Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH3:15])([C:11]([F:14])([F:13])[F:12])[CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:18][C:19]([S:22][CH2:23][CH2:24][CH:8]([S:5]([CH2:4][C:3]([CH3:15])([C:2]([F:1])([F:16])[F:17])[C:11]([F:13])([F:12])[F:14])(=[O:6])=[O:7])[C:9]#[N:10])([F:21])[F:20]
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: CC(CS(=O)(=O)CC#N)(C(F)(F)F)C(F)(F)F
Product: CC(CS(=O)(=O)C(C#N)CCSC(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
Compound II-28 was prepared from (3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-1-sulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1cccc(Br)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromothiophenol (10 g) in acetone (250 mL) was added potassium carbonate (14.6 g) and iodomethane (4.28 mL). The heterogenous mixture was refluxed for 4 hrs., cooled to room temperature, filtered, and concentrated under reduced pressure. Ether (200 mL) was added, and the mixture was filtered again and finally evaporated to dryness to yield the title compound.
Reaction SMILES: [NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1.Cl>C(Cl)Cl>[NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:10]=[CH:9][CH:2]=[CH:3][CH:4]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Agent: Cl
Solvent: ClCCl
Product: NC(/C=C(\CCCC(=O)OCc1ccccc1)CP(=O)(O)O)CC(=O)OCc1ccccc1

Procedure:
To 3.25 g (10 mmol) of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate and 10.8 g (100 mmol) of benzyl alcohol are added 10 ml of methylene chloride and 20 ml of 4N ethereal hydrochloric acid, and the mixture is allowed to stand for 1 week. The mixture is then evaporated to dryness, and the residue is dissolved in 25 ml of ethanol. To this solution is then added dropwise a solution of 15 ml of propylene oxide in 15 ml of ethanol. The readily volatile constituents are removed by evaporation under reduced pressure, affording dibenzyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:30])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4nccc34)CC2=O)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(I)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(R)-4-((R)-1-((6-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (216 mg, 0.522 mmol) was dissolved in acetonitrile (10.0 mL) and N-iodosuccinimide (124 mg, 0.548 mmol) was added. The solution was stirred at room temperature for 5 minutes. The reaction was diluted with DCM. The organic layer was washed with 1M NaOH followed by an aqueous solution of sodium thiosulfate. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford (R)-4-((R)-1-((6-chloro-3-iodopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:20][CH3:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:22])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:22])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([O:20][CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(OC)cc1)OC
Yield: 56 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-methoxybenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (56% yield); mp 87–89° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.67 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.44 (1H, s, CH), 6.87 (2H, m, aromatics), 7.26 (2H, m, aromatics). Anal. calcd for C14H17NO6: C, 56.94; H, 5.80; N, 4.74. Found: C, 57.03; H, 5.82; N, 4.68.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([OH:18])(=O)=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:19]S(O)(=O)=O>>[C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([Cl:19])(=[O:18])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)O)c2ccccc12
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
At 0° C., 4-acetamidonaphthalene-1-sulfonic acid (5 g, 19 mmol) was slowly added to chlorosulfonic acid (25 ml). The mixture was allowed to warm to RT over 30 minutes and then stirred for 2 h. After slowly adding the reaction mixture to ice water, a fine yellow precipitate formed which was filtered, washed with water and dried under vacuum to give 4-acetamidonaphthalene-1-sulfonyl chloride (4.73 g, 87%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=284.0; tR=3.06 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH2:25])=O.C[O-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 0.17 h

Procedure:
22.8 g Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate (V)were suspended under stirring and argon atmosphere in 91.2 ml 1,4-dioxane. 14.1 ml Formamide and 13.9 ml sodium methanolate were successively added to yield a clear light-orange solution, which turned to a white suspension after 10 minutes. This suspension was stirred two hours at 30° C. 200 ml deionized water were added in one portion and 1,4-dioxane was distilled off at 40° C. under reduced pressure. The remaining white suspension was stirred two hours at 0° C. and filtered. The precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide (VI)) was washed with 50 ml deionized water three times and dried under reduced pressure for 18 hours at 80° C. Crude product: 19.43 g as a white powder. m.p.>250° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3ccccc3c21
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[C:38]([OH:45])[CH:37]=1)(=[O:35])=[O:34]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][S:33]([C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[C:38]([OH:45])[CH:37]=3)(=[O:35])=[O:34])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Product: O=C(O)c1ccc(S(=O)(=O)Oc2c(Br)cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)cc2Br)cc1O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as white solid, mp 192-194° C.; MS m/e 747 (M−H)+;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH:10]2[O:20][CH2:19][CH2:18][O:11]2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: OCCO
Solvent: c1ccccc1
Product: COc1c(C2OCCO2)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
A solution of 1.0 g (4.2 mmol) of 5-tert-Butyl-2-methoxy-3-nitro-benzaldehyde, 1.18 mL of ethylene glycol, and 0.4 g of pTSA hydrate in 50 mL of benzene was refluxed for 24 h under Dean-Stark conditions. The benzene was evaporated and the resultant oil was redissolved in EtOAc. The organic layer was washed with water, sat'd NaHCO3, and brine. The extract was dried over MgSO4, filtered, and concentrated. Chromatography (10% EtOAc in hexanes) provided 1.0 g of 2-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-[1,3]dioxolane as a light yellow oil.
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[CH3:13].N([O-])=O.[Na+].C1(C)C=CC=CC=1.CCCCCC.[BrH:31]>O>[Br:31][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[CH3:13]
Reactant: Br
Reactant: Cc1c(N)c(F)cc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(F)c(C(=O)O)cc(F)c1Br
Reaction time: 1 h

Procedure:
In 658 ml of 4.7% hydrobromic acid was suspended 26.3 g of 4-amino-2,5-difluoro-3-methylbenzoic acid, and 161 g of cupric bromide was added to the suspension. To this suspension was dropwise added a solution of 16.5 g of sodium nitrite in 165 ml of water over one hour with ice-cooling, and the resulting mixture was stirred for one hour at the same temperature and then at room temperature for two hours. To the reaction mixture was added 700 ml of toluene and the organic layer formed was separated, washed with 100 ml of conc. hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. To the residue obtained was added n-hexane and the resulting crystals were collected by filtration to obtain 29.5 g of colorless, crystalline 4-bromo-2,5-difluoro-3-methylbenzoic acid.
Reaction SMILES: [C:1]1([C:13](=O)[C:14](OC)=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1>>[C:1]1([C:13]2[C:14](=[O:15])[NH:31][C:29](=[O:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
In one embodiment, the method of the present invention comprises a step of dissolving methyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl-oxoacetate and indole-3-acetamide in an organic solvent and adding the obtained solution to a base, and reacting methyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl-oxoacetate and indole-3-acetamide to form highly pure 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione. In one embodiment, the base is dissolved or suspended in an organic solvent. In a further embodiment, the base is dissolved or suspended in the same organic solvent as methyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl-oxoacetate and indole-3-acetamide. In a further embodiment, highly pure 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrolidine-2,5-dione is formed by reducing 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].N.O1CCOCC1.[Li+].C[Si]([N-:39][Si](C)(C)C)(C)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH2:39])=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(N)=O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoate (280 mg, 0.746 mmol) was dissolved in tetrahydrofuran (THF) (5 mL) and to this solution was added ammonia in dioxane (0.5 M) (4.47 mL, 2.237 mmol), followed by LiHMDS in THF (1 M, 0.895 mL, 0.895 mmol). The reaction was left to stir overnight at room temperature, under nitrogen. The reaction was quenched with water (1 mL) then combined with a previous identical trial reaction on a smaller (0.075 mmol) scale, for workup. The crude was concentrated in vacuo, then the product was extracted to the organic phase of an aqueous work up between ethyl acetate (15 mL) and brine (10 mL). The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the crude product, 263 mg. No further purification was undertaken. LCMS [LCMS1] Rt 1.14 min, m/z (ES+) 361 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.O[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:21]([O:20][C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1OCCCCNC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (21 mmol), tert-butyl 4-hydroxybutylcarbamate (21 mmol) and triphenyl phosphine (24 mmol) in THF (70 ml) was cooled to −10° C. Then, DIAD (43 mmol) was added. The mixture was stirred for 30 min at −10° C. under N2. The ice-bath was removed and the mixture was stirred overnight at 20° C. The solvent was removed under vacuum. The residue was washed with petroleum and diethyl ether. The white solid was filtered and it was confirmed to be triphenylphosphine oxide (PPh3═O). The filtrate was evaporated to dryness. The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5:1). Yield: 8.18 g (purity 90%, yield 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([O-:26])=[O:25]>C1COCC1>[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[CH2:13][CH2:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: COc1ccc(C2=NNC(=O)CC2)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=NN(Cc3ccc([N+](=O)[O-])cc3)C(=O)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
A suspension of 4.70 g of 6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one (“A”) in 150 ml of THF is treated with 2.24 g of potassium tertbutoxide and stirred for 30 minutes. 4.32 g of 4-nitrobenzyl chloride are added thereto and the mixture is stirred at room temperature for 10 hours. The solvent is removed. and the residue is worked up in the customary manner. 2-(4-Nitrobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, m.p. 126°, is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9](N(CC)CC)[CH3:10]>C(OCC)(=O)C.BrCCBr>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:10][CH2:9]1
Reactant: Nc1ccccc1S
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: c1ccc2c(c1)NCCS2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminothiophenol (5.01 g) in ethyl acetate (20 ml), 1,2-dibromoethane (4.14 ml) was added and stirred while heating at 60° C. under a nitrogen atmosphere. To the reaction mixture, triethylamine (9.72 ml) was added dropwise over 30 minutes and stirred at 60° C. for 10 hours. The reaction mixture was allowed to stand overnight at room temperature and then filtered to remove insoluble materials. The filtrate was washed sequentially with water and brine, dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 3:1) to give the titled compound, i.e., 3,4-dihydro-2H-1,4-benzothiazine (3.69 g) as a red-brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][C@H:8]([NH2:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([N:23]1[C@H:28]([C:29](O)=[O:30])[C@@H:27]2[CH2:32][C@H:24]1[CH2:25][CH2:26]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1N=C2C=CC=CC2=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:13]([O:20][C:21]([N:23]1[C@H:28]([C:29](=[O:30])[NH:11][C@H:8]([CH2:9][OH:10])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[C@@H:27]2[CH2:32][C@H:24]1[CH2:25][CH2:26]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
To a stirred solution of (S)-3-Amino-4-hydroxy-butyric acid tert-butyl ester (486 mg) and (1R,3S,4S)-2-Aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2 benzyl ester (prepared as described in Tararov etal, Tett. Asymm. 2002, 13, 25-28) (767 mg) in THF (18 ml) was added 2-hydroxybenzotriazole hydrate (452 mg), DMAP (426 mg), diisopropylethylamine (631□1) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 641 mg). The resulting mixture was stirred at ambient temperature for 18 hours then diluted with ethyl acetate. The mixture was then washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate/petrol) to afford the sub-title compound as a colorless oil (1.1 g, 91%); 1H NMR (400 MHz, d-6 DMSO) δ 1.13-1.25 (1H, m), 1.30-1.48 (9H, m), 1.49-1.88 (6H, m), 2.20-2.52 (2H, m), 3.09-3.34 (2H, m), 3.64 (1H, d), 4.00-4.16 (2H, brm), 4.80 (1H, m), 4.90-5.15 (2H, m), 7.21-7.41 (5H, m), 7.50-7.75 (1H, m); MS ES (+) 433.37.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][C:21](=O)[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][C:21](=[N:31][OH:32])[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC(CCCN2CCN(c3ccc(F)cc3)CC2)S(=O)(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=S1(=O)c2ccccc2C(=NO)CC1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 88.3 %

Procedure:
A solution of 417 mg (1 mmol) of the Compound 19, 139 mg (2 mmol) of hydroxylamine hydrochloride, and 164 mg (2 mmol) of sodium acetate in 15 ml of methanol was refluxed for 17 hours. After the post treatment in the same manner as in Example 8, the residue was recrystallized from acetonitrile to obtain 381 mg (yield: 88%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(#N)C>[N:15]1([CH2:14][CH2:13][NH:12][C:8]([C:6]2[NH:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=2)=[O:10])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: NCCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
To a suspension of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2 g, 13 mmol) in acetonitrile was added 4-(2-aminoethyl)morpholine (1.9 mL, 14 mmol), EDC (2.7 g, 14 mmol), HOBt (1.9 g, 14 mmol) and triethylamine (3.6 mL, 26 mmol) sequentially. The reaction mixture was stirred at room temperature for 12 hours and concentrated at reduced pressure. The residue was dissolved in 300 mL of 1N hydrogen chloride solution. The aqueous layer was washed with 150 mL of ethyl acetate twice and basified with sodium bicarbonate. The product was then extracted with 250 mL of dichloromethane twice, dried over MgSO4, and concentrated to afford 1.8 g (53%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide as a yellowish solid. 1H NMR (300 MHz, DMSO-d6) d 12.19 (br s, 1H, NH), 9.72 (s, 1H, CHO), 8.29 (br t, J=6.6 Hz, 1H, CONH), 6.65 (d, J=1.7 Hz, 1H), 3.5 (m, 4H), 3.3 (m, 2H, CONHCH2), 2.4 (m, 6H), 2.28 (s, 3H, CH3). MS m/z 265 [M+].