Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:6]2[CH2:7][CH2:8][N:9]([CH3:19])[CH2:10][CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:5]=2[CH:4]=1.B(Br)(Br)Br>CO>[OH:2][C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:6]2[CH2:7][CH2:8][N:9]([CH3:19])[CH2:10][CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C)CC2c1ccccc1C
Agent: BrB(Br)Br
Solvent: CO
Product: Cc1ccccc1C1CN(C)CCc2cc([N+](=O)[O-])c(O)cc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
300 mg of 7-methoxy-3-methyl-8-nitro-5-(2′-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in MEOH and cooled to −70° C. 1 g BBr3 was added slowly and the mixture was stirred for 1 h at −70° C., and stirring was continued for 1 h. Methanol was slowly added to destroy the excess of BBr3 and the mixture was evaporated to dryness. The raw material was purified by column chromatography (kieselgel, CH2Cl2/CH3OH: 98/2) giving 110 mg of the desired compound. M.p. 59-61 NMR: C5H 5.10 d; C6H 6.20 s; C9H 8.05 s ppm. respectively.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CSc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3SC)CC2)c(OC)nc1C
Yield: 56 %

Procedure:
Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][C:13](=[O:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COCCOC.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 49.2 %

Procedure:
24 g of (±)-(3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanone (compound F1) are dissolved at 60° C. in a mixture consisting of 300 ml of 1,2-dimethoxyethane and 3 ml of methanol and treated portionwise with 1.6 g of sodium borohydride. After 1 h the reaction mixture is cooled to room temperature, 300 ml of water are added and the crude title compound is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The crude title compound is purified by chromatography on silica gel using ethyl acetate/petroleum ether in the ratio 2/1 as eluent. Removal of the solvents of the corresponding eluate fractions yields 11.9 g of the title compound of melting point 119-122° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:10].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>>[Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-:10]
Reactant: Clc1nccnc1Cl
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Product: [O-][n+]1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 750 g. (5 mol) of 2,3-dichloropyrazine* in 5 l. sulfuric acid at 10° C., is gradually added 1,500 g. (5.5 mol) of potassium persulfate. The reaction mixture is stirred at room temperature for 24 hours and carefully poured into 19 l. of ice water. The aqueous solution is extracted with chloroform and the extract is washed with sat. NaHCO3 and sat. NaCl solutions and dried over MgSO4. Evaporation of the solvent provides 698 g. (85%) of white solid. MP 101° -103° C. (lit. MP 104° -106° C.). This material is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:14]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc([N+](=O)[O-])c1OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
A mixture of 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (1.0 g, 5.5 mmol), nicotinic acid 4 (0.8 g, 5.8 mmol), DCC (2.4 g, 11.6 mmol) and DMAP (0.7 g, 5.8 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 12 hours. After cooling to 0° C., the precipitated dicyclohexyl urea was removed by filtration and the filtrate concentrated. The crude residue was purified by flash chromatography eluting with Pentane/EtOAc (10:1) to give 5 (1.3 g, 81% yield).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:10]=[CH:9]2)C=CC=CC=1>O1CCCC1.Cl>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(OCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
A solution of 147 mg (0.4 mmol) of 1-triphenylmethyl-4-[3-(4-fluorophenoxy)propyl]-1H-imidazole in 1 ml of tetrahydrofuran and 2 ml of 2N hydrochloric acid is heated at 70° C. for 2 hours. The tetrahydrofuran is then evaporated under reduced pressure. The aqueous solution is filtered and basified with potassium bicarbonate. The product is extracted with chloroform and dried over magnesium sulphate. The solvent is evaporated under reduced pressure to give the title compound in the form of a white solid, M.p.: 135°-137° C.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5]CC)=O.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>O>[F:13][C:10]([F:11])([F:12])[C:8]1[C:2]([CH3:1])=[C:3]([OH:5])[C:19]2[C:17](=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:22]=[CH:21][CH:20]=2)[N:18]=1
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: Nc1ccccc1C(F)(F)F
Solvent: O
Product: Cc1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Temperature: 120 °C
Yield: 80.3 %

Procedure:
To polyphosphoric acid (101 g) heated to 75° C. was added ethyl 2-methyl-4,4,4-trifluoroacetoacetate (10.0 g, 50.5 mmol). 2-Trifluoromethylaniline (6.0 mL, 48.1 mmol) was added dropwise and the reaction mixture heated to 120° C. for 6 h, cooled in ice and treated with water. The cream precipitate was filtered and washed with water and heptane to afford the product (11.4 g, 80%) as a white solid: mp 116.2-116.8° C.; IR νmax (Nujol)/cm−1 3440, 2924, 2854, 1624, 1612, 1584, 1458, 1330, 1226, 1142, 1109; NMR δH (400 MHz, CDCl3) 2.29 (3H, s), 7.47 (1H, t, J 7.6 Hz), 7.98 (1H, d, J 7.6 Hz), 8.60 (1H, d, J 7.4 Hz).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([N:23]1[CH2:22][CH2:21][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])[CH2:25][CH2:24]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: Clc1ccccc1N1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccccc2Cl)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(2-chlorophenyl)piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH:1]([N:4]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)([CH3:3])[CH3:2].[C:36]1(S(NC2C=CC(C(F)(F)F)=CC=2NCC2C=CC(C(OC)=O)=CC=2)(=O)=O)C=CC=CC=1.[H-].[Na+].CI>CN(C=O)C>[CH3:36][N:15]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:6]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]=1[N:4]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2NS(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(CN(C)c2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 4-[2-(N-Isopropyl-phenylsulfonylamino)-5-trifluoromethylphenylaminomethyl]benzoate (200 mg) prepared by the same procedure as Example 17 by using methyl 4-(2-phenylsulfonylamino-5-trifluoromethylphenylaminomethyl)benzoate (prepared in Example 27.) was dissolved in DMF (5 ml). Sodium hydride (64 mg) and methyl iodide (200 μl) were added thereto. The mixture was stirred for 24 hours at 60° C. The reaction mixture was extracted with H2O-AcOEt, washed, dried over, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=5:1) to give the title compound (105 mg) having the following physical data.
Reaction SMILES: [NH2:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2.[OH-:27].[K+]>C(O)(C)(C)C>[NH2:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:27])=[N:23][CH:24]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccc(C#N)nc2)CCN(C)C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a solution of 5-[1-amino-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carbonitrile (400 mg, 1.15 mmol) in tert-butanol (20 mL) was added crushed KOH (194 mg, 3.47 mmol) and the reaction mixture was stirred at 80° C. for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated to dryness. The residue was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 5-[1-amino-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylic acid amide (70 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CDCl3, free base) δ (ppm): 8.5 (s, 1H), 8.2 (d, 1H), 7.9 (d, 1H), 7.2 (m, 2H), 7.0 (d, 1H), 5.6 (bs, 1H), 4.6 (t, 1H), 4.1 (d, 2H), 3.7 (q, 2H), 2.9 (t, 2H), 2.8 (m, 1H), 2.6 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccncc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 1,1-dimethylethyl (4RS,5SR)-2-oxo-5-(4-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (500 mg, 1.18 mmol) in methanol (2.8 ml) was added 0.5N sodium hydroxide (2.8 ml, 1.40 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (20 ml), and the mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (391 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=2[OH:20])[N:13]([CH2:22][CH3:23])[CH:12]=1>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:10][C:11]1[C:19]2[C:18]([OH:20])=[CH:17][C:16]([F:21])=[CH:15][C:14]=2[N:13]([CH2:22][CH3:23])[CH:12]=1
Reactant: CCn1cc(CC(=O)Nc2ccccc2N)c2c(O)cc(F)cc21
Solvent: CC(=O)O
Product: CCn1cc(Cc2nc3ccccc3[nH]2)c2c(O)cc(F)cc21
Yield: 23.9 %

Procedure:
The solution of 12-2 (0.3 g, 0.92 mmol) in 25 mL of acetic acid was heated to 80° C. for 8 h. The volatile was removed in vacuo and the residue was neutralized with Na2CO3 solution to pH:7. The mixture was extracted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4. After filtration and concentration, a residue was obtained, which was purified by preparative TLC to give 12-3 (68 mg, 23.9%)
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CCO
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
In 10 ml. of pyridine was dissolved 2.9 g. of the product obtained in Example 17, and to the solution was added 1.1 g. of acetic anhydride under stirring. The resulting mixture was then refluxed for 1 hour. The reaction mixture was then poured into 50 ml. of water, and was then extracted with n-hexane. The extract was washed with water and dried. The solvent was removed by evaporation. The residual oily product was purified by silica gel column chromatography to obtain 3.1 g. of the desired oily product.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:33][C:34](O)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:34](=[O:35])[CH2:33][N:22]2[CH2:23][CH2:24][CH2:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To 1-benzhydrylpiperazine (0.238 g, 0.943 mmol), the product from Example 91D (0.200 g, 0.857 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.358 g, 0.943 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (0.225 mL, 1.286 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, the reaction was concentrated and loaded onto a silica gel column (SF25-25, Analogix®, Burlington, Wis.) and eluted using a gradient of 0.5% to 5% methanol/dichloromethane. The product was isolated along with a slightly lower Rf spot. The mixture was rechromatographed over silica gel using a gradient of 5% to 100% ethyl acetate/hexanes to supply the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.43 (m, 4H), 7.14-7.34 (m, 11H), 4.43 (d, J=15.6 Hz, 1H), 4.24 (s, 1H), 4.00 (d, J=15.6 Hz, 1H), 3.70 (dd, J=7.7, 6.0 Hz, 1H), 3.61-3.66 (m, 2H), 3.52-3.59 (m, 1H), 3.44-3.49 (m, 2H), 3.41 (dd, J=11.6, 5.8 Hz, 1H), 2.37-2.43 (m, 4H), 2.15-2.28 (m, 1H), 1.90-2.03 (m, 2H), 1.77-1.89 (m, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:31][CH2:32][CH:33]=[CH:34][C:35]1[CH2:42][S:41][C@H:40]2[N:37]([C:38](=[O:44])[C@H:39]2[NH2:43])[C:36]=1[C:45]([OH:47])=[O:46])(=[O:30])[CH3:29]>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([O:31][CH2:32]/[CH:33]=[CH:34]\[C:35]1[CH2:42][S:41][C@H:40]2[N:37]([C:38](=[O:44])[C@H:39]2[NH:43][C:13](=[O:15])[CH2:12][S:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:36]=1[C:45]([OH:47])=[O:46])(=[O:30])[CH3:29]
Reactant: CC(=O)OCC=CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CSc1ccc2ccccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OC/C=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CSc3ccc4ccccc4c3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 10.5 g (48 mmol) of naphthalen-2-ylsulfanyl-acetic acid in 80 ml of N,N-dimethylacetamide were added 7.8 g (48 mmol) of 1,1′-carbonyldiimidazole and the reaction mixture was stirred for 0.5 h at 20° under an atmosphere of argon. To the yellow solution were added 11.93 g (0.5 mmol) of (Z and E)-(6R,7R)-3-(3-acetoxy-propenyl)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and stirring was continued for 3 h at 20°. The brown solution was diluted with ethyl acetate (0.5 1), washed with 1 N hydrochloric acid (0.2 1) and with water (5×0.1 1), dried over sodium sulfate and evaporated in vacuo. The remaining material was crystallized from ethyl acetate to give 11.7 g (58%) of (Z)-(6R,7R)-3-(3-acetoxy-propenyl)-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a light brown solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]=[C:13]([CH2:24][CH3:25])[CH2:14][CH2:15][C:16]1([OH:23])[CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17]1>C(Cl)Cl>[CH2:24]([C:13]1([CH2:12][OH:9])[CH2:14][CH2:15][C:16]2([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22]2)[O:23]1)[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CC)CCC1(O)COCCOC1
Solvent: ClCCl
Product: CCC1(CO)CCC2(COCCOC2)O1
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a stirred solution of 3.22 g of 3-chloroperbenzoic acid dissolved in 20 ml of methylene chloride under nitrogen, was added dropwise 3.05 g of tetrahydro-6-(3-methylenepentyl)-1,4-dioxepin-6-ol while maintaining the temperature below 30° C. using a water bath. After six hours and 20 minutes, the reaction mixture was washed with a 25% solution of potassium carbonate and a saturated sodium chloride solution, dried and stripped to yield 2.10 g of the desired product as a dark brown liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC1C=CC=CC=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]Cl)#[N:15]>C(O)CO>[N:1]1([C:14]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22][N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SCl
Reactant: C1CNCCN1
Solvent: OCCO
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Yield: 91 %

Procedure:
215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g of ethylene glycol were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 214.1 g (1.00 mol) of 2-cyanobenzenesulfenyl chloride was added dropwise in the melted state at about 120° C. over 1 hour while stirring, which was thereafter stirred for 2 hours to complete the reaction. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 199.5 g (m.p. 89°-90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 2-cyanobenzenesulfenyl chloride was 91.1%.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].Br[CH2:8][C:9]([OH:11])=[O:10].O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:5])([O:4][CH2:8][C:9]([OH:11])=[O:10])[CH3:3]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OCC(=O)O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a 3-neck 2-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added potassium tert-butoxide (100.00 g, 0.891 moles) and 1500 ml of toluene under nitrogen. A solution of bromoacetic acid (61.90 g, 0.446 moles) in 100 ml of toluene was then added dropwise and the mixture then heated at reflux for 24 hours. After cooling the mixture to room temperature, water (100 ml) was added and the layers separated. The aqueous layer was washed with ether (2×50 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×75 ml), dried over magnesium sulfate and concentrated in vacuo to give 27.3 g of the product as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@@H:31]3[C@@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][N:36](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:35][CH2:34]3)[N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[ClH:1].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@@H:31]3[C@@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:4])[CH2:35][CH2:34]3)[N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: O=C(CCl)N1CCOCC1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(CC(=O)N4CCOCC4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 4-(2-chloroacetyl)morpholine and starting compound A1 as described for compound 18. M.p. 159-162° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CBr)cc1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccc(Br)cn4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 12.1c from 75 mg (0.16 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 12.1b) and 89 mg (0.63 mmol) N-piperidin-4-yl-acetamide.