Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[Cl:11][CH2:12][C:13](Cl)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:11][CH2:12][C:13]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:4]=1
Reactant: NC(=NO)c1ccccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: ClCc1nc(-c2ccccn2)no1
Reaction time: 24 h

Procedure:
The title compound was prepared by a modification of a reported method: a) Mylari, B. L.; Beyer, T. A.; Scott, P. J.; Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Zembrowski, W. J. J. Med. Chem. 1992, 35, 457, and b) Palazzo, G.; Tavella, M.; Strani, G.; Silvestrini, B.; J. Med. Pharm. Chem. 1961, 4, 351. To a suspension of N′-hydroxypyridine-2-carboximidamide (25.0 g, 0.182 mol) in chloroform (350 mL) was added chloroacetyl chloride (20.5 g, 0.182 mol, 1 equiv) and triethylamine (20.23 g, 0.2 mol, 1.1 equiv). When most of the triethylamine had been added, the suspension turned to a clear light-yellow solution. The solution was allowed to stand at room temperature for 1 d. The mixture was extracted with water (3×75 mL), resulting in the precipitation of a crystalline solid. The resulting slurry was filtered, and filter cake triturated with ethanol, re-filtered, and dried, affording 29.62 g (73%) of the O-chloracetyl amidoxime intermediate. This intermediate was refluxed in xylenes (300 mL) for 3 h, and the volatiles removed completely in vacuo, affording 25.55 g (72% overall) of the pure 1,2,4-oxadiazole. 1H NMR (DMSO-d6) □ 5.20 (s, 2H), 7.62 (m, 1H), 8.06 (m, 2H), 8.76 (m, 1H). LC-MS (APCI) calcd for C8H6ClN3O: 195.02. found (M+H+): 196.0 m/z.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.8 %

Procedure:
Following general procedure II, (R)-tert-butyl (1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (175 mg, 0.34 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (140 mg, 0.51 mmol) to afford the desired product (120 mg, 57%) as a solid: ESI MS m/z 621 [M+H]+.
Reaction SMILES: [ClH:1].Br[CH2:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]([C:11]([CH3:28])([CH3:27])[CH2:12][O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:10])=[CH:6][CH:5]=1.[NH3:31]>>[ClH:1].[ClH:1].[NH2:31][CH2:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]([C:11]([CH3:28])([CH3:27])[CH2:12][O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:10])=[CH:6][CH:5]=1
Reactant: CN(Cc1ccc(CBr)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Reactant: N
Agent: Cl
Product: CN(Cc1ccc(CN)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Yield: 45 %

Procedure:
A solution of 2-[N-(4-bromomethylbenzyl)-N-methylamino]-1-diphenylmethoxy-2-methylpropane hydrochloride (800 mg -- see Example 23) in saturated methanolic ammonia (40 ml) was stirred at room temperature for 18 hours and evaporated. The residue was purified by chromatography on silica (5 g) using methylene chloride plus 0-2% methanol as the eluant. Appropriate fractions were combined and evaporated to give the free base of the title compound (310 mg, 45%) as a colourless oil which was used directly in Example 47. A small portion of the residue was dissolved in ether and the solution was treated with excess saturated ethereal hydrogen chloride. The resulting precipitated oil was collected and triturated with acetone to give the title compound as a colourless foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:20][C:21]1[C:26]([CH3:27])=[C:25](O)[CH:24]=[CH:23][C:22]=1[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:4]2[C:3]([CH2:2][O:1][C:25]3[CH:24]=[CH:23][C:22]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:21]([CH3:20])[C:26]=3[CH3:27])=[C:7]([C:8]([F:11])([F:9])[F:10])[S:6][N:5]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: N#Cc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C#N)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting from 4-[4-(hydroxymethyl)-5-(trifluoromethyl)-1,2-thiazol-3-yl]benzonitrile, following Steps 4-6 and coupling with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)-propanoate. Upon hydrolysis, compound 264 was afforded as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.6 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 5.01 (s, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.62 (t, J=7.8 Hz, 2H), 2.24 (s, 3H), 2.00 (s, 3H). 19F NMR (400 MHz, CDCl3) δ: −55.39. Mass spectrum (ESI, m/z): Calcd. for C23H19F3N2O3S, 459.0 (M−H). found 459.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:8][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 Example 45 from 6-methyl-2-nitroaniline and 4-bromophenylethyl alcohol.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[S:27](Cl)(=[O:29])=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:28])=[O:29]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1c(Cc2ccccc2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccccc3)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-benzylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.39 g) and THF (7 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from chloroform and hexanes provided 0.11 g (24%) of a tan crystalline solid, m.p. 120°-123° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:11][NH:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[F:29]>N1C=CC=CC=1>[CH2:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([F:29])=[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:11]3)[CH:22]=2)[C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19]1)[CH3:24]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: c1cc(C2CNCCN2)cs1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccsc4)C3)cc21
Yield: 27.5 %

Procedure:
A mixture of 1 g of 2-(3-thienyl)piperazine and 538 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 8 ml of pyridine was further reacted as described in Example 26 giving 220 mg of the desired product, mp 198°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-:12].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (2.29 g, 9 mmol) in CH3CN (45 mL) was added KF (2.1 g, 36 mmol) and 18-crown-6 (0.5 g), then the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude product which was purified by column to give the reagent R-10a (1.6 g, 74.4%) as a pale yellow solid. ESI-MS (M+1): 239.2 calc. for C6H4BrFO2S.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]=1.[F:15][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=1[C:24]1[NH:28][C:27](=[O:29])[O:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:22][C:21]3[C:16]([F:15])=[C:17]([C:24]4[NH:28][C:27](=[O:29])[O:26][N:25]=4)[C:18]([F:23])=[CH:19][CH:20]=3)[O:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1nc(-c2ccc(Cl)cc2)no1
Reactant: O=c1[nH]c(-c2c(F)ccc(O)c2F)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2c(F)ccc(OCc3nc(-c4ccc(Cl)cc4)no3)c2F)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloromethyl-3-(4-chlorophenyl)-[1,2,4]oxadiazole (0.080 g, 0.35 mmol) in anhydrous DMF (2 ml) was added 3-(2,6-difluoro-3-hydroxyphenyl)-4H-[1,2,4]oxadiazol-5-one (0.075 g, 0.35 mmol) and potassium carbonate (0.17 g, 1.22 mmol) was added. The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure, added water and extracted with EtOAc (3×50 ml). The combined organics was washed with water, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica (60-120 M) using ethyl acetate/hexane (45:55) as the eluent to provide the title compound as off white solid (0.0088 g, 6%).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:8])C(OCC)=O.[C:10]1([S:16][CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+].CCOCC>O>[C:10]1([S:16][CH:17]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:2]2([Cl:8])[Cl:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C=CSc1ccccc1
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1C(Sc2ccccc2)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Freshly distilled ethyl trichloroacetate (164.8 g, 0.86 mmol) is added all at once to a cold (-50° ) stirred mixture of dry methyl 3-phenylthio-2-propenoate (155.4 g, 0.8 mol), dry olefin-free pentane (600 ml) and sodium methoxide (50 g, 0.92 mol). The cold mixture is allowed to stir under nitrogen at -50° for 4 hr and is then warmed slowly to RT over a period of 24 hr. Ether and water are added, and the organic layer is separated, washed with water, dried over calcium sulfate and solvent is removed under vacuum. The residue is purified by chromatography on silica gel, giving methyl 3-phenylthio-2,2-dichlorocyclopropanecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=O)=[CH:11][CH:10]=1)#[N:2].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Product: COC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 28 %

Procedure:
A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated and the resulting residue was poured into ice-water. The mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals, which were recrystallized from chloroform--methanol to afford colorless needles (2.2 g, 28%), m.p. 154-157° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:29]=[N:30][CH:31]=[C:32]([OH:34])[CH:33]=1.[F:35][C:36]([F:40])([F:39])[CH2:37]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:29]=[N:30][CH:31]=[C:32]([O:34][CH2:37][C:36]([F:40])([F:39])[F:35])[CH:33]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(O)c3)n(-c3ccccc3)c(=O)c12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(OCC(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of (S)-2-(1-((6-amino-5-(5-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (49 mg, 0.11 mmol), 1,1,1-trifluoro-2-iodoethane (13 μl, 0.13 mmol) and potassium carbonate (30 mg, 0.22 mmol) in N,N-dimethylformamide (3 ml) was stirred at 120° C. under microwave irradiation for 2 h. Further 1,1,1-trifluoro-2-iodoethane (13 μl, 0.13 mmol) and potassium carbonate (15 mg, 0.11 mmol) were added and the reaction mixture was stirred at 120° C. under microwave irradiation for 2 h. The residue was purified by reverse phase using SP1® Purification System to give 32 mg (55% yield) as a solid. Purity 100%.
Reaction SMILES: [CH:1]([N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][C:11]([CH3:14])=[CH:12]2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2].[S]>C1C2C(CCCC2)CCC1.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2]
Reactant: CC1=CC2C(CC1)C(c1ccc(F)cc1)=NC(=O)N2C(C)C
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(-c3ccc(F)cc3)nc(=O)n(C(C)C)c2c1
Reaction time: 1 h

Procedure:
17.4 g 1-isopropyl-4-(4-fluorophenyl)-7-methyl-4a,5,6,8a-tetrahydro-2(1H)-quinazolinone are dissolved under heating in 50 ml decaline and treated portionwise at 140° with 4 g powdered sulphur. On completion of the addition stirring is continued for 1 hour at 160°. The mixture is diluted with toluene and extracted several times with 15% hydrochloric acid. The acidic phase is treated with methylene chloride and neutralized under ice cooling with sodium hydroxide solution. The water phase is extracted with methylene chloride and the combined methylene chloride extracts concentrated in vacuo. The concentrate is chromatographed on silica gel using dichloromethane and methanol as eluant. After recrystallisation from toluene the title compound is obtained, m.p. 174°-176°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:25](Br)[CH2:26][OH:27]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][OH:27])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(c2ccc(F)cc2)CC1
Yield: 79 %

Procedure:
To a mixture of 1-(4-fluorophenyl)piperazine (7.24 g), potassium carbonate powder (13.9 g) and N,N-dimethylformamide (30 ml) was added dropwise ethylene bromohydrin (10.0 g) under stirring. The mixture was stirred at room temperature for 3 hours, diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: hexane-ethyl acetate (1:3)] to give 7.12 g (79.0%) of 4-(4-fluorophenyl)-1-piperazineethanol as an oil. IR(Neat): 3150 cm-1. NMR (CDCl3)δ: 2.47-2.80(6H, m), 2.97-3.20(4H, m), 3.10(1H, s), 3.65(2H, t, J=5.5), 6.71-7.13(4H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A solution of the compound of Example 67, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.47 g, 5.14 mmol) in 40 mL 1-methyl-2-pyrrolidinone was treated with triethylamine (1.43 mL, 10.3 mmol). With vigorous stirring, the solution was treated dropwise with benzoyl chloride (0.597 mL, 5.14 mmol). After 18 h, the reaction was concentrated. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave a clear, colorless oil. The oil was triturated in ether and filtered to yield 531 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}benzamide as a white solid. mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ8.37 (t, J=7.0 Hz, 1 H), 8.05 (d, J=7.6 Hz, 1 H), 7.78-7.75 (m, 2 H), 7.61 (dd, J=1.1, 8.3 Hz, 1 H), 7.54-7.37 (m, 4 H), 7.21-7.16 (m, 1 H), 6.55 (s,2 H), 4.70 (t, J=5.0 Hz, 2 H), 3.90 (t, J=5.0 Hz, 2 H), 3.49 (t, J=6.1 Hz, 2 H), 3.34 (t, J=5.7 Hz, 2 H), 2.59 (s, 3 H); 13C NMR (75 MHz, DMSO-d6) δ166.7, 152.0, 151.1, 145.1, 134.8, 132.8, 131.4, 128.6, 127.4, 126.6, 121.3, 120.4,115.1, 69.4, 69.3, 45.8, 14.1; MS m/z 390 (M+H)+; Anal. Calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C, 67.56; H, 5.81; N, 17.87.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Cc1cc2cc(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(CC(C)C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a mixture of 10 g of 6,7-dichloro-5-hydroxy-2-isobutylbenzo[b]thiophene and 200 ml 2-butanone is added a mixture of 6.9 g of ethyl bromoacetate in 50 ml of 2-butanone and by 6.6 g of potassium carbonate and 3.4 ml sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and 100 ml of ether. The organic layers are combined, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 12 g of ethyl[(6,7-dichloro-2-isobutylbenzo[b]-thien-5-yl)oxy]acetate, mp 75°-76°.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]>CN(C)C=O>[CH3:6][O:5][CH2:4][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1ccccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1C(C)=O
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
In N,N-dimethylformamide (25 mL) was dissolved 3.39 g (24.9 mmol) of commercially available 1-(2-hydroxyphenyl)-ethanone, 1.52 g (38.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and the resulting mixture was stirred in an ice bath for 20 minutes. To the mixture was gradually added dropwise 3.00 mL (39.5 mmol) of chloro(methoxy)methane, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.33 g (24.1 mmol, Yield: 96.8%) of 1-[2-(methoxymethoxy)phenyl]ethanone.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][C:10]#[CH:11])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:17]CCC.CI>C1COCC1>[C:1]([Si:5]([CH3:14])([CH3:15])[O:6][C@H:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: C#CCC[C@@H](C=C)O[Si](C)(C)C(C)(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: C=C[C@H](CCC#CC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
Compound (4a) (481.6 mg, 2.146 mmol) was dissolved in THF (21.5 mL) and cooled to −78° C. before treated with 1.6 M n-BuLi (2.7 mL, 4.32 mmol) dropwise. The resulting solution was stirred 15 minutes at the same temperature and then methyl iodide (0.67 mL, 1.528 g, 10.765 mmol) was added. During the night the mixture was slowly warmed to room temperature. After 13 hours the reaction was quenched with water. The solution was extracted with ether (3×), the combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by chromatography (pentane/ether 200/1) provided 395.5 mg of compound (5a) as clear colourless oil with 77% yield.
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: O=C=NCCCl
Reactant: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
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).