Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Temperature: 0 °C

Procedure:
In a three necked round bottomed flask equipped with mechanical stirring and nitrogen coverage was placed methyl bromacetate (7.82 ml; 82.6 mmol) and a suspension of N4 -benzyloxycarbonyl-cytosine (9, 21.0 g; 82.6 mmol) and potassium carbonate (11.4 g; 82.6 mmol) in dry DMF (900 ml). The mixture was stirred vigorously overnight, filtered, and evaporated to dryness, in vacuo. Water (300 ml) and 4N hydrochloric acid (10 ml) were added, the mixture was stirred for 15 minutes at 0° C., filtered, and washed with water (2×75 ml). The isolated precipitate was treated with water (120 mt), 2N sodium hydroxide (60 ml), stirred for 30 min, filtered, cooled to 0° C., and 4N hydrochloric acid (35 ml) was added. The title compound was isolated by filtration, washed thoroughly with water, recrystallized from methanol (1000 ml) and washed thoroughly with ether. This afforded 7.70 g (31%) of pure compound. The mother liquor from the recrystallization was reduced to a volume of 200 ml and cooled to 0° C. This afforded an additional 2.30 g of a material that was pure by tlc but had a reddish color. M.p. 266°-274° C. Anal. for C14H13N3O5. Found (calc.); C: 55.41(55.45); H: 4.23(4.32); N: 14.04(13.86). 1H-NMR (90 MHz; DMSO-d6): 8.02 ppm (d,J=7.32 Hz, 1H,H-6); 7.39 (s,5H, Ph); 7.01 (d,J=7.32 Hz,1H,H-5); 5.19 (s,2H, PhCH2 --); 4.52 (s,2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[O-]S([O-])(=O)=O.[Na+].[Na+].ClC(Cl)(Cl)C([O:15][CH2:16][CH3:17])O.[Br:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].Cl.NC1C=CC=CC=1>O.CCO>[Br:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:16](=[O:15])[CH:17]=[N:2][OH:3]
Reactant: NO
Reactant: Nc1cccc(F)c1Br
Reactant: CCOC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(C=NO)Nc1cccc(F)c1Br
Temperature: 40 °C
Yield: 86.9 %

Procedure:
Flask A: A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, condenser, and temperature probe; the flask was charged with hydroxylamine hydrochloride (Fluka; 12.47 g, 179 mmol), Na2SO4 (51.7 g, 364 mmol), 2,2,2-trichloro-1-ethoxyethanol (15.78 g, 82 mmol), and water (240 ml). This was stirred to 40° C. to affect dissolution. Flask B: A mixture of 2-bromo-3-fluoroaniline (10.33 g, 54.4 mmol) in water (32.0 mL)/conc. HCl (14.95 mL, 179 mmol) was stirred at RT and then at 50° C. to attempt dissolution; EtOH (10 mL) was added as another attempt to dissolve the aniline to no avail. The fine slurry was added to Flask A containing the stirring 2,2,2-trichloro-1-ethoxyethanol solution at 40° C. The reaction was heated to 100° C. and was stirred for 1 h. The reaction was cooled to 5° C. in an ice bath, filtered through a disposable 0.45 micron ZapCap filter (very slow filtration), and washed with water to give N-(2-bromo-3-fluorophenyl)-2-(hydroxyimino)acetamide (12.34 g, 47.3 mmol, 87% yield) as a brown solid after it was dried in a vacuum oven. 1H NMR (400 MHz, CDCl3) δ ppm 6.92 (td, J=8.31, 1.37 Hz, 1H), 7.32 (td, J=8.31, 6.26 Hz, 1H), 7.60 (s, 1H), 7.87 (s, 1H), 8.25 (d, J=8.41 Hz, 1H), 8.98 (br. s., 1H). 19F NMR (377 MHz, CDCl3) δ ppm −104.01 (s, 1F). MS (ESI, pos. ion) m/z: 260.9/262.9 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[N:27](COCC[Si](C)(C)C)[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[N:20]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[NH:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[N:20]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(Oc3nc4cccnc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A mixture of 1-ethyl-3-[4-(3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1H-pyrazolo[4,3-b]pyridine (90 mg), 1 M TBAF in THF (0.74 mL) and THF (2 ml) was heated at 100° C. for 3 h under microwave irradiation. The mixture was stirred at 80° C. overnight. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (18 mg).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (S)-4-benzyl-2-oxazolidinone (22.9 g, 129 mmol) and tetrahydrofuran (120 mL). Cool in a dry-ice acetone bath. Add dropwise a solution of n-butyl lithium (52 mL, 2.5 M, 130 mmol). After 15 minutes, slowly add a solution of phenylacetyl chloride (20 g, 129.4 mmol) in tetrahydrofuran (50 mL). After 20 minutes, warm to ambient temperature. After 2 hours, quench the reaction mixture by the addition of a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the aqueous layer with diethyl ether. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 15% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from diethyl ether/hexane to give (S)-4-benzyl-3-phenylacetyl-2-oxazolidinone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[Cl:28])[NH:24][N:23]=[CH:22]2.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][C:19]=1[NH:18][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1NCc1ccncc1
Reactant: Nc1cc2cn[nH]c2cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(Nc1cc2cn[nH]c2cc1Cl)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
194 mg (0.85 mmol) of 2-(4-pyridylmethyl)aminobenzoic acid is mixed in 8 ml of dimethylformamide with 283 mg (1.69 mmol) of 5-amino-6-chloroindazole. Under argon and in a moisture-free environment, 215 mg (2.13 mmol) of N-methylmorpholine and 386 mg (1.02 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophophate are added to this solution. This mixture is stirred for 4 hours at room temperature. It is then diluted with about 40 ml of water and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol-10:1 as an eluant. 97 mg (30.2% of theory) of N-(6-chloroindazol-5-yl)-2-[(4-pyridyl)methyl]amino-benzoic acid amide with a melting point of 222.8° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=O.[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH:22]=[CH:28][C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
In 25 ml of methanol were suspended 2.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 1.03 g of 3,4-dimethoxybenzaldehyde. Thereto was added 5 ml of 50% aqueous sodium hydroxide. The mixture was stirred for 3 hours at room temperature. The reaction mixture was introduced into a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 2.0 with 4N hydrochloric acid. The resulting crystal was collected by filtration, washed with water and ethyl acetate in this order, and recrystallized from acetic acid to obtain 2.2 g (yield: 75.6%) of 2-(3,4-dimethoxyphenyl)vinyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14](O)=[O:15])=[CH:12][C:11]([CH3:17])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:18]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([Cl:18])=[O:15])=[CH:12][C:11]([CH3:17])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: ClCCl
Reactant: Cc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 100 mL flask, 1-(3,5-dichloropyridin-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (0.37 g, 1.38 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.35 g, 2.20 mmol) were added. After a drop of N,N-dimethyl formamide was added, a large number of gas was released. After being stirred for overnight at room temperature, the reaction mixture was concentrated under reduced pressure. Then 10 mL toluene was added, and the mixture was concentrated again under reduced pressure to give the product (0.40 g) as yellow oil in 100% yield.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11].[Cl:24][CH2:25][CH2:26][C:27](=O)[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl-:24].[C:4]1([N+:3]2[C:26]([CH3:25])=[C:27]([CH3:28])[S:11][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CCCl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1sc[n+](-c2ccccc2)c1C
Product: [Cl-]
Temperature: 100 °C
Yield: 11 %

Procedure:
A mixture of N-Formyl-aniline (8a, commercially available) (3.634 g, 30 mmol) and phosphorus pentasulfide (1.351 g, 3.04 mmol) in dry 1,4-dioxane (4 mL) was stirred at room temperature for 15 min under an argon atmosphere. 4-Chloro-2-butanone (2.131 g, 20 mmol) was added and the resulting slurry was heated at 100° C. The reaction mixture was refluxed for 50 min, initially becoming clear yellow and finally deep red. After cooling at room temperature, the crude mixture was diluted with H2O (20 mL). Na2CO3 was added to the reaction mixture until pH≈7. The solvent was evaporated under reduced pressure and the resulting solid was suspended in CH2Cl2 and purified by column chromatography (column packed with silica gel) eluting with EtOH/CH2Cl2 (15/85). Upon concentration of the last yellowish band, a viscous orange oil was obtained. This was solidified when washed under vigorous stifling with diethyl ether (3×2 mL) to afford 9a as a light pink solid (770 mg, 11%). 1H NMR (CD2Cl2, 300 MHz): δ=11.13 (s, 1H), 7.67-7.60 (m, 3H), 7.53-7.49 (m, 2H), 2.57 (s, 3H), 2.23 (s, 3H); 13C{1H} NMR (CD2Cl2, 75 MHz): δ=161.03, 142.08, 141.75, 137.19, 132.10, 130.84, 126.34, 13.10, 12.86; HRMS (FAB+) calculated for C11H12NS [M]+ 190.0690, observed 190.0693.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[N:11]=[C:12](\Cl)/[C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1.[C-:23]#[N:24].[K+]>C1COCC1.O.C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[N:11]=[C:12](\[C:23]#[N:24])/[C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/N=C(\Cl)c1cc2nccnc2s1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1/N=C(\C#N)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
To a solution of (Z)—N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carbimidoyl chloride 76 (100 mg, 0.301 mmol) in THF (15 mL), water (0.5 mL) and acetonitrile (15 mL) was added potassium cyanide (98 mg, 1.503 mmol). The reaction was stirred at rt for 6 h. Quenched in NaHCO3 solution and resulting precipitate was collected to give crude (E)-N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carbimidoyl cyanide 77 (62 mg, 63.8%) which was used without further purification. (m/z)=324 (M+H)+.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].[C:23](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:23][C:16]1([NH:15][C:12](=[O:14])[CH3:13])[CH:21]=[CH:20][C:19]([O:22][CH2:7][C:6]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][CH:10]=2)=[O:9])=[CH:18][CH2:17]1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)NC1(C)C=CC(OCC(=O)c2ccccc2)=CC1
Yield: 82 %

Procedure:
4-Methylphenacyl chloride (XVI: X=Cl) (8.4 g, 0.05 mole), 4-acetamidophenol (XV: R=CH3) (7.6 g, 0.05 mole) and anhydrous potassium carbonate (8.3 g, 0.06 mole) were added to acetone (200 ml), and the mixture was heated under reflux for 12 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 32 to obtain 11.7 g of 4-methyl-α-(4-acetamidophenoxy)acetophenone (XIII: R=CH3) as white crystals (yield, 82.7%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.[CH3:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:27][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CN
Reactant: CCCCCCOc1cccc(OCCCCC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOc1cccc(OCCCCCNC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.3 %

Procedure:
5-(3-(hexyloxy)phenoxy)pentanal (72 mg, 0.26 mmol) in 1,2-C12C2H4 (5 mL) was treated with a THF solution of MeNH2 (2.0 M, 0.4 mL, 0.8 mmol). The reaction was stirred in a sealed vial for several min at rt before NaBH(OAc)3 (76 mg, 0.36 mmol) was added in one portion. Again the vial was sealed and stirred at rt for 3 d. The reaction was diluted with H2O and extracted into DCM. The organic extracts were concentrated and the resulting material was purified by preparative TLC on silica gel (5% MeOH:DCM) to afford the title compound as clear oil (17 mg, 23%). 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (t, J=8.21 Hz, 1 H), 6.44-6.51 (m, 3 H), 3.90-3.98 (m, 4 H), 2.64 (t, J=7.07 Hz, 2 H), 2.46 (s, 3 H), 2.28 (br. s, 1 H), 1.72-1.85 (m, 4 H), 1.40-1.67 (m, 6 H), 1.29-1.40 (m, 4 H), 0.91 (t, J=6.57 Hz, 3 H). MS ESI [M+H]+, calcd for [C18H31NO2+H]+: 294.45 found m/z 294.2 (100).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][OH:8].[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.OS(O)(=O)=O>O>[CH:17]1[CH:18]=[C:10]([C:9]([OH:14])=[O:19])[C:11]([C:12]([O:7][OH:8])=[O:13])=[CH:15][CH:16]=1
Reactant: OO
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)OO
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
Deionized water (125 ml), Na2CO3 (31.0 g, 0.25 mol) and 35% H2O2 (29.15 g, 0.3 mol) are successively charged in a 500 ml four-neck flask, and the mixture was stirred in a dry ice-methanol bath at −5° C.-0° C. Thereto was added phthalic anhydride (37.0 g, 0.25 mol) and the mixture was stirred for 30 min. The bath was removed, ethyl acetate (100 ml) was added to the mixture, and the reaction system was neutralized in a solution obtained by diluting 98% H2SO4 (15 ml) with deionized water (50 ml). After partitioning, the aqueous layer was extracted with ethyl acetate (60 ml). The obtained organic layer (0.64 g) was taken up and saturated NaI-IPA (isopropyl alcohol) solution (5 ml) and 10% acetic acid-IPA solution (20 ml) were added thereto. The mixture was boiled for 5 min. It was titrated with 0.1N aqueous sodium thiosulfate solution. As a result, mono-perphthalic acid was present in 33.5 g and the yield was 76.9%.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:17])[S:7](=[O:16])(=[O:15])[C:8]2[CH:14]=[CH:13][S:12][C:9]=2[C:10]=1[OH:11])([O:3]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[S:7](=[O:16])(=[O:15])[N:6]([CH3:17])[C:5]=1[C:1]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:3]
Reactant: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sccc2S1(=O)=O

Procedure:
1.9 G. of 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide are suspended together with 0.9 g. of 2-aminothiazole in 250 ml. of absolute xylene and heated to reflux for 7 hours, by which means 150 ml. of xylene are slowly distilled off. The residual xylene is then evaporated in vacuo. The crystalline residue is recrystallized from ethanol. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 217° C. (decomposition).
Reaction SMILES: [OH-].[Li+].CC([O:6][C:7]([C:9]1[N:44]=[CH:43][C:12]2[N:13]([CH2:30][C:31]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:32])[C:14]3[C:19]([C:11]=2[C:10]=1[CH2:45][O:46][CH3:47])=[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH:17]=[CH:16][CH:15]=3)=[O:8])C.S(=O)(=O)(O)O>CO.O1CCCC1.C(OCC)(=O)C>[CH3:47][O:46][CH2:45][C:10]1[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[N:13]([CH2:30][C:31]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:32])[C:12]=2[CH:43]=[N:44][C:9]=1[C:7]([OH:8])=[O:6]
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1c(Oc3ccc([N+](=O)[O-])cc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COCc1c(C(=O)O)ncc2c1c1c(Oc3ccc([N+](=O)[O-])cc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 63.4 %

Procedure:
10 ml of an aqueous 0.5N lithium hydroxide solution is added to a solution of 610 mg of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid (1-methyl-ethyl)-ester in 10 ml of methanol and 10 ml of tetrahydrofuran, and it is stirred for 24 hours at 50° C. Then, it is cooled to 20° C., acidified with 10% aqueous sulfuric acid and diluted with ethyl acetate. The solution that is obtained is washed twice with saturated sodium chloride solution dried on sodium sulfate and evaporated to dryness in a vacuum. The crude product that is obtained is recrystallized from ethanol/tetrahydrofuran, and 360 mg of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid is obtained as pale yellowish crystals with a melting point of 231°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH:12]2[CH2:18][C:19]([NH:21][C@@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH:32]=O)[CH:28]=3)[CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](O)(C)(C)C.C1COCC1.O.C[N+]1([O-])CCOCC1.P([O-])([O-])([O-])=O>CCOC(C)=O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH:12]2[CH2:18][C:19]([NH:21][C@@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH:32]=[CH2:34])[CH:28]=3)[CH2:23]2)=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid (332 mg, 1 mmol), crude 48999-36 (190 mg, 1.1 mmol), II (135 mg, 1 mmol) and III (191 mg, 1 mmol) in 1 mL of DMF was stirred overnight at room temperature. After quenching with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:3 to 100:5 to 100:6) gave the title compound as a white solid. E. Preparation of (R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide. To a solution of the procuct of step D. (280 mg, 0.575 mmol) in 13 mL of a mixture solvent t-butanol/THF/water (10:2:1) was added NMO (135 mg, 1.15 mmol), followed by OsO4 (2.5% w/w in t-butanol, 175 mg, 0.017 mmol). After stirring overnight at room temperature, 4 mL of pH 7.2 phosphate buffer was added, followed by NaIO4 (615 mg, 2.875 mmol). After stirring for 5 h at room temperature, the reaction solution was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vaco. Flash chromatography (SiO2, EtOAc/hexane=1:1) afforded the title compound as a white solid. Preparation of (R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])O.[Na+].[CH2:17]([O:25][C:26](Cl)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>O.CO>[CH2:17]([O:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCOC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 700 ml of methanol suspended 153 g of 4-aminosalicylic acid and 84 g of sodium hydrogen carbonate, 193 g of n-octylchloroformate was dropwise added over 2 hours at room temperature. After finishing dropwise addition, the mixture was further stirred for 2 hours at room temperature. An aqueous solution containing 30 g of concentrated hydrochloric acid and 1200 ml of water was added to the reaction mixture. Precipitated crystals were filtered and dried to obtain 300 g of desired 4-(n-octyloxycarbonylamino)salicylic acid as colorless crystals. Yield was 97%.