Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:45][S:46]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:48])=[O:47].CN1CCOCC1>CN(C)C=O>[CH2:18]([O:17][C:15]([NH:14][C@H:10]([C:11]([N:52]1[CH2:53][CH2:54][N:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:50][CH2:51]1)=[O:13])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CCCCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
(S)-3-(4-cyanophenyl)-2-(butyloxycarbonylamino)propionic acid (0.5 g, 1.7 mmole) was dissolved in dimethylformamide (DMF, 20 ml) and then cooled to 0° C. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.5 g) and 1-hydroxybenzotriazole hydrate (HOBT, 0.3 g) were added to this solution and stirred until they are completely dissolved therein. To this reaction mixture were added 1-methanesulfonyl-piperazine (0.3 g) and N-methylmorpholine (0.2 ml), and then the temperature was slowly elevated to room temperature. The reaction solution was stirred for 3.5 hours. After the reaction is completed, the reaction solution was distilled under reduced pressure to remove the volatile substance and the remaining solution was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified with column chromatography using ethyl acetate/hexane (6/4, by volume) as an eluent to obtain the purified title compound (0.7 g, Yield: 93%).
Reaction SMILES: [C:1]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1cccc2cc(C(=O)CCC)c(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=Cc1cccc2c(Cl)c(C(=O)CCC)cnc12
Yield: 38.5 %

Procedure:
3-Butyryl-8-vinylquinolone (23 g, 95 mmol) was heated under reflux in a mixture of phosphoryl chloride (I00 ml) and chloroform (100 ml) for 45 minutes. The solvent was evaporated and the residue was mixed with ice, neutralized with ammonia solution and extracted into dichloromethane. The organic solution was washed successively with sodium hydrogen carbonate solution and brine, dried (anhyd. MgSO4), filtered and evaporated. Chromatography (silica gel, 2% methanol in dichloromethane) afforded 3-butyryl-4-chloro-8-vinylquinoline as a brown oil (9.5 g, 38.5%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:24]/[N:25]5[CH2:29][CH2:28][O:27][C:26]5=[O:30])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN1CCOC1=O
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\N1CCOC1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 3-aminooxazolidin-2-one. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 8.02 (m, 2H), 7.84 (m, 1H), 7.53 (m, 1H), 6.24 (s, 2H), 4.51 (t, 2H), 4.15 (t, 1H), 4.08 (t, 2H), 2.73 (s, 1H), 2.46 (s, 3H). LCMS (method B): [MH]+=389, tR=1.87 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1])=[O:20]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
10.8 g (66.4 mmoles) 3,3-dimethyl-3H-indol-2-one are slowly added (in 1 h) to a suspension of 26 7 g (200 mmoles) aluminium chloride and 15 g, that is 10.58 ml (133 mmoles) chloroacetyl chloride in 60 ml dichloromethane, then the mixture is heated under reflux for 1 h 30 min. The brown suspension obtained is slowly poured into 500 ml ice-water, the mixture is stirred for 30 min and then filtered and the solid is washed with a little ether and dried. 16.3 g of crystals are obtained, which are used as such in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:40])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[NH2:40][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Reaction time: 0.75 h
Yield: 144.1 %

Procedure:
A mixture of 4-(4-bromophenyl)phthalazin-1(2H)-one (Aldrich) (0.200 g, 0.663 mmol) and KOtBu (1 M in THF, 1.0 mL, 1.0 mmol) in THF (2 mL) was stirred for 45 minutes, diluted with DMF (1 mL), and O-(diphenylphosphoryl)hydroxylamine (0.240 g, 1.03 mmol) was added and stirred for 90 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to give 302 mg of crude material as a white solid, which was used without purification. LC/MS (APCI) M/Z 318.0 (M+H)+.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[NH2:14][C:15]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:17][C:16]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:29]([O:28][C:27]([NH:26][C:16]1[CH:17]=[CH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:20][C:15]=1[NH:14][C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3])=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-(chlorocarbonyl)benzoate (1.40 g, 7.07 mmol) and tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (2.05 g, 7.07 mmol) were combined in pyridine (10 mL) and stirred at room temperature for 18 h. The reaction mixture was poured into 3:1 CHCl3:MeOH, washed with 2 N HCl and 2 N NaOH, dried (Na2SO4), and evaporated to give the desired product as a colorless solid. MS: cal'd 475 (MNa+), exp 475 (MNa+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8](C=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[CH2:12]([NH:19][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc2nc[nH]c2c1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNc2ccc3[nH]cnc3c2)cc1
Reaction time: 8 h

Procedure:
Benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.) was dissolved in MeOH (10 ml). Benzylamine (0.109 ml; 1 mmol; 1 eq.) was added and the mixture was stirred overnight. NaBH4 (57 mg; 1.5 mmol; 1.5 eq.) was added and stirring was continued overnight. The reaction was quenched by addition of water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flashchromatography on silica using a CHCl3/MeOH gradient. Yield: 0.045 g (19%); MS m/z: 238.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 3.65 (s, 2H); 3.74 (s, 2H); 7.10-7.20 (m, 2H); 7.25-7.32 (m, 4H); 7.40-7.55 (m, 2H); 8.11 (s, 1H); 12.28 (br s, 1H); HPLC (METHOD [A]): rt 4.98 min (95.0%)
Reaction SMILES: [O:1]=[C:2]([CH2:16][CH2:17][CH:18]1[NH:21][C:20](=[O:22])[CH:19]1[NH:23][C:24](=[O:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].O=C(CCC1NC(=O)C1NC(=O)COC1C=CC=CC=1)CC(OCC1C=CC([N+]([O-])=O)=CC=1)=O.C1(C)C=CC(S([N:76]=[N+:77]=[N-])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C(#N)C>[N+:76](=[C:3]([C:2](=[O:1])[CH2:16][CH2:17][CH:18]1[NH:21][C:20](=[O:22])[CH:19]1[NH:23][C:24](=[O:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5])=[N-:77]
Reactant: COc1ccc(COC(=O)CC(=O)CCC2NC(=O)C2NC(=O)Cc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C(CCC1NC(=O)C1NC(=O)COc1ccccc1)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C(=[N+]=[N-])C(=O)CCC2NC(=O)C2NC(=O)Cc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
A solution of 4-methoxybenzyl 3-oxo-5-[(3SR,4RS)-3-phenylacetamidoazetidin-2-on-4-yl]pentanoate (1.38g, 3.15mmol) [prepared by the method described for 4-nitrobenzyl 3-oxo-5-[(3SR,4RS)-3-phenoxyacetamidoazetidin-2-on-4-yl]pentanoate, C. Bodurow and M. A. Carr, Tetrahedron Lett., 1989, 30, 4801] in acetonitrile (60ml) was treated with 4-toluenesulphonyl azide (870mg, 4.42mmol) and N,N-diisopropylethylamine (822μl, 4.73mmol) at 0° C. After 10 min., the ice-bath was removed and stirring was continued at room temperature for 2h. The reaction mixture was diluted with ethyl acetate and washed with brine. After drying over MgSO4, the solvent was evaporated in vacuo and the residue purified by chromatography on silica gel eluting with ethyl acetate to yield the title compound (1.27g, 87%); vmax (KBr) 2134, 1775, 1717, 1654, 1513 and 1304cm-1 ; δH (CDCl3, 250MHz) 1.59-1.70 (2H,m), 2.68-2.95 (2H,m), 3.55 and 3.65 (2H, ABq, J 15.6Hz), 3.78 (1H,m), 3.82 (3H,s), 5.19 (2H,s), 5.25 (1H, ddd, J 8.1, 4.9, 1.0Hz), 6.25 (1H, br s, exch.), 6.49 (1H, br d, J 8.1Hz, exch.), 6.90 (2H,d, J 8.7Hz) and 7.23-7.70 (7H,m). [Mass spectrum : +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (487)].
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH:1]([C:4]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1c(C(C)C)nn2ccccc12
Yield: 62.9 %

Procedure:
A mixture of 6.4 g (40 mmol) of 2-isopropylpyrazolo[1,5-a]pyridine, 3.7 g (40 mmol) of propionyl chloride and 400 mg of AlCl3 was stirred at RT in 5 ml of CS2 for 3 days. The mixture was quenched with saturated NH4Cl and extracted with EtOAc to provide 5.44 g of crude 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, which was purified on a silica gel column to yield 700 mg of pure intermediate along with 3.53 g of starting material. 700 mg of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was reacted with 600 μl of 1M t-BuOK in t-BuOH at −20° C. for 20 minutes, followed by the addition of 600 μl of isoamylnitrite at 0° C. and stirring at RT overnight. The mixture was quenched with saturated NH4Cl and extracted with EtOAc to provide 1.2 g of crude product, which was purified on a silica gel column to furnish 314 mg of (Z)-2-(hydroxyimino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1083.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[N:9]([CH3:25])[S:10](=[O:24])(=[O:23])[C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]([CH3:20])[C:12]=2[C:21]=1[OH:22])=[O:7])CCC.NC1[S:28][CH:29]=[CH:30][N:31]=1>>[CH3:25][N:9]1[C:8]([C:6]([NH:5][C:1]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:7])=[C:21]([OH:22])[C:12]2[N:13]([CH3:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[S:10]1(=[O:24])=[O:23]
Reactant: Nc1nccs1
Reactant: CCCCNC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 37 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino-[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 36 from N-(n-butyl)-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide and 2-amino-thiazole with a yield of 37% of theory; M.p.: 260°-261° C. (decomp.)
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.CN(C)CCN(C)C.C(O)C.N#N.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>O1CCCC1.O>[CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(OCC2CCCCC2)cc1
Reactant: BrCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: N#N
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CCCCC2)cc1Cc1ccccc1
Temperature: -100 °C
Reaction time: 1 h

Procedure:
A solution of 4-cyclohexylmethyloxybenzoic acid (19-1) (1.00 g, 4.27 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added to a solution of sec-butyllithium (1.3M, 8.21 mL, 10.7 mmol, 2. 50 equiv) and N, N, N', N'-tetramethylethylenediamine (1.61 mL, 10.7 mmol, 2.50 equiv) in tetrahydrofuran (10 mL) at -100 ° C. (ethanol-N2 (l)). The resultant orange suspension was stirred at -100° C. for 1 h, then warmed to -78 ° C. and held at that temperature for 15 min. Benzyl bromide (2.00 mL, 16.8 mmol, 3.93 equiv) was added to the cold reaction mixture, causing the color to change to light yellow. The suspension was stirred at -78° C. for 35 min, then was poured into water (150 mL). The aqueous mixture was acidified to approximately pH 2 with an aqueous 1N hydrochloric acid solution and was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography (40% hexanes in ethyl acetate initially, grading to 100% ethyl acetate) to afford the desired carboxylic acid 19-2 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][C:17]([C:19]1[C:28]2[O:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:25]([CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[ClH:43]>CO.CC(C)=O>[ClH:43].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]([C:19]2[C:28]3[O:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([CH3:35])[C:24](=[O:36])[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:11][CH2:10]1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)CBr)cccc2c1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccccc1N1CCN(CC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Reaction time: 4 h

Procedure:
A solution of 11.5 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of methanol was added dropwise at 20°-25° C. to a stirred mixture consisting of 21.4 g of Intermediate VI and 4.1 g of potassium carbonate in 120 ml of methanol. After 4 hours stirring at the same temperature, the reaction mixture was stripped in vacuo. The residue was extracted with chloroform and the organic solution was washed with water, dried on anhydrous sodium sulfate/calcium chloride, filtered and stripped in vacuo. The obtained crude product was dissolved in acetone and a slight excess of ethanolic hydrogen chloride was added. After collection by suction filtration and recrystallization from 95% ethanol, 16.3 g of the title compound was obtained (m.p. (189) 195°-199° C.).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:15])(=O)=O.O.[Cl-].[Na+]>C(Cl)(Cl)Cl>[OH:1][N:2]=[C:3]([C:9](=[O:11])[CH2:10][Cl:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 31.83 g) in chloroform (70 ml) was added dropwise sulfuryl chloride (29.7 g) over 6 minutes under ice-cooling, and the mixture was stirred for 4.5 hours at ambient temperature. The mixture was cooled to 7° C., and sulfuryl chloride (13.498 g) was further added thereto. The mixture was stirred at ambient temperature for overnight. After the reaction mixture was cooled with ice-water, chloroform (50 ml) and water (40 ml) were added thereto with stirring. The mixture was saturated with sodium chloride, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (40 ml×2), dried over magnesium sulfate and then filtered. The filtrate was evaporated to give ethyl 2-hydroxyimino-3-oxo-4-chlorobutyrate (syn isomer), quantitatively.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([C@@H:22]1[C@@H:29]2[C@@H:25]([O:26][C:27](=[O:30])[CH2:28]2)[CH2:24][C@H:23]1[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)=O>ClCCl.C(#N)C>[O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:3]=[CH:20]/[C@@H:22]1[C@@H:29]2[C@@H:25]([O:26][C:27](=[O:30])[CH2:28]2)[CH2:24][C@H:23]1[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of dimethyl (2-oxo-4-phenylbutyl)phosphonate (69.1 g) in dichloromethane (200 mL) was added dropwise at 0° C. to a suspension of sodium hydride (11.9 g) in dichloromethane (700 mL). The mixture was stirred at 0° C. during 1 h. The cold (0-5° C.) solution of aldehyde [3a] in dichloromethane prepared in the previous stage was added dropwise to the stirred mixture at 0-5° C. The obtained mixture was stirred for 1 hour at the same temperature (TLC monitoring), filtered through Celite and acidified with acetic acid to pH 5 at 0-5° C. The organic layer was separated, washed with water until the pH of the water layer was not less than 6.8, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was triturated with ether (500 mL). The precipitated crystals were filtered and dried under reduced pressure to a constant weight to give 93.4 g (85% yield) of crude crystalline product. A solution of the product in acetonitrile was passed through Celite and evaporated under reduced pressure The crystalline residue was recrystallizated from methanol (2 L) gave 83.6 g (76.2% yield) of compound [4a] with mp 134-135° C. and [α]D20−141.7° (c 1.26, MeCN). 1H NMR (CDCl3, δ) 2.32-2.63 (m, 3H); 2.84-2.97 (m, 7H); 5.00-5.10 (m, 1H); 5.20-5.35 (m, 1H); 6.20 (d, J=16 Hz, 1H); 6.65 (dd, J=16 and 8 Hz, 1H); 7.15-7.67 (m, 12H); 8.03 (d, J=8 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH2:13].[N+:14]([C:17]1[CH:18]=[C:19]2[C:30](=O)[O:29][C:27](=[O:28])[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=1)[C:20]2=3)([O-:16])=[O:15]>C(N(CCO)C1C=CC(N2C(=O)C3C=CC([N+]([O-])=O)=C4C=3C(=CC=C4)C2=O)=CC=1)C>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[N:13]1[C:30](=[O:29])[C:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:26]=[C:25]3[C:20]=2[C:21](=[CH:22][CH:23]=[CH:24]3)[C:27]1=[O:28]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Reactant: COc1ccc(N)c(NCCO)c1
Agent: CCN(CCO)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1
Product: COc1ccc(N2C(=O)c3cccc4cc([N+](=O)[O-])cc(c34)C2=O)c(NCCO)c1

Procedure:
The reaction of N-(2-hydroxyethyl)-5-methoxy-2-aminoaniline with 3-nitronaphthalene-1,8-dicarboxylic anhydride in imidazole (synthesis and work-up as in Example 2, Step 1) afforded the product as a dark-red powder. For purification, the crude product in ethanol/acetone was filtered through a bed of silica gel UV/Vis (CHCl3: λmax: 411, 524 nm
Reaction SMILES: [CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:4]=1[CH:5]=[CH:6][C:7]1[C:13]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[CH2:11][C:10]([CH3:21])=[N:9][N:8]=1.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:4]=1[CH:5]=[CH:6][C:7]1[C:13]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[CH2:11][CH:10]([CH3:21])[NH:9][N:8]=1
Reactant: COc1cccc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(C=CC2=NNC(C)Cc3cc4c(cc32)OCO4)c1OC
Yield: 45.8 %

Procedure:
1.5 g (4.12 mmoles) of 1-(2,3-dimethoxystyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine is reduced as specified in Example 1, the evaporation residue is dissolved in ethyl acetate and 10 ml of 10% by mass of ethyl acetate saturated with gaseous hydrogen chloride are added to the solution. The separated product is filtered, washed three times with 5 ml each of ethyl acetate and dried at a temperature between 80° C. and 100° C. Thus 0.76 g (45.8%) of the desired product is obtained. M.p.: 193-195° C. (decomp)