Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21]Br>O>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21][O:15][C:12]1[CH:13]=[CH:14][C:9]([I:8])=[CH:10][CH:11]=1
Reactant: BrCC1OCCO1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(OCC2OCCO2)cc1
Reaction time: 3 h
Yield: 46.5 %

Procedure:
A suspension of 65% sodium hydride (9.3 g)/dimethylformamide (100 ml) was ice-cooled, followed by the addition of 4-iodophenol (50.5 g)/dimethylformamide (200 ml) solution, and the mixture was stirred for 3 hr. To the mixture solution was added (1,3-dioxolan-2-yl)methylbromide (46.0 g), and the mixture was reacted at 60° C. for 1 day. The reaction solution was poured into water, and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and then dried (over magnesium sulfate). The solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (chloroform), and then recrystallized from ethyl acetate/hexane, to give 32.7 g of the title compound as pale yellow prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH2:36][OH:37]>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][N:18]([CH2:35][CH2:36][OH:37])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCO)CC1
Temperature: 80 °C

Procedure:
3.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate and 2.07 g of potassium carbonate were added to a solution of 1.17 cm3 of 2-iodoethanol in 80 cm3 of acetonitrile, at a temperature in the region of 20° C. with stirring and under an inert atmosphere. After heating for 23 hours at a temperature in the region of 80° C., a further 1.17 cm3 of 2-iodoethanol were added. After heating for 40 hours at a temperature in the region of 80° C., the reaction mixture was cooled to about 20° C., filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained was purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 40-60μ; diameter 4 cm; height 60 cm), eluting with a dichloromethane/methanol/aqueous ammonia mixture (89/10/1 by volume) and collecting 50-cm3 fractions. Fractions 14 to 17 were combined and then concentrated as previously. 1.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[I-:21].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][I:21])[N:14]=1)=[O:8]
Reactant: [I-]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea (Intermediate 2, 1 eq) in acetone was added sodium iodide (10 eq) at once. The mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the mixture was taken up in water and EtOAc. The layers were separated and the organic phase was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford 1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea as a tan-colored solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[S:22]1C2CCCC(N)C=2C=C1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[CH:15]=[CH:14][S:22][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCCc2sccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCCc3sccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.10 (d, J=5.2 Hz, 1H), 6.93 (d, J=5.2 Hz, 1H), 5.40 (m, 1H), 4.50 (bs, 1H), 2.83 (m, 2H), 2.66 (q, J=7.5 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 2.10 (m, 1H), 1.96 (m, 3H), 1.29 (m, 6H); (MS/CI) calcd for C16H21N3S+H 287.4, found 287.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]([O:21][CH2:4][CH2:3][O:2][CH3:1])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(O)cc1Br
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(OC)c(Br)c1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
2-bromoethyl methyl ether (0.07 mL, 0.74 mmol) was added to a mixture of potassium carbonate (136 mg, 0.99 mmol) and 3-bromo-4-methoxy-phenol (100 mg, 0.49 mmol) in DMF (2 mL) and mix heated at 100° C. for 1 hr. Reaction mixture was allowed to cool and partitioned between ethyl acetate (20 mL×2) and water (20 mL). The combined organic phases were washed with sat. aqueous sodium chloride solution (40 mL) and dried over sodium sulphate. Solvents were removed in vacuo to afford a crude oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford the title compound (113 mg, 88%) as a colourless liquid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31](=[NH:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: COCCC(=N)NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.43 mmol) of the compound from Example 25A and 232 mg (1.58 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 398 mg (53% of theory)
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].O>C(COC)OC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (500 mg, 0.001 mol) and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (594 mg, 0.0015 mol) were reacted under palladium catalyzed Suzuki coupling conditions with Pd(dppf)C12 and Cs2CO3 water and dimethoxyethane to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate together with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.[OH-].[Li+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:32]([O:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3]3([O:2][CH2:1][CH2:29][O:28]3)[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1

Procedure:
A solution of 32.7 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol (see Example 1h) in 327 ml of dimethylformamide is mixed at room temperature with 5.73 g of lithium hydroxide and stirred with 15.1 ml of benzyl bromide for 2 hours at 60° C. Then, it is diluted with ethyl acetate, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene is obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:22](=O)([O-])[O-:23].[K+].[K+]>O>[OH:23][CH2:22][N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 g of 5,5-diphenylhydantoin (0.08 moles) and 80 ml (32 g) of formalin are introduced into a suitable reaction vessel containing 720 ml of water and one g of potassium carbonate. The reaction is stirred at room temperature for 24 hours, after which the subject compound, mp 186.5°-188.5° C., yield 22.58 g (91.86%) is obtained by filtration.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 4-nitrobenzyl bromide (0.500 g, 2.31 mmol), 1H-pyrazole (0.362 g, 5.23 mmol), and potassium carbonate (0.704 g, 5.09 mmol) in acetonitrile (30 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.380 g, 76%) as a white solid. MW=203.20. 1H NMR (CDCl3, 500 MHz) δ 8.21-8.19 (m, 1H), 8.19-8.16 (m, 1H), 7.61-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.32-7.28 (m, 2H), 6.35 (t, J=2.1 Hz, 1H), 5.44 (s, 2H); APCI MS m/z 204 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:13]([N:6]([CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCBr
Reactant: CCCC(C)Nc1ccccc1
Product: CCCCCCCN(c1ccccc1)C(C)CCC

Procedure:
N-n-heptyl-N-(1-methylbutyl)aniline was prepared from N-(1-methyl butyl)aniline and 1-heptylbromide using the same method as in Example 2ii).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:20])[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.I[CH3:22]>C1COCC1>[CH3:22][O:20][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:11][CH2:12][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:18][CH2:19]1
Reactant: CI
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Sodium hydride (1.27 g, 31.7 mmole) was added to a solution of 8-(4-fluoro-phenyl)-1,4-dioxaspiro[4.5]decan-8-ol (8.0 g, 10 mmole) in THF (100 ml) and the mixture stirred for 16 hr and heated at reflux for 4 hr. The solution was cooled to 25° C. and iodomethane (6.75 g, 47.6 mmole) was added. The mixture was stirred for 112 hr and concentrated in vacuo. The residue was suspended in water and the mixture extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol methyl ether (98.8%, mp: 52°-54° C.).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3]>CO.[Pd]>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[N:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cccc(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-({3-[(1-methylethyl)oxy]phenyl}oxy)-5-nitropyridine (Intermediate 28, 670 mg, 2.45 mmol) in methanol (50 mL) was added Pd/C (10%, 100 mg, 0.1 wet. e.q.) and the flask was filled in with H2. The resulting mixture was stirred at room temperature under H2 atmosphere overnight and filtered. The filtrate was concentrated under vacuum to afford the title compound as a brown solid (560 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.C[O:16][C:17](=[O:46])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=3Br)[CH:28]=2)=[CH:22][C:21]=1[CH3:45]>>[CH3:45][C:21]1[CH:22]=[C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][C:35]=3[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:14])([F:13])[F:1])[CH:28]=2)[CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][C:17]([OH:46])=[O:16]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3OC(F)(F)F)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-trifluoromethoxyphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 94 mg (58%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H22O5F6 576, found 577 (M+1, 100%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C@@H:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[C:29](=[O:31])[NH2:30])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:6][CH:5]=1.[CH2:33]([NH2:35])[CH3:34]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3](=[O:2])[NH:35][CH2:33][CH3:34])=[CH:9][CH:8]=2)[C@H:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[C:29]([NH2:30])=[O:31])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CN([C@@H]2CCCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CCN
Product: CCNC(=O)c1ccc(CN([C@H]2CCCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
cis-4-[[(2-Carbamoyl-cycloheptyl)-(4-chlorobenzenesulfonyl)-amino]-methyl]-benzoic acid methyl ester (50 mg, 0.10 mmol) and ethylamine (1.0 M in MeOH, 6 mL) were heated with stirring at 60° C. for 16 h. The solution was concentrated to dryness and the product purified by silica-gel column chromatography (20%–90% EtOAc/Hexanes) to afford 9.0 mg (18% yield) of the titled compound: 1 H NMR (DMSO-d6) δ 7.89 (m, 1 H), 7.80 (d, 2 H, J=8.0 Hz), 7.72 (d, 2 H, J=8.0 Hz), 7.64 (d, 2 H, J=8.0 Hz), 7.36 (d, 2 H, J=8.0 Hz), 7.32 (s br, 1 ), 6.67 (s br, 1 H), 4.58 (AB2,2 H,Δv=16,Jab=108 Hz), 3.97 (m, 1 H), 2.76 (m, 1 H), 2.26 (m, 2 H), 1.72 (m, 2 H), 1.35 (m, 8 H), 1.12 (t, 3 H, J=8.0 Hz); MS m/e 492.29 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([C:10](=[O:12])[CH3:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:15]Br>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([C:10](=[O:12])[CH2:11][Br:15])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: CC(=O)c1oc2ccc(F)cc2c1C
Solvent: CC(=O)O
Product: Cc1c(C(=O)CBr)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
In this Reference Example, 38.4 g of 5-fluoro-3-methyl-2-acetylbenzo [b] furan is dissolved in 200 ml of acetic acid and 32.0 g of bromine is addeddropwise thereto at room temperature. The mixture solution is then stirred for 30 minutes at room temperature, whereby the color of bromine disappears and crystals are deposited from the solution. Then, the solution is filtered to obtain 38.0 g of 5-fluoro-3-methyl-2-(α-bromoacetyl) benzo [b] furan as crystals. (Yield: 70%). Melting point of the desired compound recrystallized from ethanol is 120°-123° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:26])[CH2:16][CH:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[N:23][O:24][CH3:25])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[Cl:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:28][CH2:29][CH2:30][NH:31][C:32]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:26])[CH2:16][CH:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[N:23][O:24][CH3:25])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:33]
Reactant: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=C=NCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NCCCl)CS[C@H]12
Yield: 35.4 %

Procedure:
A solution of 3-hydroxymethyl-7β-(2-methoxyiminophenylacetamido)ceph-3-em-4-carboxylic acid (synisomer) (0.35 g.), 2-chloroethylisocyanate (0.097 g.) and triethylamine (1.79 g.) in dimethylformamide (10 ml.) was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate solution, and the aqueous phase washed with ethyl acetate, acidifed and extracted with ethyl acetate. The combined extracts were dried, concentrated to ca. 5 ml. and dropped dropwise with stirring to petroleum spirit (250 ml.). The resulting solid was filtered and dried to give the title acid (0.157 g., 35%) λmax (pH 6 buffer) 258 nm (ε 6,800), λmax (Nujol) 3250 (NH), 2600 and 1715 (CO2H), 1700 and 1530 (NHCO2R), 1660 and 1540 cm.-1 (CONH), τ (DMSO-d6) values include 0.22 (doublet J 9 Hz; 7β-NH), 2.3 to 2.6 (multiplet; aromatic protons), 6.05 (singlet; OCH3), 6.40 (multiplet; C-2 CH2 and --CH2Cl), 6.65 (multiplet; --NHCH2).
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][C:6]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[CH3:7])C.CO.[OH-].[Na+]>C(OCC)(=O)C>[SH:3][CH2:4][CH2:5][C:6]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CC(=O)SCCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CCS)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
S-3-(Benzyloxycarbonylamino)-3-methylbutyl ethanethioate (3.00 g, 10.2 mmol) was dissolved into methanol (100 mL). Sodium hydroxide solution (5 N, 6.1 mL, 30.6 mmol) was added to the solution in one portion and stirred at room temperature for 1 hour. Thin-layer chromatography (40% ethyl acetate in hexanes) analysis of reaction mixture indicated all the starting material was consumed. The organic solvent was removed and the resulting aqueous solution was made acidic (˜pH 5) with 1 N HCl, while cooled in an ice bath. The aqueous suspension was extracted with ethyl acetate (2×100 mL) and the combined organic layer washed with water (50 mL) and brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (2.83 g, quant). The material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.29 (s, 6H), 2.02 (m, 2H), 2.48-2.5 (m, 2H), 2.83 (t, 20 Hz, 2H), 3.60 (t, 20 Hz, 2H), 4.63 (br s, 2H), 5.05 (s, 2H), 7.29-7.37 (m, 5H). LRMS (ESI/APCI) m/z 316 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19]3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of ethyl 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (641 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 5 hours, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (485 mg, yield: 78%). This was recrystallized from ethanol-hexane. Melting point: 114–115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:16])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:15][CH:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:16])[C:11]([O:13][CH3:14])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(3,4-dichlorophenyl)(hydroxy)methyl]prop-2-enoate (13.6 g) and triethylamine (8.74 ml) in methanol (100 mL) was added benzylamine (6.84 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.7 g).