Norsocryl® MAA) in 100 ml of hexane are mixed and heated. Azeotropic distillation of acetic acid affords trimethylsilyl methacrylate.