Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[ClH:19].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 75 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (10 g, 34 mmol), 2-chloro-1-phenylethanone (5.80 g, 37 mmol) and anhydrous K2CO3 (16.5 g, 119 mmol) was treated according to general preparation 2 to give 10.51 g of N1-(4-nitrobenzyl)-N4-phenacyl piperazine dihydrochloride (A), yield 75%, mp 236-8° C.
Reaction SMILES: [BrH:1].C[O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[CH:14][C:15]3[C:19]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][O:17][C:16]=3[CH:26]=2)[CH:7]=[CH:8][C:9]=1[O:10]C>>[BrH:1].[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]2[C:15]3[CH:14]=[CH:13][C:12]([C:6]4[CH:5]=[C:4]([OH:3])[C:9]([OH:10])=[CH:8][CH:7]=4)=[CH:26][C:16]=3[O:17][CH:18]=2)[CH:21]=1
Reactant: COc1ccc(-c2ccc3c(-c4cccnc4)coc3c2)cc1OC
Agent: Br
Product: Oc1ccc(-c2ccc3c(-c4cccnc4)coc3c2)cc1O
Yield: 82 %

Procedure:
47% hydrobromic acid solution (1.6 ml) was added to 3-[6-(3,4-dimethoxyphenyl)benzo[b]furan-3-yl]pyridine (80 mg, 0.2414 mmol) obtained in Example 10, and the mixture was refluxed for 12 hours. The precipitate was filtered to obtain a pale yellow powder of 4-[3-(3-pyridyl)benzo[b]furan-6-yl]-1,2- benzenediol hydrobromide (76 mg, 82%)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:30])[C:6]([C:31]([O:33]CC)=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:30])[C:6]([C:31]([OH:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN(C)C(=O)OCC)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N(C)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 75.9 %

Procedure:
A solution of 4.93 g of ethyl 1-cyclopropyl-6,8-difluoro-7-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylate obtained by Example 49(1), 5 ml of 18% aqueous hydrochloric acid in 50 ml of ethanol is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 50 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the obtained crystals are recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 3.53 g of 1-cyclopropyl-6,8-difluoro-7-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 76% yield, melting at 128°-131° C.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[C:26]1[S:25][C:24]([C:30]#N)=[N:23][C:22]=1[CH:21]=[CH:20]2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.O.Cl.[NH2:49][C@@H:50]([C:53]([OH:55])=[O:54])[CH2:51][SH:52].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:8][C@H:9]([C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[C:26]1[S:25][C:24]([C:30]3[S:52][CH2:51][CH:50]([C:53]([OH:55])=[O:54])[N:49]=3)=[N:23][C:22]=1[CH:21]=[CH:20]2)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(ccc3nc(C#N)sc32)c1
Reactant: N[C@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@H](N)C(=O)Nc1ccc2c(ccc3nc(C4=NC(C(=O)O)CS4)sc32)c1
Reaction time: 1 h

Procedure:
7-(Boc-leucinyl)aminonaphtho[2,1-d]thiazole-2-carbonitrile (69 mg, 0.16 mmol) was combined with 0.5 mL of thioanisole and 1.5 mL of DCM and stirred in an ice bath. Trifluoroacetic acid (1.5 mL) was added, and the reaction monitored by HPLC. After 1 h, solvents were removed under reduced pressure, and the remaining residue triturated with ether. The resulting solid was taken up in MeCN/H2O and treated with D-cysteine hydrochloride hydrate (55 mg, 0.31 mmol) and potassium carbonate (55 mg, 0.40 mmol). After 20 min, the reaction was filtered and the product was isolated by preparative HPLC eluting with 2→50% MeCN in 0.1% formic acid. Calcd for C21H23N4O3S2 (M+H): 443.1. found 443.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
A solution of oxalyl chloride (6 mL, 70 mmol) in dichloromethane (60 mL) at −78° C. was treated dropwise with dimethyl sulfoxide (10 mL, 0.14 mol). After 15 minutes, 1-tert-butoxycarbonyl-4-piperidinemethanol (3.0 g, 14 mmol) was added as a solution in dichloromethane (35 mL). The mixture was stirred at −78° C. for 1 hr, then triethylamine (29 mL, 0.21 mol) was added dropwise. The mixture was warmed to ambient temperature and poured into a saturated ammonium chloride solution (200 mL). The organic layer was separated and the aqueous layer was washed with dichloromethane (75 mL). The organic layers were combined and washed with brine (75 mL); then dried with MgSO4, filtered and concentrated. The residue was redissolved in ethyl acetate-hexanes (1:1) and filtered through Florisil (100–200 mesh). The resulting filtrate was concentrated yielding 3.0 g (100%) of the title aldehyde as a yellow oil; which was used without further purification.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[NH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(Cl)Cl>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NC1CCOCC1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(NC1CCOCC1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (prepared according to method B, step 1, 2.0 g, 6.92 mmol) in anhydrous THF (40 mL) are added 4-aminotetrahydropyran (0.70 g, 6.92 mmol) and Cs2CO3. The reaction is heated to 60° C. for 48 h. After cooling the reaction mixture is partitioned between DCM (100 mL) and water (100 mL). The organic layer is separated and dried over Na2SO4. Filtration and concentration of the filtrate gives a yellow oil. The oil is dissolved in DCM and extracted with 1M aqueous HCl solution. The acidic aqueous extract is basified with 5M aqueous NaOH solution and extracted with DCM (3×100 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to give N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-2-(tetrahydro-pyran-4-ylamino)-propionamide (0.89 g, 42%). m/z 310 [M+H+]. Conversion into its hydrochloride salt is achieved upon treatment with 1M HCl solution in diethyl ether (2.89 mL).
Reaction SMILES: [OH-].[Na+].C(N(CC)CC)C.CN1[C:15](=[O:16])/[C:14](=[CH:17]/[CH:18]2[C:22](=[O:23])[CH2:21][CH2:20][C:19]2=O)/[S:13]C1=S.[OH:26]P([O-])(O)=O.[K+]>O>[O:23]=[C:22]1[C:18]2[CH:17]=[C:14]([C:15]([OH:16])=[O:26])[S:13][C:19]=2[CH2:20][CH2:21]1
Reactant: CN1C(=O)/C(=C/C2C(=O)CCC2=O)SC1=S
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc2c(s1)CCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
In a 500-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser, was charged with sodium hydroxide (3.34 g, 83.6 mmol) and water (65 mL). The solution was degassed with nitrogen for 15 min. 4 (7.19 g, 20.2 mmol) was added and the mixture was stirred at room temperature for 3 h. After this time, 1 M aqueous potassium phosphate monobasic was added to adjust the pH of the reaction mixture to 8.0, followed by water (200 mL). After heating at 50° C. for 16 h, the water was evaporated to 50 mL under reduced pressure, and 12 N hydrochloric acid was added to adjust the pH to 2.8 (pH meter). The resulting precipitate was collected by vacuum filtration, washed with water (5 mL) and dried for 16 h under vacuum at 50° C. to afford 5 in 37% yield (1.37 g) as a green solid: mp 195-196° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.30 (br s, 1H), 7.64 (s, 1H), 3.23 (t, 2H, J=5.5 Hz), 2.76 (t, 2H, J=5.5 Hz); MS (APCI+) m/z 183.2 (M+H).
Reaction SMILES: [CH2:1](O)C.[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:33][CH3:34])=[N:14][C:13]=3[N:12]([CH3:35])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C=O.C(=O)([O-])O.[Na+]>C(O)=O>[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:32][CH2:31][CH2:30][N:29]([CH3:1])[CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:33][CH3:34])=[N:14][C:13]=3[N:12]([CH3:35])[N:11]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1cc(N2CCCNCC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CCO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COc1cc(N2CCCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 84 %

Procedure:
To a 2 ml ethanol/2 ml water mixed solution of 60 mg (0.14 mmol) of the compound obtained in Example 133, 30 mg of paraformaldehyde and 1 ml of formic acid were added, and the mixture was heated under reflux for 24 hours. Then, the reaction mixture was brought to room temperature, an aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 53 mg (84%) of the captioned compound.
Reaction SMILES: Cl/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:28])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28]/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3]/[C:4]([O:6][CH3:7])=[O:5])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(S)cc1OC
Reactant: COC(=O)/C=C(/Cl)CCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)/C=C(\CCCCc1ccccc1)Sc1ccc(OC)c(OC)c1
Yield: 30.4 %

Procedure:
A mixture of methyl (E)-3-chloro-7-phenyl-2-heptenoate (1.3 g, 5.1 mmol), 3,4-dimethoxythiophenol (0.86 g, 5.1 mmol) and potassium carbonate (0.7 g, 5.1 mmol) in methanol (50 mL) is heated under reflux for 3 hours. The mixture is filtered and the filtrate is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed (4:1 hexane:ethyl acetate) to obtain methyl (E)-3-[(3,4-dimethoxyphenyl)thio]-7-phenyl-2-heptenoate (0.6 g, 31% ). A small amount is recrystallized from hexane to give m.p. 53-5° C. Anal.(C22H26O4S) C, H: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.68-1.82 (m, 4H), 2.60-2.70 (m, 2H) 2.80-2.92 (m, 2H), 3.57 (s, 3H), 3.86 (s,3H), 3.90 (s, 3H), 5.12 (s, 1H), 6.82-6.92 (m, 2H), 6.98-7.08 (m, 1H), 7.13-7.31 (m, 5H); MS (EI) m/e 386 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1Cl
Product: O=C(Cl)c1ccc(I)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-4-iodo-benzoic acid (470 mg) in thionyl chloride (6 mL) was stirred at 60° C. for 3 h. The excess thionyl chloride was removed in vacuo. The residue was washed with ether and dried to afford 2-chloro-4-iodo-benzoyl chloride (0.5 g), which was used directly in the next step where it was dissolved in 1,4-dioxane (10 mL). Phosphoryl chloride (5 mL) and IId (246 mg) were added, and the mixture was stirred at 90° C. for 1.5 h. The volatiles were removed in vacuo. The residue was partitioned between water and DCM. The organic layer was washed with sat. aq. NaHCO3, dried over NaSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: pentane:EtOAc 10:1 to 5:1) to afford example Id7 (250 mg). LC/MS (method WXE-AB10): RT(PDA)=2.26 min; PDA/ELS purities 99%/99%; mass observed 422.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].Cl.[CH3:20][C:21]1[CH:30]=[C:29]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:39]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:20])[CH:30]=3)=[CH:34][CH:35]=2)(=[O:40])=[O:41])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a mixture of 4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.3 g, 5 mmol] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (1.9 g, 5.50 mmol) in CH2Cl2 (20 mL) was added saturated aqueous NaHCO3 (20 mL) at 0° C. The solution was allowed to warm to 25° C. over 19 h. The reaction was then further diluted in CH2Cl2 (100 mL) and water (30 mL). The organic layer was washed with water (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide a crude oil (2.6 g). The crude product was purified by Biotage Flash 40M chromatography, eluting with 1:1 ethyl acetate-hexanes, to afford 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a white solid (1.6 g, 55%). MS: 570 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:2]=1.[H-].[Na+].S(OC)(O[CH3:24])(=O)=O>CN(C=O)C>[CH3:24][N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]1=[O:17]
Reactant: COS(=O)(=O)OC
Reactant: O=c1ccc2cc(-c3cccnc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(-c3cccnc3)ccc21
Reaction time: 1.5 h

Procedure:
A stirred solution of 6-(3-pyridyl)-2-[1H]-quinolone (0.05 g) in DMF (0.5 cm3) was treated at room temperature with sodium hydride (0.012 g of a 50% dispersion in oil) for 1 hour. A solution of dimethyl sulphate (0.016 g) in DMF (0.2 cm3) was added and the mixture was stirred for 1.5 hours. The mixture was concentrated in vacuo, water (5 cm3) was added and the mixture was extracted with ethyl acetate (3×10 cm3). The combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385") eluting with chloroform to yield a solid which was triturated with ether to afford 1-methyl-6-(3-pyridyl)-2-(1H)-quinolone 0.25H2O, m.p. 116°-118°, (0.02 g).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH3:24])([CH3:23])[CH3:22].BrCCBr.[OH-].[Na+]>CCCCCC.C1COCC1.O.CN(P(N(C)C)(N(C)C)=O)C>[C:21]([CH:25]1[CH2:1][CH2:29][O:28][C:26]1=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CC(C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: BrCCBr
Solvent: O
Product: CC(C)(C)C1CCOC1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of lithium di-isopropylamide, prepared by addition of 8.33 mL (20 mmol) of 2.4 M n-butyllithium in hexane to a 0° C. solution of 3.40 g (20 mmol) of di-isopropylamine in 50 mL of dry THF, is cooled to -78° C. and to it is added dropwise over 30 min a solution of 2.60 g (20 mmol) of methyl t-butylacetate in 50 mL of dry THF. The mixture is stirred at -78° C. for 1 h, then 18.8 g (100 mmol) of 1,2-dibromoethane and 10 mL of HMPA is added all at once. The mixture is stirred for 4 h at -78° C., then allowed to warm slowly to room temperature. Water (100 mL) is carefully added, and the mixture is then extracted with three 100-mL portions of hexane. The combined organic extract is washed with water (100 mL) then with satd. NaCl (50 mL) and dried over Na2SO4. The solvent is removed and the product, methyl 2-t-butyl-4-bromobutyrate, is purified by vacuum distillation. The ester is hydrolyzed by refluxing for 2 h with 25 mL (50 mmol) of 2 N NaOH, the water is removed in Vacuo, and the residue is suspended in 25 ml of di-n-butylphthalate in a 200 mL round-bottomed flask with an efficient stirrer, connected to a distillation apparatus, and heated slowly under vacuum (0.5 torr) in an oil bath to 180° C. with vigorous stirring. The distillate is collected and the reaction is terminated when di-n-butylphthalate begins to reflux in the still head. The product, α-t-butyl-γ-butyrolactone, is then purified by vacuum distillation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.O>O1CCOCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][S:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:17]=2[CH:16]=1
Reactant: Sc1ccccc1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCSc1ccccc1

Procedure:
A solution of the bromide (58) (41 mg, 0.085 mmol) prepared as described in example 172, thiophenol (9.5 μL, 0.093 mmol) and triethylamine (0.25 mL, 3.40 mmol) in p-dioxane (1.5 mL) was refluxed for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness the sulfide (131) directly (37.2 mg, 85%), which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 229–231° C. 1H NMR δ [(CD3)2SO] 11.06 (br s, 1H), 9.37 (s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.76 (s, 1H), 7.60–7.42 (m, 5H), 7.25–7.19 (m, 4H), 7.16–7.10 m, 2H), 4.57 (t, J=6.8 Hz, 2H), 2.98 (m, 2H), 2.01 (m, 2H). Found: C, 67.36; H, 4.29; N, 5.36. C29H21ClN2SO3.114H2O requires C, 67.31; H, 4.19; N, 5.41.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:8])[NH:5][CH:6]=1.Br[CH2:27][CH2:28]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:12]([O:24][CH3:25])[CH:11]=3)[CH2:28][CH2:27][N:5]2[CH:6]=1
Reactant: COc1cc(NC(=O)c2cc(Br)c[nH]2)ccc1OCCN1CCCC1
Reactant: BrCCBr
Product: COc1cc(N2CCn3cc(Br)cc3C2=O)ccc1OCCN1CCCC1
Yield: 95 %

Procedure:
The title compound was prepared by alkylating the carboxamide of step B with 1,2-dibromoethane via the procedure described in step D of Example 1 in 95% yield. MS (ESI) 434, 436 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:3])=[O:2].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
A solution of 11.60 g (48 mmol) of S-(o-nitrophenyl)-D-cysteine in 36 mL of 4N sodium hydroxide (NaOH) was cooled to 0° C. To this solution was added dropwise 6.85 mL (48 mmol) of carbobenzyloxychloride, and the mixture was stirred at room temperature for 2.5 hours. The pH was maintained at 10.8 with the addition of 4N NaOH as needed. The solution was then extracted with ether and the pH adjusted to 1.0 with 12N HCl. The resulting precipitate was dissolved in CH2Cl2, dried with Na2SO4 and evaporated to yield 17.0 g of product as a yellow gum. This material was used as is in the next reaction.
Reaction SMILES: [ClH:1].Cl.C([O:7][CH:8](OCCCC)[C@H:9]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])[NH:10][C:11](=[O:33])[C@H:12]([CH3:32])[NH:13][C:14](=[O:31])[C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])CCC.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:24]([O:23][C:21]([N:16]1[C:17](=[O:20])[CH2:18][CH2:19][C@@H:15]1[C:14]([NH:13][C@H:12]([C:11]([NH:10][C@H:9]([CH:8]=[O:7])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])=[O:33])[CH3:32])=[O:31])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C[C@H](NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@H](C=O)CCCNC(=N)N
Yield: 86 %

Procedure:
After 1N hydrochloric acid aqueous solution (22 ml) was added to a solution of N-benzyloxycarbonyl-D-pyroglutamyl-L-alanyl-L-argininal dibutylacetal hydrochloride (0.28 g, 0.44 mmol) in acetonitrile (44 ml), the mixture was reacted at 36° C. for 1.5 hour with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 0.19 g (86%) of N-benzyloxycarbonyl-D-pyroglutamyl-L-alanyl-L-argininal hydrochloride.