Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][Cl:7].[NH3:23]>CCOCC>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([NH2:23])=[O:13])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][Cl:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(N(CCCl)CCCl)c([N+](=O)[O-])c1
Reactant: N
Solvent: CCOCC
Product: NC(=O)c1cc([N+](=O)[O-])c(N(CCCl)CCCl)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The above acid (XV: X=Cl, Z=OH) was converted to the crude acid chloride (XV: X=Cl, Z=Cl), which was dissolved in dry Et2O (100 mL), cooled to 5° C., and treated dropwise with aqueous NH3 (20 mL of a 3N solution, 60 mmol). After 10 min the solution was worked up, and the residue was chromatographed on silica. Elution with EtOAc/petroleum ether (3:7) gave foreruns, while EtOAc/petroleum ether (7:3) gave 4-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzamide (23) (Ig: X=Cl, R=CONH2) (80% overall yield), mp (EtOAc/petroleum ether) 113°-116° C. 1H NMR (CD3COCD3) δ 8.61 (s, 2 H, H-2,6), 7.98, 7.24 (2xbr, 2 H, CONH2), 3.75 (t, J=7.0 Hz, 4 H, CH2Cl), 3.50 (t, 4 H, CH2N). 13C NMR δ 164.91 (CONH2), 149.32 (C-4), 140.07 (C-3,5), 132.18 (C-1), 128.91 (C-2,6), 56.37 (CH2N), 42.55 (CH2Cl). Anal. (C11H12Cl2N4O5) C,H,N,Cl.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.S(=O)(=O)(O)O.N=O.[OH2:22]>C(O)(C)(C)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:22])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: O
Agent: N=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 40 mL of water and three-fourths of a solution of 25.0 g (0.37 mol) of 50% aqueous hydrogen peroxide are added simultaneously over 2.5 hours to 40° C. to a mixture of 1.46 g (4.1 mmol) of ferric acetylacetonate, 25 mL of water, 0.5 mL of 98% sulfuric acid and 200 mL of tert-butyl alcohol. At the conclusion of the nitroxyl addition, 0.18 g (0.5 mmol) of ferric acetylacetonate is added to the reaction mixture. The remaining one-fourth of the peroxide solution is added over one hour at 40° C. After heating for two hours, gas chromatography shows less than 10% nitroxyl compound remaining in the reaction mixture. Sulfuric acid (0.3 mL) and a solution of 4.9 g (72 mmol) of 50% aqueous hydrogen peroxide are added to the reaction mixture at 40° C., and the reaction mixture is stirred overnight at room temperature. Work-up as in Example 20 affords 18.1 g (74% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12](Cl)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>CN(C=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)(N)CO
Reactant: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Solvent: CN(C)C=O
Product: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Yield: 70.7 %

Procedure:
A solution of 2-(biphenyl-4-ylmethyl)-6-chloro-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (26 mg, 0.074 mmol) and 2-amino-2-methyl-1-propanol (71 μL, 0.74 mmol) in DMF (1 mL) is heated at 110° C. overnight. The reaction mixture is then purified by chromatography to give 21.1 mg product (Yield: 71%). MS (FAB) m/z 404.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7](O)[C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1ccc(F)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(F)c2c1CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, 154 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (30.2 g, 50%) as a yellow oil: LC/MS m/e calcd for C19H19BrFNO2 (M+H)+: 393.27, observed: 392.0 & 394.0.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[N:12]([CH:13]=[N:14][N:15]=2)[C:11]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].CO>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:22][C:19]1[CH:20]=[CH:21][C:10]2[CH2:9][NH:8][CH2:17][C:16]3[N:12]([CH:13]=[N:14][N:15]=3)[C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2c(c1)-n1cnnc1CNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester, (1.45 g, 4.76 mmol) in dry DCM (15 mL) was added trifluoroacetic acid (14.30 mL, 3 mL/mmol) at 0° C. The reaction mixture was stirred at r.t. for 2 h under argon. After completion of the reaction as confirmed by TLC, MeOH (2×10 mL) was added and the reaction mixture was evaporated under vacuo to remove excess of solvent and trifluoroacetic acid. The remaining solvents were removed under vacuo and 9-fluoro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene trifluoroacetate (1.50 g, 4.71 mmol, 99%) was obtained as thick brown jelly. The crude compound was used as such without any further purification for the next step.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:38])([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 750 mg (1.41 mmol) (R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 6 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 15 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 581 mg (98%) of the title compound as a white powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:10]=[C:9]1[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])=O)(C)(C)C>C(O)(C)C.Cl>[C:33]1([S:30]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][C:15]=3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:31])=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)n(C(=O)OC(C)(C)C)c23)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=S(=O)(c1ccccc1)c1cc2cccc(N3CCNCC3)c2[nH]1

Procedure:
A solution of 2-benzenesulfonyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert butyl ester 1-4 (160 mg, 0.3 mmol) in isopropanol (15 mL) and concentrated HCl (4 mL) was refluxed for 1 hour. The reaction mixture was concentrated and the remaining powder was triturated with isopropanol (10 mL) and ether (20 mL). This was filtered to afford 2-benzenesulfonyl-7-piperazin-1-yl-1H-indole, Compound 1 of Table 1 as a white solid (90 mg, 89%). M+H=342.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:17][CH2:18][CH:19]([NH:28][S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:31])=[O:30])[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>>[CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][C:32]=1[S:29]([NH:28][CH:19]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[CH2:18][NH:17][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])(=[O:30])=[O:31]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCC(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Agent: Cl
Product: O=C(NCC(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1)C1CCN(c2ccncc2)CC1
Yield: 17 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[3-amino-2-(2-naphthalenesulphonamido)propionyl]piperidine hydrochloride salt to give N-[2-(2-naphthalenesulphonamido)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)-piperidine-4-carboxamide in 17% yield;
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH:18](O)[CH:17](O)[CH2:16][C:15]=2[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C(O)C.[Pt]>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCCC(O)c1cccc(OCc2ccc3c(n2)CC(O)C(O)C3)c1
Agent: [Pt]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCc2ccc3c(n2)CCCC3)c1

Procedure:
The intermediate 5,8-dihydroquinoline derivative from Example 5 is dissolved in ethanol and hydrogenated over platinum catalyst. Hydrogen uptake is monitored and the reaction stopped when exactly one equivalent of hydrogen is absorbed. The catalyst is removed by filtration and the filtrate concentrated and chromatographed to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@@H:8]([OH:28])/[CH:9]=[CH:10]/[C:11]#[C:12]/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C@@H:17]([OH:27])[C@@H:18]([OH:26])[CH2:19][O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:4][CH:3]=1.[OH-].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@@H:8]([OH:28])/[CH:9]=[CH:10]/[C:11]#[C:12]/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C@@H:17]([OH:27])[C@@H:18]([OH:26])[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][CH:3]=1
Reactant: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, (0.4 g, 0.95 mmol) in methanol (20 mL) was treated with 1 N NaOH (aq) (4 mL, 4 mmol) solution and shaken and allowed to stand for three hours. The reaction mixture was then treated with saturated potassium monophosphate and poured onto an HP20 column. Elution with a gradient of methanol in water gave 0.35 g of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, which solidified upon standing; 1H NMR (CD3OD) δ 3.63 (m, 2H), 3.667 (m, 1H), 3.91 (m, 2H), 4.113 (s, 2H), 4.150, (t, 1H), 4.498, (m, 1H), 5.762 (dd, 1H), 5.953 (dd, 1H), 6.003 (dt, 1H), 6.202 (dd, 1H), 6.380 (dd, 1H), 6.596 (dd, 1H), 6.928 (m, 2H), 6.988 (m, 2H) ppm.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:10]=[CH2:11].CCN(C(C)C)C(C)C.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:9]([N:12]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:10]=[CH2:11]
Reactant: COC(=O)CC(=O)Cl
Reactant: C=CCNc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)CC(=O)OC)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Methyl 3-chloro-3-oxopropanoate (9.4 ml, 87 mmol) was added into a solution of N-allyl-4-fluorobenzenamine (12 g, 79 mmol), DIEA (15 ml, 87 mmol) and DMAP (0.97 mg, 7.9 mmol) in CH2Cl2 (200 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour. The reaction mixture was poured into ice and water, extracted with CH2Cl2, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc in hexane) to afford the product (18.3 g, 92% yield) as brown oil. 1H NMR (400 MHz, CDCl3): δ 7.16-7.22 (m, 2H), 7.08-7.12 (m, 2H), 5.80-5.90 (m, 1H), 5.07-5.17 (m, 2H), 4.27-4.32 (m, 2H), 3.67 (s, 3H), 3.20 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][CH:10]1[CH2:13][CH:12]([NH:14]C(=O)OC(C)(C)C)[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:2]([O:9][CH:10]1[CH2:13][CH:12]([NH2:14])[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CC(OCc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: NC1CC(OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
HCl (5-6 N in IPA, 3 mL) was added to a solution of tert-butyl 3-(benzyloxy)cyclobutylcarbamate (1.07 g, 3.86 mmol) in THF (10 mL). The mixture was stirred at 50° C. for 3 h, then cooled to RT. The solvent was removed in vacuo and EtOAc (10 mL) was added. The resulting suspension was cooled to 0° C. for 1 h, then the solid was collected by filtration to give the amine as a white solid (601 mg, 73%).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)[CH3:5])C.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C.O>ClCCl.CO>[Br:14][C:10]1[CH:9]=[C:8]([C:7]2[N:17]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(C)=NC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2cccc(Br)c2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 8 h
Yield: 66.1 %

Procedure:
N-(1-ethoxy-ethylidene)-3-bromo-benzamide 565 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3-bromo-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (543 mg, yield: 66%) was obtained as a solid phase.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[OH-].[Na+:28]>>[Na+:28].[C:20]1([NH:19][C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][C:3]([O-:26])=[O:2])[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCN1CCN(c2ccc(Nc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CCCN1CCN(c2ccc(Nc3ccccc3)cc2)CC1
Yield: 92.2 %

Procedure:
The title compound (80 mg, 92.3%) was prepared from 4-[4-(4-phenylamino-phenyl)-piperazin-1-yl]-butyric acid methyl ester (86 mg, 0.24 mmol) and 1 N NaOH (0.25 mL, 0.25 mmol) by the procedure described in Example 2: MS (ESI) m/z 361 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 1.59 (m, 2H), 1.84 (t, J=7.2 Hz, 2H), 2.27 (t, J=7.6 Hz, 2H), 2.47 (t, J=4.8 Hz, 4H), 3.03 (t, J=4.8, 4H), 6.67 (m, 1H), 6.88 (m, 4H), 6.98 (d, J=9.2 Hz, 2H), 7.13 (m, 2H), 7.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8](N)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].[ClH:19].N([O-])=O.[Na+].[OH-].[Na+]>O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Cl:19])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (5.1 g, 20.13 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in water (40 mL) and 37% HCl (40 mL) at 0° C. was added sodium nitrite (1.67 g, 24.16 mmol, 1.2 equiv). After 10 min copper(I) chloride (12.0 g, 120.81 mmol, 6.0 equiv) was added, the reaction mixture stirred for an additional 5 h at 0° C. and then the ice bath was removed. After stirring for 18 h, the crude reaction mixture was adjusted to pH=8 by addition of a solution of 1 M NaOH and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.32 (t, J=7.0 Hz, 4H), 1.40 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 4.30 (q, J=7.0 Hz, 2H), 7.18 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 13.33, 13.66, 60.29, 64.16, 105.75, 115.88, 128.25, 154.49, 165.01. MS (ISP): 273.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:34]3[CH:35]=[CH:36][O:32][CH:33]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccoc3)c12
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (285 mg, 0.75 mmol) was mixed with K2CO3 (207 mg, 2.2 eq), furan-3-boronic acid (101 mg, 1.2 eq), Pd(Ph3)4 (43 mg, 0.05 eq), 3 mL of 1,2-dimethoxyethane and 0.5 mL of water. The mixture was heated and stirred in a 85° C. oil bath for 2 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography to give 153 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([CH2:17][OH:18])[O:13][C:12]2=[O:19])=[CH:7][CH:6]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([CH2:17][O:18][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[O:13][C:12]2=[O:19])=[CH:9][CH:10]=1
Reactant: COc1ccc(N2C(=O)O[C@H](CO)[C@@H]2C)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 70.2 %

Procedure:
To a suspension of 200 mg of 60% sodium hydride in anhydrous N,N-dimethylformamide (1 ml) was added dropwise an N,N-dimethylformamide (7 ml) solution of 0.98 g of (4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-ylmethyl alcohol obtained in Reference Example 11 at room temperature in a stream of nitrogen, and the mixture was stirred at 50° C. for 25 minutes. A solution of 500 mg of p-fluorobenzonitrile in anhydrous N,N-dimethylformamide (2 ml) was added thereto at the same temperature and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 0.98 g of the title compound (yield 70%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7].O>C(O)(=O)C>[CH2:6]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH2:17][Cl:4])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]
Reactant: CCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCON=C(C(=O)CCl)C(=O)OCC
Yield: 93.1 %

Procedure:
Sulfuryl chloride (35.2 g.) was added all at once to the stirred solution of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer, 48.9 g.) in acetic acid (49 ml.) at room temperature, and stirred at the same temperature for an hour. After adding the resultant solution into water (200 ml.), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous solution of sodium bicarbonate and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer, 53.8 g.), pale yellow oil.