Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]3[NH:15][C:16]([Cl:19])=[C:17]([Cl:18])[C:8]2=3)=[CH:4][N:3]=1.BrBr.CC(O)=[O:24]>>[NH2:1][C:2]1[NH:6][C:5](=[C:7]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]3[NH:15][C:16]([Cl:19])=[C:17]([Cl:18])[C:8]2=3)[C:4](=[O:24])[N:3]=1
Reactant: Nc1ncc(C2CCNC(=O)c3[nH]c(Cl)c(Cl)c32)[nH]1
Reactant: CC(=O)O
Agent: BrBr
Product: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c(Cl)c(Cl)c32)N1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one, prepared as in reference 2, (38 mg, 0.13 mmol) in AcOH (3 mL) is added NaOAc trihydrate (86 mg, 0.63 mmol). A solution of Br2 (40 mg, 0.25 mmol) in AcOH (1 mL) is added drop-wise, the mixture is stirred for an additional 30 minutes and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (DMSO-d6) δ 3.18-3.26 (m, 2H), 3.26-3.32 (m, 2H), 8.09 (t, 1H, J=4.8 Hz), 8.68 (s, 1H), 9.37 (s, 2H), 11.11 (s, 1H), 13.46 (s, 1H); m/z [M++1] 314.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([O:32]CC)=[O:31])[CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C(O)C.[OH-].[Na+].O>C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([OH:32])=[O:31])[CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2cc3c(cc2C)[nH]c(=O)c2cnn(C4CCOCC4)c23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCC[C@@H](C(=O)O)C1
Temperature: 70 °C
Reaction time: 9 h
Yield: 79.5 %

Procedure:
To 95 mg of ethyl (3R)-1-{[7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-8-yl]carbonyl}piperidine-3-carboxylate were added 5 mL of ethanol and 200 μL of a 3 M aqueous sodium hydroxide solution, followed by stirring at 70° C. for 9 hours. The reaction mixture was cooled, and water and ethyl acetate were added thereto, and then the organic layer was separated. The aqueous layer was adjusted to about pH 4 with 1 mL of 1 M hydrochloric acid, then the solution was coevaporated with toluene. After forming a precipitate, f the precipitared powder was collected by filtration. The obtained powder was dried under reduced pressure to obtain 71 mg of (3R)-1-{[7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-8-yl]carbonyl}piperidine-3-carboxylic acid as white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[N:14][CH:13]=[CH:12][CH:11]=2)(=O)=O.FC(F)(F)S(OC1C=[N:27][C:28]2C(C=1)=CC=CC=2)(=O)=O.Cl.[NH2:38]O>>[NH:38]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:27]=[CH:28]1
Reactant: NO
Reactant: O=S(=O)(Oc1cnc2cccnc2c1)C(F)(F)F
Reactant: O=S(=O)(Oc1cnc2ccccc2c1)C(F)(F)F
Agent: Cl
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (3) of Reaction Scheme VI, a [1,5]naphthyridin-3-yl trifluoromethanesulfonate or quinolin-3-yl trifluoromethanesulfonate of Formula LIX is reacted with a hydroxylamine hydrochloride of Formula R1ONH2.HCl and cyclized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine or a 1H-imidazo[4,5-c]quinoline of Formula XXXIII. The reaction can be carried out using the method described in step (3) of Reaction Scheme I.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:46]2[CH2:48][CH2:47]2)[C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:9]1)=O)(C)(C)C.C(OC(N1C[C@@H](CN(C(C)C)C(=O)C2C=CC(OC)=C(OCCCOC)C=2)[C@H](CNC2CC2)C1)=O)(C)(C)C.C(N(CC)CC)C.C(N=C=O)C1C=CC=CC=1>C1COCC1.O>[CH2:39]([NH:38][C:36](=[O:37])[N:35]([CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:46]1[CH2:47][CH2:48]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)NCc2ccccc2)C2CC2)C(C)C)ccc1OC
Agent: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Agent: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C(=O)NCc2ccccc2)C2CC2)C(C)C)ccc1OC

Procedure:
(3R*,4R*)-3-(3-Benzyl-1-cyclopropyl-ureidomethyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl Ester To a solution of ((3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (235 mg, 0.440 mmol) in THF (6 mL) is added triethylamine (123 μL, 0.880 mmol) followed by benzylisocyanate (54 μL, 0.440 mmol). The mixture is stirred at RT for 2 h before water is added. Extraction with ethyl acetate, drying of the combined extracts (Na2SO4), filtration and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent gradient: CH2Cl2 100% to CH2Cl2/MeOH 9:1) to give the title compound. MS (LC-MS): 667.1M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.26 min.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH2:5]O.CCOCC.P(Br)(Br)[Br:18]>N1C=CC=CC=1>[Br:18][CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: CCCCCC(C)=CCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC(C)=CCCBr
Temperature: 25 °C

Procedure:
A solution of 3 g. of 4-methyl-3-nonen-1-ol in a mixture of 20 ml. of ether and 1.25 ml. of pyridine under nitrogen is cooled in an ice-salt bath and stirred while 2.7 ml. of phosphorus tribromide is added slowly. The ice bath is removed and the mixture is allowed to warm to room temperature, then is heated under reflux for about 2.5 hrs. The mixture is then cooled in an ice bath while 10 ml. of water is added slowly. The layers are separated and the ether layer is washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated, giving a residue comprising 1-bromo-4-methyl-3-nonene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[C:18]([CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(O)=[O:19].C(Cl)Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:18](=[O:19])[CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-(N-Boc-2-aminoethyl)glycine ethyl ester (8, 13.5 g; 54.8 mmol), DhbtOH (9.84 g; 30 60.3 mmol) and N-1-carboxymethyl thymine (4, 11.1 g; 60.3 mmol) were dissolved in DMF (210 ml). Methylene chloride (210 ml) then was added. The solution was cooled to 0° C. in an ethanol/ice bath and DCC (13.6 g; 65.8 mmol) was added. The ice bath was removed after 1 hour and stirring was continued for another 2 hours at ambient temperature. The precipitated DCU was removed by filtration and washed twice with methylene chloride 5 (2×75 ml). To the combined filtrate was added more methylene chloride (650 ml). The solution was washed successively with diluted sodium hydrogen carbonate (3×500 ml), diluted potassium hydrogen sulfate (2×500 ml), and saturated sodium chloride (1×500 ml). Some precipitate was removed from the organic phase by filtration, The organic phase was dried over magnesium sulfate and evaporated to dryness, in vacuo. The oily residue was dissolved in methylene chloride (150 ml), filtered and the title compound was precipitated by the addition of petroleum ether (350 ml) at 0° C. The methylene chloride/petroleum ether procedure was repeated once. This afforded 16.0 g (71%) of the title compound which was more than 99% pure by HPLC.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([OH:23])=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[C:20]([C:8]1[C:7]2[O:23][C:1](=[O:2])[NH:5][C:6]=2[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(=[O:22])[CH3:21]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
51.1 mL (97.04 mmol) of a phosgene solution (20% by weight in toluene) are added at 0° C. to a solution of 22.7 g (88.22 mmol) of 1-(3-amino-5-benzyloxy-2-hydroxyphenyl)ethanone in toluene (200 mL). Then 30.7 mL (220.6 mmol) of triethylamine is added dropwise such that the temperature does not exceed 5° C. After 1 hour stirring at ambient temperature, a further 4.6 mL of phosgene solution and 12 mL of triethylamine are added at 0° C. The mixture is stirred for 1 hour at ambient temperature, diluted with dichloromethane and combined with saturated aqueous ammonium chloride solution (500 mL) and 2 N aqueous hydrochloric acid (10 mL). After the aqueous phase has been separated off it is exhaustively extracted with dichloromethane. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated down in vacuo, during which time a beige solid is precipitated. The precipitate is filtered off, washed with a little toluene, and dried at 50° C. in vacuo. Yield: 18.5 g (74%); Rf=0.19 (silica gel, toluene/acetone 95:10); ESI-MS: [M+H]+=284.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[O:19]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:3]([O:6][CH3:7])=[O:8]
Reactant: O=C1CCCc2ccccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere, a mixture of sodium hydride (60% dispersion in mineral oil, 887 mg, 22.0 mmol), dimethyl carbonate (15 mL) and 3,4-dihydronaphthalen-1(2H)-one (1.46 g, 10.0 mmol) was stirred at 80° C. for 3.5 hr. The reaction mixture was quenched with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium carbonate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/0→5/1) to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)([CH2:8][OH:9])[CH2:6][OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH:1]1([CH2:4][C:5]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)([CH2:6][O:7][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8][O:9][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC4CC4)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC4CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of 2-cyclopropylmethyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-propane-1,3-diol (200 mg, 0.441 mmol) and Et3N (184 μL, 1.32 mmol) in DCM (20 mL) cooled at 0° C. was added methanesulfonyl chloride (86 μL, 1.10 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless solid (264 mg, 98%). LCMS (Method B): RT 3.34 min [M+H]+ 610
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].C=O.[C:8]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:15]([O:17][CH3:18])(=[O:16])[CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][OH:2]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A three necked one-liter flask equipped with a drying tube, a thermometer and a stopper was flame-dried, cooled and then charged with sodium bicarbonate (2.1 g; 0.025 mole), paraformaldehyde (34.74 g; mole) and 300 mL of dimethylsulfoxide (DMSO). The air in the flask was purged with dry nitrogen and methyl phenylacetate (150.18 g; 1 mole) was added in one portion. Residual ester was washed into the flask using dry DMSO (5 mL). The slurry was then stirred magnetically (initial temperature 22°-23° C.) and the temperature rose slowly over one hour to 33° C. The temperature remained at about 32°-33° C. for 1.5 hrs. at which time the reaction liquid was almost a clear solution. The temperature was then raised to 45°-46° C. over 30 min. and kept at this temperature for 12 hrs. The solution was then allowed to cool and left at room temperature for 9 hrs. The reaction mixture was clear and essentially colorless with only a small amount of a white solid appearing at the bottom of the flask. NMR analysis of the solution indicated approximately an 80% yield of methyl tropate.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1COCO[CH2:13]1>ClC(Cl)C>[CH2:7]1[S:8](=[O:9])(=[O:10])[NH:11][CH2:13][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]1=2
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: C1OCOCO1
Solvent: CC(Cl)Cl
Product: O=S1(=O)Cc2ccccc2CN1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the method described in Bravo, R. D. et al. Synth. Commun. 2002, 32, 3675. A flask was charged with alpha-toluenesulfonamide (1 g, 5.8 mmol) and 1,3,5-trioxane (0.175 g, 1.9 mmol) in anhydrous dichloroethane (23 mL) and amberlyst 15H+ resin (3.7 g). The mixture was stirred at 80° C. overnight, after which the resin was filtered off and washed with methylene chloride. The organic solution was concentrated to afford a white solid (0.848 g, 79%). 1H NMR (d6-DMSO, 300 MHz) δ 7.41-7.37 (t, 1H, J=6.8 Hz), 7.30-7.24 (m, 2H), 7.19-7.16 (m, 1H), 7.12-7.09 (m, 1H), 4.42-4.40 (d, 2H, J=6.6 Hz), 4.35 (s, 2H).
Reaction SMILES: [CH:1]1[NH:5][C:4]([C:6]2[NH:10][CH:9]=[CH:8][N:7]=2)=[N:3]C=1.[H-].[Na+].[C:13]1([CH3:24])C(S(OC)(=O)=O)=CC=CC=1.[CH3:25]N(C=O)C>>[CH3:25][N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:4]1[N:5]([CH3:1])[CH:13]=[CH:24][N:3]=1
Reactant: c1c[nH]c(-c2ncc[nH]2)n1
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Product: Cn1ccnc1-c1nccn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 2,2′-biimidazole (Fieselmann, B. F., et al. Inorg. Chem. 17, 2078 (1978)) (4.6 g, 34.3 mmoles) in 100 mL dry DMF in a 250 ml round bottom flask cooled in an ice/water bath was added in portions NaH (60% in mineral oil, 2.7 g, 68.6 mmoles). After the solution was stirred at 0° C. for one hour under N2, methyl toluenesulfonate (10.3 mL, 68.6 mmoles) was added in small portions using a syringe over 30 min. The stiffing of the solution in the ice/water bath was continued for 1 h and then at room temperature for 3 h. The solvent was removed by vacuum distillation. The dark residue was triturated with ether and then suction filtered and dried under vacuum. The product was purified by sublimation. Yield: 80%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])[CH:12]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C(=O)N(C)C)c2)CC1

Procedure:
5-Chloro-N,N-dimethyl-2-nitrobenzamide (1.131 g), 4-piperidinecarboxylic acid ethyl ester (0.77 mL), and potassium carbonate (1.4 g) were reacted in N,N′-dimethylformamide (20 mL) at 100° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated to give the title compound (1.578 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].ClOC(C)(C)C.[CH3:17][S:18][CH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.C[O-].[Na+]>ClCCl.O.CO>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:20]([CH:19]([S:18][CH3:17])[C:7]2[CH:8]=[CH:9][CH:10]=[C:4]([CH2:3][O:2][CH3:1])[C:5]=2[NH2:6])[N:25]=1
Reactant: COc1cc(OC)nc(CSC)n1
Reactant: COCc1ccccc1N
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COCc1cccc(C(SC)c2nc(OC)cc(OC)n2)c1N
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
2-Methoxymethylaniline (0.68 g, 4.96 mmol) was dissolved in dichloromethane (50 ml) and the solution was cooled to −70° C. To the cooled solution a solution of tert-butyl hypochlorite (0.54 g, 4.96 mmol) in dichloromethane (1 ml) was added dropwise and the solution was stirred at −70° C. for 10 minutes. To the obtained reaction solution a solution of 2-methylthiomethyl-4,6-dimethoxypyrimidine (0.893 g, 4.46 mmol) in dichloromethane (5 ml) was added dropwise and the solution was stirred at −70° C. for 30 minutes. To the obtained reaction solution a 28% methanol solution of sodium methoxide (4 ml) was added and the solution was stirred until its temperature reached room temperature. Water was added to the reaction solution and the organic layer was separated. The water layer was further extracted twice with dichloromethane. The organic layer was washed with water and dried. Then dichloromethane was distilled off under reduced pressure and the obtained oily substance was purified by column chromatography using 1:6 mixed solvent of ethyl acetate and hexane as eluent to obtain 2-[(4,6-dimethoxypyrimidin-2-yl)-methylthiomethyl]-6-methoxymethylaniline (0.88 g, yield 53%) as oily substance;
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[N:19]([O-])=O.[Na+].[CH3:23][C:24]1[CH2:25][C:26](=[O:39])[N:27]([C:29]2[CH:38]=[CH:37][C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[CH:30]=2)[N:28]=1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[F:8][C:6]1[CH:7]=[C:2]([NH:1][N:19]=[C:25]2[C:26](=[O:39])[N:27]([C:29]3[CH:38]=[CH:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[CH:30]=3)[N:28]=[C:24]2[CH3:23])[C:3]([OH:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)[CH:5]=1
Reactant: Nc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Reactant: O=N[O-]
Reactant: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1=NNc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Yield: 13 %

Procedure:
Upon cooling by an ice-water bath, 3′-amino-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid 2f (250 mg, 1.01 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) followed by addition of 10 mL of aqueous sodium nitrite (77 mg, 1.12 mmol) and 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 4i (230 mg, 1.01 mmol). The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, followed by addition of 10 mL of ethanol. The reaction was warmed up to room temperature overnight and monitored by TLC until the disappearance of the starting materials. The mixture was filtered, dried and recrystallized from methanol to obtain the title compound 5′-fluoro-2′-hydroxy-3′-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-biphenyl-3-carboxylic acid 4 (64 mg, yield 13.1%) as a red solid.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]=C.[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25](=[O:47])[C@H:26]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:27]([CH2:40]C=C)[C:28]([NH:30]CC2C=C(F)C=C(F)C=2)=[O:29])[C:8]1=[O:48].C([O-])(=O)CCC([O-])=O.CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NC(N)C1=O>>[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@H:9]([NH:24][C:25](=[O:47])[C@H:26]([CH2:43][CH:44]([CH3:45])[CH3:46])[C@H:27]([CH2:40][CH2:3][CH:2]=[CH2:1])[C:28]([NH2:30])=[O:29])[C:8]1=[O:48]
Reactant: C=CCCBr
Reactant: C=CC[C@H](C(=O)NCc1cc(F)cc(F)c1)[C@@H](CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])CCC(=O)[O-]
Product: C=CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
A procedure analogous to the preparation of Example 5 was followed. The appropriate succinate ester was prepared using the method disclosed in PCT publication WO 98/51665), using 3-butenyl bromide for R3—X in place allyl bromide (see Scheme 2). The anti-succinate half-ester was coupled to (S)-isomer benzodiazepine (30) using the procedures of Step 1. After Steps 2 and 3, the title compound was isolated. MS (M+H)+=475.3; (M+Na)+=497.3.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[O-:13][C:14]#[N:15].[K+]>O>[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:14]([NH2:15])=[O:13])[CH2:5][CH2:4]1
Reactant: N#C[O-]
Reactant: NC1CCC(=O)c2sccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21

Procedure:
An aqueous solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride (1.01 g/5 ml water) is treated with 0.81 g of potassium cyanate in 2 ml of water at pH 6-7 to afford the title compound, which is collected and washed with water to afford 0.93 g, m.p. 241° C. to 242° C. dec.