Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:11]=3[C:12]=2[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9](=[O:34])[C:10]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:11]=3[C:12]=2[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: CCOC(C)=O
Product: O=C(C1=C(c2ccc(O)cc2)S(=O)c2cc(O)ccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 1.0 gram (3.26 mmoles) of 2-(4-hydroxyphenyl)-3-benzoyl-6-hydroxybenzothiophene in 50 ml. of ethyl acetate was prepared and cooled to 0° C. The mixture was stirred, and 620 mg. (3.59 mmoles) of m-chloroperbenzoic acid were added. The mixture was stirred for one hour and then was allowed to stand overnight under refrigeration. The product was chromatographed rapidly over silica gel in a fritted glass funnel, elution being carried out with a 7:3 mixture of benzene and ethyl acetate followed by pure ethyl acetate to obtain 220 mg. (19 percent) of the title compound. Mass spectrum: Theory, 362; Found, 362.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9]([Cl:15])=[C:10]([Cl:14])[C:11]([OH:13])=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:14][C:10]1[C:11]([O:13][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[S:8][C:7]=2[C:9]=1[Cl:15]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Yield: 42.6 %

Procedure:
To a solution of 9.0 g of 2-acetyl-6,7-dichloro-5-hydroxybenzo[b]thiophene and 200 ml of 2-butanone is added a solution of 6.62 g of ethyl bromoacetate in 50 ml of 2-butanone, 5.2 g of potassium carbonate and 2.2 ml of dimethylformamide. The reaction mixture is heated under reflux for 2 hrs, allowed to cool and filtered. The filtrate is extracted with ether (3 times). The layers are separated and the organic phase is washed with water, saturated sodium chloride solution, dried and filtered. The filtrate is evaporated. The residue is dissolved in dichloromethane and chromatagraphed on alumina, using dichloromethane as the eluant. Evaporation of the eluant gives 5.1 g of ethyl [(6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([N:38]([CH3:39])[CH3:36])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (470 mg, 1.04 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (250 mg, 1.56 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine (2.0N in THF, 1.0 ml, 2.0 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was dissolved in ethyl acetate (30 ml) and extracted with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC(CH3CN: Water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (160 mg, 30%): mp 80-82° C.; 1H NMR: δ (CDCl3): δ 0.33-0.39 (m, 2H), 0.60-0.68 (m, 2H), 1.21-1.30 (m, 1H), 2.25 (s, 3H), 2.90 (s, 3H), 2.97 (dd, J=5 Hz, the other doublet is buried, 1H), 3.05 (s, 3H), 3.87 (d, J=7.5 Hz, 2H), 3.94 (dd, J=10 Hz, the other doublet is buried, 1H), 5.83 (dd, J=5, 10 Hz, 1H), 6.69 (t, JH-F=75 Hz, 1H), 7.12-7.15 (m, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 8.73 (d, J=8.5 Hz, 1H), 9.53 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.8, 25.6, 35.4, 36.1, 37.7, 51.9, 74.5, 112.6, 116.7, 120.8, 114.9, 116.0, 118.5, 120.9, 123.4, 125.3, 131.9, 136.4, 138.0, 138.6, 140.7, 151.2, 168.7, 169.8, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O6: C, 60.58; H, 5.28; N, 8.15. Found: C, 60.23; H, 5.26; N, 8.02.
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][I:10].[P:11](OCC)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>>[I:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(OCC)OCC
Reactant: ICCOCCOCCI
Product: CCOP(=O)(CCOCCOCCI)OCC
Temperature: 160 °C

Procedure:
1,2-bis(2-iodoethoxy)ethane (1.0 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 85-100% EtOAc/Hex to give diethyl 2-(2-(2-iodoethoxy)ethoxy)ethylphosphonate as a colorless oil.
Reaction SMILES: [Cl:1]CCl.[F:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](O)=[O:16])[C:10]1=[O:18].C(Cl)(C(Cl)=O)=O>CN(C=O)C>[F:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([Cl:1])=[O:16])[C:10]1=[O:18]
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The flask was charged with dichloromethane, 20 mg of 1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid, DMF, (COCl)2 was added slowly via syringe. Then the resulted mixture was allowed to stir at room temperature for 3 h. After TLC show the reaction was complete, the solvent was removed under high vacuum to give 25 mg of crude product, which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1.I[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(O)ccc43)cc2s1
Reactant: ICCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCN5CCOCC5)ccc43)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg, 0.23 mmol) from Step 1 of this Example, 4-(2-iodoethyl)morpholine (111 mg, 0.46 mmol) from Step 2 of this Example, Cs2CO3 (250 mg, 0.69 mmol), and NMP (2 mL) was stirred at rt for 3 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a gradient of 33% DCM in THF to 100% THF, to afford (3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (84 mg, 67%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.14-7.19 (m, 2H), 6.90 (m, 1H), 5.35 (s, 2H), 4.11-4.17 (m, 2H), 3.70-3.75 (m, 4H), 3.65 (m, 1H), 3.08 (m, 1H), 2.76-2.84 (m, 3H), 2.57-2.60 (m, 4H), 2.17 (m, 1H), 1.82-1.92 (m, 2H), 1.78 (s, 3H), 1.46 (s, 3H), 1.33-1.39 (m, 4H); LCMS (ESI) m/z 548 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])([O-:3])=[O:2].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH2:22]([O:21][CH:20]=[C:15]([C:16](=[O:18])[CH3:17])[C:14]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])[CH3:23]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
A mixture of 1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione (11.0 g), triethyl orthoformate (11.3 g) and acetic anhydride (12.3 g) was stirred and heated at reflux for 3 hours. After cooling, the mixture was evaporated to dryness. Toluene (50 ml) was added and the mixture was evaporated to dryness to give 2-ethoxymethylene-1-(2-nitro4-trifluoromethylphenyl)-butan-1,3-dione as a crude brown oil which was not further purified.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH3:25][N:26]=[C:27]=[S:28]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:27]([NH:26][CH3:25])=[S:28])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CN=C=S
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Solvent: ClCCl
Product: CNC(=S)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 56.6 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in dichloromethane (10ml) and methyl isothiocyanate (0.11 g, 1.5 mmol) was stirred at room temperature for twenty six hours. The solvent was evaporated, and the residue washed with diethyl ether to give 0.34 g of 6-nitro-2,2-dimethyl-3-(N'-methylthioureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:20]/[C:21](/[CH3:28])=[CH:22]/C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[C:15](/[CH3:16])=[CH:22]/[C:21](=[O:20])[CH3:28])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc(C2CCCCCC2)c(Cl)c1
Reactant: CCOC(=O)/C=C(\C)OCC
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCCC2)c(Cl)c1
Yield: 51 %

Procedure:
(E)-4-(3-chloro-4-cycloheptyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 3'-chloro-4'-cycloheptyl-acetophenone (b.p. 136°-139°C at 0.1 mm Hg; nD23 = 1.5572) and ethyl (E)-3-ethoxy-crotonate with a yield of 51% of theory. B.p. 160°-165°C at 0.1 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc2s1
Temperature: 85 °C

Procedure:
To a solution of 96 mg (0.25 mmol) {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) in 5 ml acetonitrile was added 120 mg potassium carbonate and 0.3 ml (2-bromoethoxy)-tert-butyldimethylsilane. The reaction mixture was heated at reflux for 90 min and at 85° C. for 2 h and poured into 5% aqueous citric acid. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 4:1 and then 9:1). [2-({5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzo[b]thiophene-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (40) (63 mg, 0.116 mmol) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[CH2:3][OH:4].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O.C(Cl)Cl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)([F:13])[F:1]
Reactant: BrCCCCCCBr
Reactant: COc1cccc(C(F)(F)CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(F)(F)COCCCCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of Intermediate 68 (3.19 g, 16.95 mmol) in dimethylformamide (20 mL) was added 60% sodium hydride (1.36 g, 33.9 mmol) and 1,6-dibromohexane (5.2 mL, 33.9 mmol). The mixture was stirred at room temperature for 2 hours. The crude was diluted with methylene chloride (50 mL) and washed with water (3×50 mL), dried (MgSO4) and concentrated. The excess of 1,6-dibromohexane was eliminated by distillation at reduced pressure (P=0.15-0.18 mmHg, T=60-65° C.) and the crude was purified by column chromatography with silica gel using methylene chloride as eluent. The title compound was obtained (3.41 g, 57%) as oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[N:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:26]([CH2:29][Cl:30])[CH2:27][S:28][C@H:23]12>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([O:33][CH:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:32])=[C:26]([CH2:29][Cl:30])[CH2:27][S:28][C@H:23]23)=[O:10])[N:3]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid (III-1), (2.1 g, 10 mmole) in dry CH2Cl2 (50 ml) was added PCl5 (2.09 g, 10 mmole) at -30° C., and the mixture was stirred for 20 minutes at -15° to -20° C. To the above acid chloride solution was added a solution of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II) (4.5 g, 10 mmole) in CH2Cl2 (50 ml) containing N,O-bis-(trimethylsilyl)acetamide (10 g, 50 mmole) at -30° C. After stirring at -10° C. for 1 hour, the mixture was concentrated to remove the CH2Cl2 and diluted with ethyl acetate (200 ml). The mixture was washed with 10% aqueous NaHCO3 (2×40 ml), H2O (2×20 ml) and brine (10 ml), successively, and dried over MgSO4. The solvent was evaporated in vacuo and the resulting oily residue (10 g) was dissolved in CHCl3 (20 ml) and chromatographed on a silica gel (Wako gel C-200, 100 g containing 10 ml of 1/1.5M pH 7 phosphate buffer) using 1-3% CH3OH--CHCl3. Fractions containing the title compound were evaporated to give 5.7 g (95%) of IV-1 as a yellow amorphous powder. M.p. >140° C. (dec.).
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:35])[C:14]([CH3:34])=[C:15]([CH:20]3[CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21]3)[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl>CO.[C].[Pd]>[NH:22]1[CH2:23][CH:20]([C:15]2[O:16][C:17]3[C:12]([C:13](=[O:35])[C:14]=2[CH3:34])=[CH:11][CH:10]=[C:9]([OH:8])[C:18]=3[CH3:19])[CH2:21]1
Reactant: Cc1c(C2CN(C(=O)OCc3ccccc3)C2)oc2c(C)c(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C2CNC2)oc2c(C)c(O)ccc2c1=O
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of benzyl 3-[7-(benzyloxy)-3,8-dimethyl-4-oxo-4H-chromen-2-yl]azetidine-1-carboxylate (625 mg, 1.33 mmol) obtained in Example 1-2 in methanol (12 mL), 10% palladium-carbon (water content: 50%, 200 mg) was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere. Dichloromethane (20 mL) and methanol (20 mL) were added to the reaction solution, and the palladium-carbon was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain 297 mg of the title compound (yield: 91%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: O=C(O)c1ccccc1
Reactant: NCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Product: O=C(NCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)c1ccccc1
Yield: 58.9 %

Procedure:
A procedure similar to that described in Example 15 was carried out with 9-bromo-5-aminomethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione hydrochloride (800 mg, 2.31 mmol) and benzoic acid (312 mg, 2.56 mmol) to give 564 mg of the title compound (59%): mp 169~175° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.03 (s, 1H), 8.66 (t, 1H, J=5.4 Hz), 7.77 (d, 2H, J=8.6 Hz), 7.41~7.56 (m, 3H), 7.24 (s, 1H), 7.19 (s, 1H), 5.03~5.13 (m, 1H), 3.62 (dt, 1H, J=11, 6.5 Hz), 3.28~3.40 (m, 1H), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.78 (dm, 1H, J=17.1 Hz), 2.14 (dm, 1H, J=13.5 Hz), 1.73~1.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH:29]=O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: O=CCc1ccccc1F
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3ccccc3F)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Fluoro-phenyl)-acetaldehyde following the procedure of Example 457: mp 186-187° C.; MS m/z 384, HRMS: calcd for C22H13F4NO+H+, 384.10060; found (ESI, [M+H]+), 384.1.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]([NH2:52])[CH:43]=1>C(#N)C>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]([NH:52][C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=[CH:8]3)=[O:17])[CH:43]=1
Reactant: CCCCCn1ccc2cc(C(=O)O)ccc21
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCCCCn1ccc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21

Procedure:
A solution of 1-pentyl-1H-indole-5-carboxylic acid (0.687, 2.97 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (1.18 g, 3.11 mmol) and N,N-diisopropylethyl (1.14 mL, 6.53 mmol) in acetonitrile (20 mL) was stirred at ambient temperature for 5 minutes. Quinolin-3-ylamine (1.93 g, 13.4 mmol) was added, and the solution was heated at reflux for 18 hours. The solvent was evaporated in vacuo, and the residue was partitioned between dichloromethane and water. The product was preabsorbed onto silica gel and purified by flash chromatography using ethyl acetate in hexane as the eluant, to give the product, 0.40 g (38%). MS: m/z 358 (MH+). 1H NMR (DMSO-d6): 0.84 (t, 3 H), 1.23-1.34 (m, 4 H), 1.73-1.83 (m, 2 H), 4.24 (t, 2 H), 6.64 (d, 1 H), 7.53 (d, 1 H), 7.56-7.69 (m, 3 H), 7.86 (d, 1 H), 7.98 (t, 2 H), 8.37 (s, 1 H), 8.89 (d, 1 H), 9.21 (d, 1 H) and 10.60 (s, 1 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:2]([CH2:3][C:4]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:5]=2[O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH3:1])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Product: CN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid and 4-chlorobenzenesulfonyl chloride. M+H=514.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 9 h
Yield: 75.8 %

Procedure:
13.4 g (46.6 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 100 ml of tetrahydrofuran were charged in a 300 ml three-necked flask and dissolved. 7.76 g (56.1 mmol, 1.2 equivalents) of potassium carbonate and 8.20 g (49.1 mmol, 1.05 equivalents) of ethyl bromoacetate were added thereto at room temperature, the mixture was stirred at 60° C. for nine hours. After cooling the mixture to room temperature, salts were removed by filtration, and the solvent was concentrated. The residue was extracted with 250 ml of toluene and 250 ml of a 1N sodium hydroxide aqueous solution. The organic layer was washed with 250 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 13.2 g of 4-[(4-dipropylaminobutyl)ethoxycarbonylmethylamino]methylbenzonitrile (11) as an oily substance (yield: 76%).