Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([O:21]C)=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>C1COCC1.O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([OH:21])=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 98.3 %

Procedure:
A solution of methyl 1-(4-bromobenzyl)-5-methoxy-2-methylindole-3-acetate (10 g, 24.9 mmol) and KOH (1.7 g, 30 mmol) in 45 mL of THF, 5 mL of H2O, and 2 mL of methanol was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. and neutralized with concentrated HCl. The solvent volume was reduced by rotary evaporation. The precipitate was collected and washed with H2O. The white solid was dried in a vacuum oven to give 9.5 g (98%) of the carboxylic acid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:17]([CH3:18])=[C:16]([Cl:19])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10](O)=[O:11]>>[Cl:5][C:6]1[C:17]([CH3:18])=[C:16]([Cl:19])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10]([Cl:3])=[O:11]
Reactant: Cc1c(Cl)ccc(OC(C)C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Product: Cc1c(Cl)ccc(OC(C)C(=O)Cl)c1Cl
Yield: 106.2 %

Procedure:
Thionyl chloride (17.9 g; 0.15 mole) was added to 12.5 g (0.05 mole) of 2-(2,4-dichloro-3-methylphenoxy)-propionic acid, and the mixture was heated under reflux for 3 hours. The excess of thionyl chloride was distilled off from the reaction mixture to give 14.2 g of crude 2-(2,4-dichloro-3-methylphenoxy)propionyl chloride. A solution of 14.2 g of the crude chloride in 50 ml of diethyl ether was added dropwise to a mixture of 4.65 g (0.05 mole) and 40 g (0.05 mole) of a 5% aqueous solution of sodium hydroxide with stirring over the course of 15 minutes. The mixture was then stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water and dried. Recrystallization from hexane yielded 10.7 g of the desired product as colorless needles. Yield: 66.0%; melting point 147.5 to 148.0° C.
Reaction SMILES: ClCCl.[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].[Na+].[Cl-]>C(N(CC)CC)C>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: OCc1ccc(O)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
300 ml of dichloromethane followed by 60 g of triethylamine are added to 30 g of 4-hydroxymethyl-phenol introduced into a 500 ml flask maintained under a hydrogen atmosphere. The temperature of the obtained solution is brought to 10° C. and 64 g of trimethylsilyl chloride are added thereto in about one hour, keeping the temperature at 10° C. Thus, the temperature is left to spontaneously rise to 25° C., maintaining such conditions for one hour. Then, the reaction of the substrate is controlled under TLC. Upon ascertaining the disappearance of the initial product, 200 ml of an aqueous saturated NaCl solution are added and the two-phase system is stirred vigorously for 10′ and then the two phases are decanted. The lower organic phase is washed with two 200 ml portions of deionised water and then concentrated to residue, obtaining a yellowish oil. Such residue is recovered using 500 ml of DMF in a 2-liter flask and a solution constituted by 3 g of Lithium acetate in 60 ml of water is added to the obtained solution. The mixture is maintained at 25° C. for one hour, then the removal of the trimethylsilyl group on the phenolic hydroxyl is controlled under TLC. Then, 650 ml of a saturated NaCl solution and 455 ml of toluene are added to the reaction mixture and the mixture is stirred vigorously for 10′, then the two phases are left to decant. The upper organic phase is then washed with two 650 ml portions of deionised water and concentrated under vacuum, obtaining 33 g of the desired product (70% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(N(C(C)C)CC)(C)C>[I-].[K+].O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[CH3:14])=[O:4])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: COc1ccc(C)c(NC(=O)CCl)c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)c(NC(=O)CNc2ccc(F)c(Cl)c2)c1
Yield: 86.7 %

Procedure:
2-Chloro-N-(5-methoxy-2-methylphenyl)-acetamide (3 g), 3-chloro4-fluoroaniline (7.56 g), diisopropylethylamine (13.8 ml), potassium iodide (0.005 g) and anhydrous tetrahydrofuran (20 ml) were heated together at 105° C. in a sealed tube for 19 hours. The mixture was then cooled and concentrated. Purification of the residue by silica gel chromatography (eluting with 1:1 iso-hexane/ethyl acetate) gave the sub-title compound (3.93 g).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].Cl.C(=O)([O-])[O-].CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH:39][CH2:28][C@H:26]([OH:27])[CH2:25][O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:31][CH3:32])[N:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=3)[O:16][N:15]=2)=[CH:18][C:19]=1[CH2:29][CH3:30])[CH3:35]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC[C@H](O)COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Yield: 9.7 %

Procedure:
A solution of (S)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-3-(3-ethyl-5-methyl-4-(oxiran-2-ylmethoxy)phenyl)-1,2,4-oxadiazole (500 mg, 1.15 mmol), glycine ethylester hydrochloride (320 mg, 2.30 mmol), of which the hydrochloride was removed by filtration over a carbonate loaded silica resin prior to use, and DIPEA (0.2 mL) in methanol (3 mL) is stirred at 60° C. for 3 days. The mixture is diluted with DCM and washed with sat. aq. NaHCO3 solution. The aq. phase is extracted once with DCM. The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. TLC using DCM:methanol 9:1 to give (S)-2-((3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-2-hydroxypropyl)amino)acetic acid ethyl ester (60 mg) as a white solid; LC-MS: tR=1.03 min, [M+H]+=537.29.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.7 %

Procedure:
The procedure described in Example 2 was followed, using 1.4 g of 4-n-butylphenyl isocyanate, 3.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 0.8 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (25% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 252°-254° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:25](=[O:27])=[O:26].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:25]([OH:27])=[O:26]
Reactant: COc1ccc(F)cc1
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(=O)O)c1
Temperature: 0 °C
Yield: 40 %

Procedure:
Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled solution (−78° C.) of 2,2,6,6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the temperature below −70° C. The mixture was maintained at this temperature for 12 h, and then dry CO2 gas was passed into the solution. The resulting mixture was allowed to warm up to 0° C. and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide (1 M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40%) as a white solid. MS m/e=168.9 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-:10].[K+].[CH2:12]=O.Cl>O>[F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[C:7]=1[CH2:12][OH:10]
Reactant: Oc1cc(F)cc(F)c1
Reactant: [OH-]
Reactant: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: OCc1c(F)cc(O)cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
A mixture of 3,5-difluorophenol (25 g, 0.19 mol) and KOH (85%, 12.7 g, 0.19 mol) was treated dropwise with water (50 mL), stirred at 60° C. for 1 h, treated dropwise with formaldehyde solution (37%, 15.6 mL, 0.19 mol) and water (50 mL) and stirred overnight at 40° C. The mixture was cooled, acidified with 6-M HCl, filtered and the resulting solid washed with water and dried to give the title compound (15 g, 49%) as a white solid: NMR δH (400 MHz, DMSO) 10.28 (1H, s), 6.43 (2H, m), 4.99 (1H, t, J 5.6 Hz) and 4.37 (2H, d, J 5.6 Hz).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCCl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:19]=[CH2:1])[CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a flame dried 500 mL 3-neck flask under an atmosphere of argon, was charged methyltriphenylphosphonium bromide (43.8 mmol) dissolved in anhydrous THF (120 mL), followed by the dropwise addition of n-butyllithium (21.9 mL, 35.04 mmol). The dark red mixture was stirred at ambient temperature for 1 h. Next 5-benzyloxy-2-hydroxybenzaldehyde (2.0 g, 8.76 mmol) (Acta. Chem. Scand., Ser. B, B40(5), 400-1, (1986) was added followed by the addition of anhydrous dichloromethane (40 mL). The mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and water (500 mL each). The organic layer was washed with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified using the Biotage FlashElute chromatography system using a 65M normal phase cartridge, eluting with 15% EtOAc/Hexanes to give a yellow solid (1.75 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.30, (m, 4H), 7.14 (d, J=2.9 Hz, 1H), 6.94-6.87 (m, 1H), 6.79 (dd, J=8.8, 2.9 Hz, 2H), 6.72 (d, J=8.8 Hz, 1H), 5.71 (dd, J=17.6, 1.5 Hz, 1H), 5.35 (dd, J=11.2, 0.98 Hz, 1H), 5.02 (s, 2H), 4.60 (s, 1H); MS (FIA) m/e 227 (M+1).
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[CH:25](=[S:27])[NH2:26]>C1COCC1>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:26]=[CH:25][S:27][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: NC=S
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3scnc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.7 %

Procedure:
To a solution of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.60 g, 1.5 mmol, Preparation #A.2) in THF (25 mL) was added methanethioamide (0.19 g, 3.0 mmol, prepared according to Euro. J. Med. Chem., 2004, 39, 867-872). The reaction mixture was stirred at ambient temperature for about 15 h. The solvent was removed under reduced pressure. The crude material was purified by silica gel flash chromatography using DCM/MeOH (gradient, 100:0 to 95:10). This residue was then repurified by silica gel flash chromatography using DCM/ACN (gradient, 90:10 to 0:100). The residue was dissolved in Et2O and solvent removed under reduced pressure to give a yellow solid. The solid was dried overnight under high vacuum to afford the title compound (0.095 g, 17%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.39 min; MS m/z: 358.2 (M+H.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[CH:27][C:28]=1[F:29].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:25]5[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(F)c(F)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,4-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (60 ml), washed with water and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (85 mg) as a white solid.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.C>CS(O)(=O)=O.C(O)CC>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)O
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
A solution of 10.3 gm. of N-isopropyl-(3,4-methylenedioxyphenyl)urea, 7.1 ml. of benzaldehyde, and 3 drops of methanesulphonic acid in 250 ml. of toluene is refluxed under a water separator for 21 hours. The cooled solution is then washed with 200 ml. of water, dried and evaporated to yield a powder. This product is decolorized in hot propanol with a small amount of activated charcoal and recrystallized from propanol to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 169°-172°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:8]=1)[NH2:7].Cl.[CH2:20]([O:22][C:23](=[O:29])[CH:24]([Cl:28])C(C)=O)[CH3:21].[N:30]([O-])=O.[Na+].CC([O-])=O.[Na+]>CC(O)=O.O>[Cl:28]/[C:24](=[N:30]/[NH:7][C:6]1[CH:8]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)/[C:23]([O:22][CH2:20][CH3:21])=[O:29]
Reactant: Nc1cc(F)ccc1OC/C=C/c1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(Cl)=N\Nc1cc(F)ccc1OC/C=C/c1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
5-Fluoro-2-{[(2E)-3-phenylprop-2-enyl]oxy}aniline (5-2, 2.19 g, 9.0 mmol) was suspended in a 1.2 N solution of HCl in 60% aq. AcOH (18 mL) and treated with ethyl-2-chloroacetoacetate (3.7 mL, 27 mmol). The mixture was cooled to −5° C. in a NaCl/ice bath and a 1.4 M solution of NaNO2 (12.6 mmol) in water was added dropwise under vigorous stirring. Upon completion of the addition, the mixture was adjusted to pH=4 with NaOAc and stirred to 25° C. for 2 h. The organics were extracted with CH2Cl2 (3×50 mL), dried (Na2SO4) and evaporated under reduced pressure. The crude was recrystallized from EtOAc/hexanes to give ethyl (2E)-chloro[(5-fluoro-2-{[(2E)-3-phenylprop-2-enyl]oxy}phenyl)hydrazono]ethanoate (5-3) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.32 (m, 5H), 6.87 (dd, J=9.0, 4.7 Hz, 1H), 6.79 (d, J=15.9 Hz, 1H), 6.64 (app dt, J=8.3, 2.9 Hz, 1H), 6.40 (app dt, J=15.9, 5.5 Hz, 1H), 4.76 (d, J=5.2 Hz, 2H), 4.39 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H); MS (M+H+, C19H18ClFN2O3) 377.1 found 377.8 required.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](Cl)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>[Cl-].[Na+].O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C1CCNC1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N3CCCC3)CS[C@H]12
Reaction time: 1 h

Procedure:
To a solution of 0.988 g. (2 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate in 10 ml. of dry DMF maintained at ice-bath temperature were added 0.375 ml. (4.4 mmole) of pyrrolidine. The reaction mixture was allowed to stir for about one hour and the mixture was then diluted with brine and ethyl acetate. The ethyl acetate was washed with brine several times and dried over magnesium sulfate. Evaporation of the dried extract gave 845 mg. of product.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
1,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1-naphthaldehyde (6 g, 35 mmoles) and potassium carbonate (24 g, 175 mmoles) in DMF (110 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 8.5 g (88%) of 4-(2-bromoethoxy)-1-naphthaldehyde as a solid. M.p.: 83-84° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N:12]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH:21]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH:21]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2oc(N3CCN4CCC3CC4)nc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Yield: 80.9 %

Procedure:
10% Palladium on carbon (300 mg) was added to a solution of 4-(5-nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (288 mg, 1 mmol, prepared as in Example 21) in ethanol (5 mL) and subjected to hydrogen gas at 50 PSI at RT for a period of 16 h. The reation mixture was diluted with ethanol (20 mL) and filtered through a pad of celite. Concentration in vacuo gave 209 mg of the title compound as a brown oil: 1H NMR (CD3OD, 400 MHz) δ 7.06 (d, 1H, J=8.3 Hz), 6.75 (d, 1H, J=1.3 Hz), 6.50 (dd, 1H, J=8.3, 1.3 Hz), 4.56 (br s, 1H), 4.08 (br s, 2H), 3.62-3.47 (m, 6H), 2.34-2.31 (m, 2H), 2.20-2.16 (m, 2H); MS (Cl) m/z 259.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:31][CH2:30]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3cccc(OC)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-methoxyphenyl)-piperazine.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]=[CH:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:20](Br)[CH:21]=[CH2:22].N>C1COCC1>[CH2:22]([CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH:9]=[CH:8][CH2:7][CH:3]12)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=C1CC2CC=CC2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1C(=O)OC2C=CCC21

Procedure:
Analogously to the procedures of Example 1, the title compound was prepared from 0.31 g (2.5 mmol) of 3,3a,4,6a-tetrahydro-cyclopenta[b]furan-2-one, 2.5 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.36 g (2.5 mmol) of allyl bromide in 7 ml of THF. Yield: 278 mg (67.8%) of a colourless oil. MS (DCI/NH3): m/e=182 [M+NH4+]