Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11](Cl)(=O)=O.Cl.S(=O)(=O)(O)O>[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[SH:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: Nc1ccc(Cl)c(S)c1

Procedure:
For production of the compound (III), 2-chloro-5-nitrobenzenesulfonyl chloride, i.e. the compound (V), is first reacted with stannous chloride and hydrochloric acid or with zinc and hydrochloric acid or sulfuric acid at a temperature of 40° to 100° C. to give 2-chloro-5-aminothiophenol, i.e. the compound (IV). The amount of the stannous chloride or zinc is usually from 6 to 10 equivalents to the compound (V).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH:36]([CH3:38])[CH3:37])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH:36]([CH3:38])[CH3:37])=[O:11]
Reactant: COc1cccc(C(CN)C(C)C)c1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CNC(=O)Cc2c(Cl)cncc2Cl)C(C)C)c1
Yield: 97.9 %

Procedure:
By working in a way similar to that described in example 30 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (4.62 g, 22.4 mmoles), carbonyldiimidazole (4 g, 24.64 mmoles), THF (60 ml) and 2-(3-methoxy-phenyl)-3-methyl-butylamine (4.33 g, 22.4 mmoles), obtained as described in example 37, 8.36 g of the title compound were obtained (yield: 97.9%), m.p.: 94-95° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[F:50][C:51]1[CH:59]=[C:58]2[C:54]([C:55]([CH2:70][CH:71]3[CH2:75][CH2:74][CH2:73][NH:72]3)=[CH:56][N:57]2[CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH3:69])=[CH:53][CH:52]=1>CN1C(=O)CCC1.C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([N:72]1[CH2:73][CH2:74][CH2:75][CH:71]1[CH2:70][C:55]1[C:54]2[C:58](=[CH:59][C:51]([F:50])=[CH:52][CH:53]=2)[N:57]([CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH3:69])[CH:56]=1)=[O:18])([CH3:1])([CH3:3])[CH3:4]
Reactant: COCCOCCOCCn1cc(CC2CCCN2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COCCOCCOCCn1cc(CC2CCCN2C(=O)C(NC(=O)OC(C)(C)C)C2CCCCC2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
To a solution of Boc-L-cyclohexylglycine (172 mg, 0.67 mmol) in NMP (2 mL) was added HATU (255 mg, 0.67 mmol) followed by NMM (0.1 mL, 0.95 mmol). After 5 min, 81 (190 mg, 0.55 mmol) in DCM (1 mL) was added and the reaction mixture was stirred at room temperature overnight. Ethyl acetate (20 mL) was added to the reaction mixture and the organic solution was washed with water, 1 N HCl (5 mL), aqueous NaHCO3 (10 mL), and brine, dried over Na2SO4. Solvent was removed under reduced pressure and the product was purified by flash silica gel chromatography to afford 280 mg (85%) of 82 as a wax. [TLC (60% EtOAc/hexane): Rf(82)=0.18)]. 1H NMR (CDCl3, 300 MHz) δ 7.83 (m, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 7.09 (m, 1H), 6.98 (s, 1H), 5.32 (m, 1H), 4.0-4.6 (5H), 3.79 (t, J=5.7 Hz, 2H), 3.40-3.70 (9H), 3.37 (s, 3H), 2.65 (m, 1H), 1.6-2.0 (10H), 1.46 (s, 9H), 1.0-1.4 (6H) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[C:25]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][N:17]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[N:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:24][C:25]=1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OC2CCCCO2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(CO)cc2OC2CCCCO2)c1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Under a nitrogen atmosphere, to a suspension of lithium aluminum hydride (74 mg) in THF (9.7 mL) was added dropwise a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)nicotinate (466 mg) in THF (3.2 ml) at 0° C., and the mixture was stirred for 1 hr. Sodium sulfate decahydrate was added by small portions, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (193 mg) as a colorless gummy substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][SH:13])[CH2:9][S:8]1)[CH3:2].[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH:29]1[O:31][CH2:30]1)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]([OH:31])[CH2:30][S:13][CH2:12][CH:10]2[CH2:9][S:8][C:7]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[S:11]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCC(O)CSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (1.5 g, 0.004 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1,2-epoxypropane (described in U.S. Pat. No. 4,565,882) (1.1 g, 0.004 mol) and anhydrous potassium carbonate (1.75 g) in methyl ethyl ketone (15 ml). The crude product was chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to give 1.9 g (60%) of the product as an oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:31])[C:16](N2[C@H]3C4C=CC=CC=4C[C@H]3OC2=O)=[O:17])[NH:13][C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH2:33].OO.[OH-].[Na+].O>CO.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:31])[C:16]([OH:17])=[O:33])[NH:13][C:12]1=[O:32])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)O[C@@H]2Cc3ccccc3[C@@H]21
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Yield: 89 %

Procedure:
To a solution of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl)propionyl}-(3aS-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (308 mg) dissolved in a methanol-water solvent mixture (2:1, 3 ml), 30% hydrogen peroxide water (0.15 g, 1.35 mmol) was added at room temperature. To the resulting mixture, a 28% aqueous solution of sodium hydroxide (0.12 g, 0.81 mmol) was added dropwise at the same temperature. Stirring was continued until the full consumption of the starting material was confirmed by HPLC. After the completion of the reaction, cool water (10 ml) was added to the reaction mixture. After washing with methylene chloride (5 ml), the pH of the mixture was adjusted to 2 with 35% hydrochloric acid. The crystals so precipitated were collected by filtration, washed with water and then dried, whereby 160 mg (β:α=96:4) of the colorless title compound was obtained (yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>ClCCl>[Br:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ncc(Cl)nc1Br
Temperature: 25 °C
Yield: 62 %

Procedure:
A 250 ml round bottom flask was charged with 5-chloro-pyrazin-2-ylamine (1) (3 g, 23 mmol, N-bromosuccinimide (4 g, 23 mmol) and dichloromethane (100 ml) under nitrogen. The reaction mixture was refluxed for 1 h, then allowed to cool to room temperature and concentrated in vacuo. The compound was purified by flash chromatography, using as eluent pentane/EtOAc 0% to 50%, to give the title compound (3 g, 62 %). 1H NMR (DMSo-d6) 6.8-6.9 (2H, brs), 8.0 (1H, s). MS(ES+): 210, 212.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][S:17][CH2:18][CH:19]=[CH2:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:26][CH:27]1[C:37](=[O:38])[N:29]2[C:30]([C:34]([OH:36])=[O:35])=[CH:31][CH2:32][S:33][C@H:28]12.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.O1CCCC1.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][S:17][CH2:18][CH:19]=[CH2:20])[C:10]([NH:26][CH:27]2[C:37](=[O:38])[N:29]3[C:30]([C:34]([OH:36])=[O:35])=[CH:31][CH2:32][S:33][C@H:28]23)=[O:12])[N:8]=1)=[O:2]
Reactant: C=CCSCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-allylthioethoxyiminoacetic acid (syn isomer, 1.95 g.), N,N-dimethylformamide (0.543 g.), phosphoryl chloride (1.14 g.) and tetrahydrofuran (19 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. A suspension of 7-amino-3-cephem-4-carboxylic acid (1.24 g.) in a mixture of acetone (12.4 ml.) and water (6.2 ml.) was adjusted to pH 7 with 20% aqueous sodium carbonate. To the solution was added dropwise the activated acid solution at -5° to 0° C. while keeping at pH 7.0 to 7.5 and stirred at the same temperature for 30 minutes. After distilling off the organic solvent in vacuo, the aqueous solution was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C[C@@H](CN)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNC[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and (R)-(+)-β-methylphenethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)OC)c(NCc2ccc(Cl)cc2Cl)c1
Yield: 42.8 %

Procedure:
Dimethyl 2-aminoterephthalate (10.45 g), 2,4-dichlorobenzyl chloride (11.74 g), potassium iodide (8.33 g) and potassium carbonate (13.82 g) in a mixed solvent of toluene (50 ml) and water (30 ml) were heated under reflux for 20 hr. After cooling, toluene (50 ml) was added and the precipitated yellow crystals were collected by filtration. The crystals were washed with water and toluene and dried to give the objective compound (7.87 g). The mother liquor was concentrated and crystallized from ethyl acetate to give the second crystals (4.43 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:12][NH2:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15]([C:17]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])[CH3:16].OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:12][NH:13][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[C:25]([CH3:26])[C:17]=2[CH2:15][CH3:16])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNC(=O)C(O)c1cc(F)cc(F)c1
Reactant: CCc1c(C(=O)O)ccc(OC)c1C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)NNC(=O)C(O)c2cc(F)cc(F)c2)ccc(OC)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
106.0 g of 3,5-difluorophenylhydroxyacetohydrazide (B2) are dissolved in 820 ml of N,N-dimethylformamide. 104.9 g of 2-ethyl-4-methoxy-3-methylbenzoic acid (B1), 153.9 g of N-3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (DAPECI) and 42.8 g of hydroxybenzotriazole (HOBt) are subsequently added. The reaction mixture is cooled in an ice bath during the addition of the compounds enumerated above. The solution is then stirred at room temperature for 24 hours. For work-up, the reaction mixture is diluted with 3.5 litres of water. The resultant suspension is stirred for one hour, subsequently filtered off and washed with additional water. The filter cake is recrystallised from 2.5 litres of methanol, giving 129.0 g of the title compound as colourless solid having a melting point of 197.1° C. (MS: 401 (MNa+)).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O.[Na]>CO.C1COCC1>[CH2:14]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: O=Cc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1Nc2ccccc2CC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 528 mg (3.0 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 45 mL of absolute methanol at room temperature was treated with 4.5 g of powdered 3A molecular sieves followed by dropwise addition of a solution of 954 mg (9.0 mmol, 3 eq.) of benzaldehyde in 15 mL of methanol. The pH of the mixture was adjusted to 7 by addition of trifluoroacetic acid then stirred at room temperature for 2 hours. Sodium cynaoborohydride (18 mL of 1.0M THF solution: 18 mmol, 6 eq.) was added and the mixture stirred at room temperature for 18 hours. The mixture was filtered and the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours, then all volatiles removed under vacuum and the residue dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by chromatography on silica, eluting with ethyl acetate/hexane (70:30), to afford 410 mg (1.54 mmol, 51%) of the product. 1H NMR (200MHz,CDCl3): 2.05 (m,1H), 2.5-3.0 (m,3H), 3.37 (dd;7.11Hz;1H), 3.57 (d,12Hz,1H), 3.90 (d,12Hz,1H), 7.05 (d,8Hz,1H), 7.1-7.4 (m,8H), 7.75 (br s,1H). FAB-MS: calculated for C17H18N2O 266; found 267 (M+H,75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=C1CC[CH2:29][CH2:28][CH2:27]2.C(Br)C=C.O>C(O)C.C(OCC)(=O)C>[CH2:29]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:28]=[CH2:27]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
A 0.3 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 6 ml of ethanol, 0.22 g of allyl bromide was added thereto, and the mixture was heated and refluxed for 4 hours. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.18 g of white powdery 3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[CH:29]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][CH2:34][S:35][CH3:36])=[O:30]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][S:18][C:37](=[O:38])[CH:32]([NH:31][CH:29]=[O:30])[CH2:33][CH2:34][S:35][CH3:36])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 24.5 %

Procedure:
The title compound (0.34 gm) was prepared from 9-fluoro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-thiol (1.00 gm) and N-formyl-L-methionine (1.30 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:20]3=[O:34])[CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:19]([CH2:18][C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[C:16]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[C:20]1=[O:34]
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2ccn3C(=O)OC(C)(C)C)c2ccccc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
6-Chloro-4-[3-(2-methoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (570 mg 1.1 mmol) is dissolved in 2.5 mL of dichloromethane and 2.5 mL of trifluoroacetic acid is added. The reaction is stirred for one hour, and then the solvent evaporated in vacuo to give an oil. The oil is taken up 3× in methanol and evaporated in vacuo to give the desired compound (450 mg, 1.1 mmol, 100%)
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([C:12]1[O:13][C:14]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:15]=2[CH:16]=1)([CH3:11])([CH3:10])[CH3:9].FC(F)(F)C(O)=O.[OH-].[Na+]>>[C:8]([CH:12]1[CH2:16][C:15]2[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([OH:25])[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:20][C:14]=2[O:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1cc2c(C(C)(C)C)c(O)c(C(C)(C)C)cc2o1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1O)CC(C(C)(C)C)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
Triethylsilane (76 ml) was added to 2,4,6-tri-tert-butyl-5-hydroxybenzofuran (24.7 g, 82 mmol) and trifluoroacetic acid (38 ml) was added dropwise to the mixture under ice cooling. The mixture was stirred first at 0° C. for 15 min, then at room temperature for 15 min before it was poured into ice water. The mixture was neutralized with an aqueous solution of 1N sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (chloroform) to afford 2,4,6-tri-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [19.0 g (yield, 76%)].
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Reactant: C1CCNC1
Product: CCc1cc(-c2cc(C(=O)N3CCCC3)ccn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [OH-].[K+].[C:3]([OH:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[C:13]([O-])(=O)[C:14]1[C:15](=CC=CC=1)[OH:16].[K+].C(Cl)(=O)C=C.FC(F)(F)C(O)=O>CO.C1C=CC=CC=1.O.C(OCC)C>[C:15]([O:6][C:5]1[C:4](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:12])=[O:11])(=[O:16])[CH:14]=[CH2:13]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C([O-])c1ccccc1O
Agent: C=CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: C=CC(=O)Oc1ccccc1C(=O)O
Reaction time: 2 h

Procedure:
Potassium hydroxide (11.2 g, 0.2 mole) was dissolved in 50 ml of methanol and salicylic acid (13.8 g, 0.1 mole) was added. The formed precipitate was separated and dried in vacuum. The precipitate (0.1 mole, 17.6 g) of potassium salicylate was dissolved in 50 ml of benzene, heated to boiling and acryloyl chloride (22.1 g, 0.2 mole) was added with intense stirring for 2 hours. The formed precipitate was centrifuged, the benzene solution was evaporated using a rotor evaporator and the formed solid product, potassium acryloyl salicylate, was dried in a vacuum. The prepared salt (12.8 g, 0.06 mole) was dissolved in 150 ml of distilled water and 150 ml of a 20% solution of trifluoroacetic acid was added. The formed emulsion was stirred for 40 min. Then, 300 ml of diethyl ether was added and the mixture was stirred for 5-6 hours. The ether layer was separated, dried over magnesium sulfate, and evaporated in a vacuum to a dry state. The white precipitate was recrystallized from benzene. The yield of ASA from the mixture was 30%.
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[OH:11]>CCOCC>[CH:9]1[C:10]2[C:1]3[C:1]4[CH:10]=[CH:5][CH:4]=[CH:3][C:2]=4[O:11][C:2]=3[CH:3]=[CH:4][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc2ccccc2c1
Solvent: CCOCC
Product: c1ccc2c(c1)ccc1oc3ccccc3c12

Procedure:
Next, the β-naphthol derivative having a halogen group (b3) is intramolecularly cyclized by formation of an ether bond according to a Williamson ether synthesis to form a benzo[b]naphtho[1,2-d]furan ring, so that a benzo[b]naphtho[1,2-d]furan compound (b4) can be obtained.