Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([CH3:36])[CH3:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)c1ccc(CN2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)cc1

Procedure:
1-[1-(4-Isopropyl-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-isopropylbenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, 6H, J=6.6 Hz), 1.94-1.99 (m, 2H), 2.15-2.24 (m, 4H), 2.85-2.90 (m, 1H), 2.95-2.99 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.60 (s, 2H), 4.74-4.80 (m, 1H), 7.20-7.27 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=506.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][I:28]>ClCCl>[I-:28].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:25][CH:26]=3)[CH:8]=[N+:9]2[CH3:27])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc3ccc(Cl)cc3[n+](C)c2)cc1
Product: [I-]

Procedure:
Ethyl 2-{4-[(7-chloro-1-methylquinolinium-3-yl)oxy]phenoxy}propionate iodide salt (6) was prepared by reacting a mixture of ethyl 2-{4-[(7-chloroquinolin-3-yl)oxy]phenoxy}propionate (see Example 5) and methyl iodide in dichloromethane at ambient temperature for a period of four days. The product, a viscous oil, was characterized by its proton magnetic resonance spectrum. Pmr spectrum (CDCl3 ; δ in ppm): 9.8 (1H, d); 8.6 (2H, m); 8.3 (1H, d); 7.75 (1H, d of d); 7.1 (4H, d of d); 4.8 (4H, m); 4.15 (2H, q); 1.55 (3H, d); 1.25 (3H, t).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:19]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:24])([CH3:23])[CH3:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCO>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:19][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNCc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (Example 22 E, 50 mg, 0.17 mmol) in EtOH (1 mL) was added 4 A molecular sieves (50 mg), (3-amino-propyl)-carbamic acid tert-butyl ester (Fluka, 33 mg, 0.19 mmol) and NaBH(OAc)3 (55 mg, 0.26 mmol) under Ar. The reaction mixture was stirred at rt for 2 h, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 1–2% MeOH/CHCl3) to afford the desired compound, as a colorless oil (12 mg, 16%): MS (ESI+) 446 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1C=Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1c2ccccc2ccc2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To 500 g (1.933 mol) of (E/Z)-2-[2-(3-chlorophenylethenyl]benzoic acid (in a ratio of about 23:77) in 500 ml of methylene chloride were added dropwise with stirring at the reflux temperature 241.6 g (2.031 mol) of thionyl chloride in the course of 1 hour and stirred in for 1 hour. Thereafter a suspension of 333 g (2.497 mol) of anhydrous aluminum chloride in 100 ml of methylene chloride was added at room temperature in the course of 45 min and stirred in at room temperature for 30 min, and the reaction mixture was then poured with stirring onto a mixture of 3 kg of ice and 1 l of water. The hydrolysis mixture was stirred for about 30 min. 1 l of petroleum ether (boiling range from 40° to 60° C.) was then added with stirring. The mixture was stirred for a further 30 min and then filtered with suction. The filter residue was washed first with 5 l of water and then with 1 l of petroleum ether (boiling range from 40° to 60° C.) and dried. 270 g were isolated of 2-chloro-5H-dibenzo-[a,d]cyclohepten-5-one in 58% yield; melting point 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:23]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH:27]=[N:26][CH:25]=[N:24]1>CC#N.O>[N:23]1([C:28]2[CH:29]=[CH:30][C:31]([NH:32][C:6]3[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:33][CH:34]=2)[CH:27]=[N:26][CH:25]=[N:24]1
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1.4) (600 mg, 2.714 mmol), in CH3CN (12 mL), was added DIEA (0.750 mL, 4.313 mmol, 1.589 equiv), followed by 4-(1H-1,2,4-triazol-1-yl)aniline (465 mg, 2.902 mmol, 1.07 equiv). The mixture was stirred at room temperature for 20 h, then diluted with water (6×) to precipitate ii. The solid product was collected by filtration, rinsed with water (100 mL), and air dried; Yield, 850 mg (91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1CC#N.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: N#CCc1cccc(C(=O)c2cccs2)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc(C(=O)c2cccs2)c1Cl

Procedure:
A mixture of 4.2 parts of 2-[2-chloro-3-(2-thenoyl)phenyl]acetonitrile, 7 parts of acetic acid, 7 parts of water and 12 parts of sulfuric acid is stirred and boiled for 1h.30. The reaction mixture is cooled, poured onto water and extracted with ether. The extract is washed with water, extracted with 50 parts of a 5% sodium hydroxide solution and the alkaline solution is washed with ether. After acidification with diluted hydrochloric acid solution, the whole is extracted again with ether. The extract is washed with water, treated with charcoal, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 2-[2-chloro-3-(2-thenoyl)phenyl]acetic acid; mp. 112.2° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CCCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nc(N2CCCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloroquinazoline (1.0 g) in tetrahydrofuran (10 mL) were added triethylamine (2.1 mL) and perhydroazepine (0.745 mL) with ice cooling and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water (20 mL) and the resulting mixture was concentrated. The residue was extracted with methylene chloride three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane-diethyl ether (10:1) to give the title compound (991 mg) having the following physical data.
Reaction SMILES: [O:1]1CCO[CH2:3][CH2:2]1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:18]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:18]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])[C:2]([CH3:3])=[O:1]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C1COCCO1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 35 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 1,4-dioxane, acetic acid and water, obtained from a previous reaction mixture by taking a low-boiling cut, was metered into a stirred mixture of 320.4 g (2.0 mol) of diethyl malonate and 160 g (2.3 mol) of sodium nitrite (technical grade), maintained at 35° C. 12.0 g of water were then metered in and 166 g (207. mol) of acetic acid (96%) were added dropwise over 2 hours. The mixture was allowed to continue reacting for 2 hours at 40° C. and was worked up as described in Example 4. There remained 425 g of light yellow oil, which, after catalytic hydrogenation and recrystallization of the crude product, gave diethyl acetaminomalonate at a yield of 86% of theory, based on the diethyl malonate employed, and with a purity of >99.8 FID area percent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:22][C:23](O)=[O:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [CH2:1]([C:8]1[CH:31]=[CH:30][CH:29]=[CH:28][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:8]1[CH:31]=[CH:30][CH:29]=[CH:28][C:9]=1[C:10]([N:12]([CH2:13][C:14]1[CH:15]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=1)[CH3:32])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1ccccc1Cc1ccccc1
Yield: 86.7 %

Procedure:
To a solution of 100 mg (0.23 mmol) 2-benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-benzamide in 1 ml N,N-dimethylformamide at 0° C. were added 50 mg (0.25 mmol) potassium hexamethyldisilazide. Stirring was continued for 1 h at this temperature and 0.016 ml (0.25 mmol) methyl iodide were added. After stirring for 3 h at room temperature, ethyl acetate was added. The mixture was washed with brine, dried (magnesium sulfate) and evaporated. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 90 mg (87%) of the title compound as a colourless oil.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]2[CH:24]=[CH:25][C:26]([CH2:32][CH3:33])=[C:27](B(O)O)[CH:28]=2)=[CH:21][CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]2[CH:24]=[CH:25][C:26]([CH2:32][CH3:33])=[C:27]([Pb+3:17])[CH:28]=2)=[CH:21][CH:20]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Temperature: 40 °C

Procedure:
To a mixture of lead tetraacetate (2.15 g, 4.85 mmol) and mercuric diacetate (0.15 g, 0.47 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40° C., and 4′-chloro-4-ethylbiphen-3-ylboronic acid (1.17 g, 4.50 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is then cooled to room temperature, concentrated to a small volume and triturated with hexanes and filtered to yield crude 4′-chloro-4-ethylbiphen-3-yllead triacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CC(C)=O.[SH2]=N.[C:21]1([NH:27][C:28](C2C=CC=CC=2C(O)=O)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:21]1([NH:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccccn1
Yield: 54.5 %

Procedure:
A solution of 0.5 g aminopyridin and 0.7 ml triethylamine with 5 ml acetone was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 15 ml aceton, under stirring. The reaction mixture was stirred for 45 minutes at room temperature, then diluted with 100 ml water. The acetone was distilled off, the residue was cooled, and the precipitated solid product was filtered, washed with water and dried. 0.6 g 1-phenyl-3-(2-pyridyl)-urea was obtained with a melting point of 185°-186° C.
Reaction SMILES: [O:1]1CC(=O)N=N1.C(OC(=O)CCN[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][O:23][C:24](=[O:26])[N:25]=2)=[CH:17][CH:16]=1)C.O.[OH-].[Na+]>C1COCC1.CO>[O:23]1[C:24](=[O:26])[N:25]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([OH:27])=[O:1])=[CH:20][CH:19]=2)[NH:22]1
Reactant: O=C1CON=N1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2nc(=O)o[nH]2)cc1
Yield: 97 %

Procedure:
p-Cyanobenoic acid methyl ester (5.0 g, 31 mmol) was converted into the corresponding oxadiazolinone as described for the synthesis of compound 3. The crude product (4.6 g, 20.9 mmol) was dissolved in a mixture of THF (50 mL) and MeOH (50 mL). H2O (50 mL) was added, which gave a suspension, followed by 4 N aq. NaOH (10 mL). After 6 h the organic solvents were removed by distillation under reduced pressure. The aq. layer was extracted with EtOAc/toluene (1/2, v/v), acidified with 2 N hydrochloric acid and the precipitate was filtered off. The crude product was dried at 40° C. under reduced pressure to give 4.2 g (97%) of compound 60. ESI-MS: 207 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(=O)C.O.NN.CCOC(C)=O.[Na+].[Cl-]>CO>[OH:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)OCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of 14.1 g (47.7 mmol, 1.00 eq.) of t-butyl 4-(acetoxymethyl)-3-nitrobenzoate in MeOH (200 mL) was added 27.0 mL (477 mmol, 10.0 eq.) of hydrazine hydrate (55% hydrazine). The resulting yellow solution was stirred at 25° C. for 4 hr. EtOAc (250 mL) and saturated aq. NaCl (85 mL) were added, and the organic layer collected after shaking. The organic layer was washed further with saturated aq. NaCl (2×85 mL, and then dried (MgSO4). Removal of volatiles in vacuo gave the product in 93% yield as yellow crystals. The reaction is represented in Scheme 5.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(#N)C>[CH3:34][N:35]([CH3:39])[C:36]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:37]
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.46 g, 3.3 mmol) and acetonitrile (20 ml) was stirred at room temperature for 20 minutes. Successively N,N-dimethylcarbamoyl chloride (0.47 g, 4.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (20:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.31 g, 77%) as white crystals.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]([CH2:36][Si](C)(C)C)[CH2:33]OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:36][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:36][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %
Yield: 36 %

Procedure:
To a solution of the compound (40.0 g) obtained in step 1 and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (30.5 g) in toluene (230 mL) was added at 0° C. a solution of trifluoroacetic acid (1.80 mL) in toluene (20 mL), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→50% ethyl acetate/hexane) to give (4R)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one (20.0 g, 36%) as a less polar compound, and (4R)-4-benzyl-3-{[(3R,4S)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one (15.6 g, 28%) as a more polar compound, each as a white powder. property data of less polar compound:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([OH:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH2:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1
Reactant: Oc1cc(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1

Procedure:
An acetone solution of 3-[4-(trifluoromethoxy)phenyl]-1-naphthol (50 mg, 0.166 mmol), methyl 4-(bromomethyl)benzoate (73 mg, 0.32 mmol) and K2CO3 (44 mg, 0.32 mmol) was heated at reflux until no starting material remained by HPLC analysis. The solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 4.64 min. (M+H)=453
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[C:30](O)([CH3:33])([CH3:32])[CH3:31]>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:6]
Reactant: CC(C)(C)O
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
3-Methyl-4-nitrobenzoic acid (500 g, 2.76 mol) was added to pyridine (1.25 L) and stirred until it dissolved. Benzenesulfonyl chloride (609 g, 3.45 mol) was added rapidly while maintaining the internal temperature <30° C. with an ice bath. A precipitate formed towards the end of the addition and pyridine (500 mL) was added to improve stirring. The mixture was stirred for 30 min and t-butanol (523 mL) was added dropwise over 30 min at <30° C. The mixture was stirred for 2 h, dissolved in hexane:ethyl acetate (4:1; 2.5 L) and the resulting mixture was extracted with water. The organic phase was concentrated to give a light yellow oil which crystallized on cooling to give the title compound (635 g, 97%). mp 56-58° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(O)C.N>CO.[Ni]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(Oc2ccccc2F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: NCc1ccc(Oc2ccccc2F)cc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
Add 4-(2′-fluorophenoxy)-benzonitrile (1.5 g, 7.0 mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add a 7N solution of ammonia in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the reaction and heat to 60° C. Continue the reaction for 18 h, turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Concentrate in vacuo and purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.2 g, 79%). MS (ES+) m/z: 201 (M+H—NH3)+.