Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N+]([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:28][C:27]([O:26][CH3:25])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2[N+](=O)[O-])C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of 3-(4-Chloro-2-nitro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.8 g, 10.7 mmol) in DMF (40 mL) was added Bromo-acetic acid methyl ester (1.01 mL, 10.7 mmol) and K2CO3 (1.48 g, 10.7 mmol). The resultant suspension was stirred at 70° C. overnight. The reaction mixture was diluted with water and ethyl ether. The organic extract was dried over MgSO4, filtered and concentrated to provide the desired product as an oil. The crude product was purified on SiO2 and concentrated to provide the desired product as an oil (2 g, 44%). LCMS (retention time=3.03, ES+428).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]([OH:52])[CH3:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (1.71 g, 2.36 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 30 mL) were added o-dichlorobenzene (1.74 g, 11.8 mmol) and 10% Pd/C (250 mg, 0.236 mmol) at room temperature. The mixture was stirred under H2 at room temperature for 1.5 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (prep-HPLC) to give the title compound 1 as a white solid (544 mg, 51.3%, HPLC: 99.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 451.2 [M+H]+; and 1H NMR (400 MHz, CDCl3) δ (ppm): 7.35 (m, 1H), 7.29-7.21 (m, 2H), 7.04 (m, 2H), 6.75 (m, 2H), 4.71 (br, 1H), 4.51 (br, 1H), 4.14 (m, 1H), 4.01 (m, 3H), 3.98 (m, 2H), 3.89 (m, 1H), 3.77 (m, 2H), 3.60 (m, 1H), 3.52 (br, 1H), 3.06 (br, 1H), 1.34 (t, 3H), 0.91 (d, 3H).
Reaction SMILES: [O:1]([NH2:3])[CH3:2].N1C=CC=CC=1.[CH:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[C:11]1=O)[CH2:17]2>Cl.CO>[CH3:2][O:1][N:3]=[C:11]1[CH:12]2[CH2:18][CH:16]3[CH2:15][CH:14]([CH2:19][CH:10]1[CH2:17]3)[CH2:13]2
Reactant: CON
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 66 h
Yield: 66 %

Procedure:
3.76 g (45 mmol) of methoxylamine, in hydrochloride form, and 4.36 g (55.1 mmol) of pyridine are added to 4.51 g (30 mmol) of 2-adamantanone in 30 ml of methanol. The reaction medium is stirred at ambient temperature for 66 h, the solvents are evaporated off under vacuum, and the residue is then diluted with 50 ml of dichloromethane and 50 ml of water. The organic phase is separated and the aqueous phase is then extracted again with 30 ml of dichloromethane. The organic phases are combined, washed with two times 30 ml of dilute hydrochloric acid (1 M) and 30 ml of brine, and then dried over magnesium sulphate. After filtration and evaporation in a rotary evaporator, the product 35 is obtained in the form of a white powder: 3.57 g (yield=66%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH3:7]O.[Br:9][C:10]([F:31])([F:30])[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19](SC)=[CH:18][CH:17]=2)[C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[Br:9][C:10]([F:30])([F:31])[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:3]([CH3:7])(=[O:5])=[O:2])=[CH:20][CH:21]=2)[C:12]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2noc(C(F)(F)Br)c2-c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)Br)c2-c2ccccc2)cc1
Yield: 81 %

Procedure:
A mixture of Oxone® (120 mg), H2O (3 mL) and MeOH (1 mL) was added dropwise to a solution of 6 (43 mg, 0.108 mmol) in THF (5 mL) with stirring. The reaction mixture was stirred for 2 h and diluted with H2O (10 mL). The product was extracted with CH2Cl2 and the organic extracts were dried over anhydrous MgSO4. After filtration, the filtrate was concentrated and the resulting residue was purified by flash column chromatography with hexanes-EtOAc (4:1) to give 7 (39 mg, 81%) as a colorless solid: 1H NMR (CDCl3) δ 3.11 (3H, s, SO2Me), 7.27-7.98 (9H, m, Ar). HRMS (FAB) Calculated for C17H13BrF2NO3S (MH+, 427.9766). Found: 427.9765.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Br[C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[F:23][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[CH:19][C:18]=1[N+:20]([O-:22])=[O:21]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 89.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 4.2 g of 3-ethoxyphenylboronic acid, 5.0 g of 5-bromo-2-fluoronitrobenzene and 22 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, water was added and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, then dried, and concentrated. The residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give 5.3 g (90% yield) of crude 4-fluoro-3'-ethoxy-3-nitrobiphenyl as a yellow oil.
Reaction SMILES: C1CO[C:3]2([CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=[O:10])[CH:4]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOC1.C1COC2C(C(C)(CCCCC)C(=O)C2)O1>O.O1CCOCC1>[CH:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:3](=[O:2])[CH:4]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]
Reactant: CCCCCC1C(CC=O)CCC12OCCO2
Agent: CCCCCC1(C)C(=O)CC2OCCOC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCO1
Solvent: C1COCCO1
Solvent: O
Product: CCCCCC1C(=O)CCC1CC=O
Yield: 56.1 %

Procedure:
A mixture of 24 g of 1,1-ethylenedioxy-3-formylmethyl-2-n-pentyl-cyclopentane, 40 ml of dioxane, 32 ml of water and 0.18 g paratoluenesulphonic acid is refluxed for 3 hours. It is then cooled, 120 ml of water added and extracted three times with 100 ml of benzene. The benzene solutions are washed to neutrality and concentrated under reduced pressure. There are obtained 22 g of crude product which are rectified and which yield 15.5 g of product; b.p.1.0 = 110°-140°C. The distillate is a mixture of keto aldehyde and the dioxolane of the aldehyde function (3-ethylenedioxymethyl-2-n-pentyl-1-cyclopentanone) in the proportions of 75/25. By careful rectification of this mixture, there is obtained 11 g of pure 3-formylmethyl-2-n-pentyl-1-cyclopentanone exhibiting: b.p.0.5 = 90°C, nD15 = 1.4688.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](Cl)=[O:28])=[CH:21][CH:20]=1.N1C2C(=CC(N)=CC=2)C=CC=1N>CC(O)=O.CCOCC>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[C:27]([NH:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:16]=[CH:15]3)=[O:28])=[CH:23][CH:24]=1
Reactant: O=C(Cl)/C=C/c1ccc(Cl)cc1
Reactant: Nc1ccc2nc(N3CCCCC3)ccc2c1
Agent: Nc1ccc2nc(N)ccc2c1
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cl
Product: O=C(/C=C/c1ccc(Cl)cc1)Nc1ccc2nc(N3CCCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Step D (91 mg, 0.4 mmol) in 2 mL HOAc was added the product of Step E (64 mg, 0.32 mmol). The resulting mixture was stirred at r.t. for 3 h then diluted with 3 mL ether. The resulting mixture was filtered and the resulting solids were washed with ether. The solids were dried under vacuum to afford the product, MS: m/z 392 (MH+), as an off-white solid. Using the appropriate starting materials and following procedures similar to those described above for Example 1, the following compounds were prepared from the corresponding quinoline-2,6-diamine intermediates:
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([NH:14][CH:15]([C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]>C1COCC1>[C:11]([NH:14][C@H:15]([C@H:21]([OH:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.5 %

Procedure:
A dehydrated THF solution (0.5 ml) of triethylamine (131.9 mg, 1.30 mmol) and a dehydrated THF solution (0.5 ml) of formic acid (64.2 mg, 1.37 mmol) were added to a dehydrated THF solution (4.0 ml) of RuCl[(R,R)-TsDPEN](p-cymene) complex (19.6 mg, 0.03 mmol) and ethyl 2-acetylamino-3-oxooctadecanoate (7.70 g, 0.20 mmol) synthesized in the same method as Example 1. After the mixture was stirred for 3 days at room temperature, the reaction solvent was removed in reduced pressure. Water was added thereto, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, solely ethyl acetate) to obtain the title compound (71.3 mg, yield: 94%). The product was analyzed by HPLC to find that anti-form:syn-form was 93:7 and the optical purity of the anti-form was 98% ee.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:33]([C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)=[O:34])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.125 g, 0.43 mmol) and diisopropylethylamine (0.171 g, 1.32 mmol) in methylene chloride (5.0 mL) at 0° C. was added 4-fluorobenzoyl chloride (0.080 g, 0.51 mmol) and the reaction mixture was warmed to room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 100:0 to 95:5 dichloromethane/methanol) to provided (4-(2-tert-butylphenyl)piperazin-1-yl)(4-fluorophenyl)methanone (0.044 g, 30%) as a white solid, mp 137-139° C.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][CH2:10][C:11]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:26])[C:13]=3[CH:12]=2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CCC[CH2:29][CH2:28]1>CN(C)C=O>[N:1]1([C:6]([O:8][CH2:9][CH2:10][C:11]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:26])[C:13]=3[CH:12]=2)=[O:7])[CH2:2][CH2:29][CH2:28][CH2:4][CH2:5]1
Reactant: C1CCNCC1
Reactant: O=C1c2ccccc2C(=O)c2cc(CCOC(=O)n3ccnc3)ccc21
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2cc(CCOC(=O)N3CCCCC3)ccc21
Temperature: 0 °C
Yield: 43 %

Procedure:
To the solution dissolved 12.1 g of N,N′-carbonyldiimidazole (75 mmol; produced by Wako Pure Chemical Industries, Ltd) into 50 mL of dehydrated dimethylformamide (dehydrated DMF), 15.8 g of 2-anthraquinonyl-1-ethylalcohol (62 mmol) obtained by the same method as Synthetic Example 5 was added, then, the solution was reacted by stirring for 1 hour at room temperature. After completing reaction, ice-water was poured into the reaction solution, and this mixed solution was extracted with toluene, and further after organic layer after extraction was washed with water, the organic layer was condensed. The resultant condensed residue was purified with column chromatography (Filler: Silica-gel (Wako-gel C-200; produced by Wako Pure Chemical Industries, Ltd.), Developing solvent: ethyl acetate/n-heptane=1/9) to obtain 12.3 g of 2-anthraquinonyl-1-ethyl 1-imidazolylcarboxylate (yield: 57%) as yellow crystal. Subsequently, to the solution dissolved the resultant crystal of 2-anthraquinonyl-1-ethyl 1-imidazolylcarboxylate into 50 mL of dehydrated dimethylformamide (dehydrated DMF), 4.2 g of piperidine (50 mmol) was added, then, the solution was reacted for 1 hour at room temperature. After completing reaction, ice-water was poured into the reaction solution, this mixed solution was extracted with toluene, and further, organic layer after extraction was washed with water, the organic layer was condensed. The resultant condensed residue was purified with column chromatography (Filler: Silica-Gel (Wako-Gel C-200; produced by Wako Pure Chemical Industries, Ltd.), Developing solvent: ethyl acetate/n-heptane=1/9) to obtain 9.8 g of 2-anthraquinonyl-1-ethyl piperidinecarboxylate (yield: 43%) represented by the above-described formula [12] as yellow crystal. Measurement results of 1H-NMR and melting point are shown as the follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O.Cl[C:11](Cl)(Cl)[CH:12]=[O:13].Cl.ON.S([O-])([O-])(=O)=[O:20].[Na+].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12](=[O:13])[C:11](=[O:20])[NH:5]2)=[CH:7][CH:8]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1cccc(F)c1
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Product: O=C1Nc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
9.6 g of 3-fluoroaniline were added to 590 mL of water followed by the addition of 17.2 g of trichloroacetaldehyde monohydrate, 21.9 g of hydroxyamine hydrochloride and 98.2 g of anhydrous sodium sulfate and stirring the mixture for 5 hours at 50° C. After cooling the resultant to room temperature and allowing to stand overnight, 31 mL of 2 N HCl were added thereto followed by stirring the mixture for 30 minutes and then filtering out the crystals. After drying the resulting crystals, the crystals were added to concentrated sulfuric acid heated to 70° C., followed by stirring the mixture for 1 hour at 80° C. to 90° C. The reaction mixture was poured over ice followed by extracting with ethyl acetate and washing with saturated saline. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 7.96 g of a crude product of 6-fluoroisatin.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]3)[C:4]=2[O:3][CH2:2]1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33]N)=[CH:32][C:27]=2[O:26][CH2:25]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]4[N:33]([C:31]5[CH:30]=[CH:29][C:28]6[O:24][CH2:25][O:26][C:27]=6[CH:32]=5)[N:20]=[CH:19][CH:18]=4)=[N:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OCO3)ccc1=O
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc3c2OCO3)nc1-c1ccnn1-c1ccc2c(c1)OCO2

Procedure:
The product was obtained starting from 1-Benzo[1,3]dioxol-4-yl-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-14) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=403.2 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15]([OH:29])([CH2:16][C@@H:17]([OH:28])[CH2:18][C@@H:19]2[OH:27])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15]([OH:29])([CH2:16][C@@H:17]([O:28][C:30](=[O:32])[CH3:31])[CH2:18][C@@H:19]2[OH:27])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Temperature: 0 °C

Procedure:
In 5 ml of pyridine was dissolved 400 mg of 20-(1,3-dioxolan-2-yl)pregn-6-ene-1α,3β,5α-triol. To this solution was added 0.11 ml of acetic anhydride at a temperature of -10°-0° C. and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture thus obtained was poured in ice-water and stirred at room temperature for 30 minutes. This mixture was then extracted with ether and the extracts were pooled, washed successively with water, cold diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to give 420 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxypregn-6-ene-1α,5α-diol showing the following properties.
Reaction SMILES: C(N[C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]#[N:15])(=O)C.C([OH:18])C.Cl.[OH2:20]>>[OH:20][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([NH2:15])=[O:18]
Reactant: CCO
Reactant: CC(=O)Nc1sc2ccccc2c1C#N
Reactant: O
Agent: Cl
Product: NC(=O)c1c(O)sc2ccccc12

Procedure:
A mixture of 2-acetamido-3-cyanobenzo(b)thiophene (2.2 g, 0.01 m), ethanol (25 ml), water (15 ml) and concentrated hydrochloric acid (25 ml) is heated under reflux for 12 hours. The reaction mixture is diluted with water, aged and filtered to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH2:13][CH2:14][CH3:15])[CH3:30]
Reactant: CCCNCCCCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CCCCNC(=O)OC(C)(C)C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (339.0 mg) obtained in Example 84-1 was dissolved in chloroform (5.1 ml) and added with triethylamine (0.41 ml). Ethyl bromoacetate (0.20 ml) was dropped to the solution and the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (273.9 mg) as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.F[C:10]1[CH:11]=[CH:12][C:13]([CH3:33])=[C:14]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[CH2:19]2)=[O:17])[CH:15]=1>CCCCCC>[CH3:33][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)=[CH:15][C:14]=1[C:16]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]2[N:29]=[CH:30][CH:31]=[CH:32][C:20]=2[CH2:19]1)=[O:17]
Reactant: Cc1ccc(F)cc1C(=O)N1Cc2cccnc2Nc2ccccc21
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C)c(C(=O)N3Cc4cccnc4Nc4ccccc43)c2)n1
Yield: 71.7 %

Procedure:
Sodium hydride (60% suspension in oil, 0.25 g, 6.25 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). Neat 3-methylpyrazole (0.28 mL, 3.5 mmol) was added in one portion at ambient temperature. Stirring was continued until the gas evolution subsided. The (5-fluoro-2-(methyl)-phenyl)-(6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step B (0.75 g, 1.94 mmol) was added in one portion to the clear solution. The mixture was heated to reflux for 26 hours, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate (gradient from 8:2 to 7:3) provided the title product (0.55 g) as a pale yellow foam which was crystallized by sonication from hexane-ethanol, m.p. 209-210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:11][CH:12](CC=C)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:10]=1)[CH3:2].C[N+]1([O-])CC[O:25]CC1.Cl.[CH3:30][C:31]([CH3:33])=[O:32]>O.[Os](=O)(=O)(=O)=O>[OH:32][CH:31]([CH2:33][OH:25])[CH2:30][CH:12]([CH2:11][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[N:10]1)[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: C=CCC(CC(=O)OC)CC1CCCCC(OCC)=N1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Solvent: O
Product: CCOC1=NC(CC(CC(=O)OC)CC(O)CO)CCCC1
Reaction time: 8 h

Procedure:
Example 212 A) The title product of Example 211 dissolved in a 1:1 mixture of acetone and water and treated with osmium tetraoxide (2.5 equivalent %) and 4-methylmorpholine oxide (2 equivalents) at room temperature is allowed to stir overnight. The mixture is then carefully neutralized with dilute HCl, concentrated on a rotary evaporator, and extracted with 3 portions of EtOAc. The combined organic extracts are then dried (Na2SO4), stripped and purified by column chromatography on silica gel to yield methyl b-(2,3-dihydroxypropyl)-7-ethoxy-3,4,5,6-tetrahydro-2H-azepine-2-butanoate