Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.ClCCl>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:24])(=[O:21])=[O:20]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNc1cc(C(=O)OCC(=O)N(CC)CC)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 95 °C
Yield: 63.6 %

Procedure:
Bumetanide (1.2 g, 3.29 mmol) was dissolved in dimethylformamide (12 mL) and 2-chloro-N,N-diethylacetamide (500 mg, 3.35 mmol) was added followed by triethylamine (0.68 mL) and sodium iodide (500 mg 3.33 mmol). The reaction was heated to 95° C. for 8 hours, at which time TLC and LC/MS indicated the reaction was complete. The reaction was cooled to room temperature brought up in dichloromethane and washed with water, saturated ammonium chloride and reduced to a thick slurry. To the slurry was added water (25 mL), and the resultant solids precipitated from the solution. The product was filtered and dried in a vacuum oven at 50° C. for 12 hours to yield 1.0 g of N,N-diethylaminocarbonylmethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[CH:19]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:17]=[C:16]3[C:11]=2[N:12]=[CH:13][CH:14]=[N+:15]3[O-])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:28]=P(Cl)(Cl)Cl>>[CH:1]1([NH:6][S:7]([C:10]2[C:11]3[N:12]=[CH:13][C:14](=[O:28])[NH:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ncc[n+]([O-])c2c1
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ncc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(N-cyclopentylsulfamoyl)-7-(3,5-dimethylisoxazol-4-yl)quinoxaline 1-oxide was dissolved in POCl3 and heated to reflux for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure and dissolved in acetic acid (4 ml). Sodium acetate (100 mg) was added and the solution stirred for 4 hours. Volatiles were removed under reduced pressure and the crude product was purified by preparatory HPLC (5-95% MeCN/H20, 0.1% TFA) to afford the product as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([F:25])=[CH:17][CH:16]=2)=[C:5]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:4]2[O:3][C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH3:26])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCc1nc(Cl)oc1-c1ccc(F)c2ccccc12
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCc1nc(-n2ccnc2C)oc1-c1ccc(F)c2ccccc12
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-chloro-5-(4-fluoro-1-naphthyl)-4-oxazolebutanoate (700 mg), 2-methylimidazole (821 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanoate was obtained as an oil (675 mg, 77%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH3:31]>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Product: CCCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 38 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and 1-bromopropane. Yield: 38%. MS M+H calculated 409.19; found 409.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:9]=[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[OH:16]
Reactant: O=Cc1ccccn1
Reactant: Nc1ccccc1O
Solvent: CCO
Solvent: CC(=O)O
Product: OC1C=CC=CC1=NCc1ccccn1
Reaction time: 12 h
Yield: 100 %

Procedure:
200 μl (2 mmol) of 2-pyridinecarboxaldehyde (reagent 1) and 220 mg (2 mmol) of 2-aminophenol (reagent 2) were dissolved in 10 mL of dry ethanol. One drop of glacial acetic acid was added and the reaction mixture was stirred during 12 h. The solution was filtered on paper and the filtrate was evaporated to dryness. After a chromatography on silica gel (CH2Cl2, 100 ml then AcOEt 200 ml), 394 mg of ligand L1 were obtained as orange solid with a yield of 100%.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]([CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[CH3:13].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH2:10]([N:5]1[C:4](=[O:12])[C:3]([CH3:13])=[C:2]([O:1][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[N:7]=[C:6]1[S:8][CH3:9])[CH3:11]
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Reactant: CCn1c(SC)nc(O)c(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCn1c(SC)nc(OCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.4 %

Procedure:
In 10 ml of hexamethylphosphoric triamide were dissolved 1 g of 6-hydroxy-3-ethyl-5-methyl-2-methylthio-4(3H)-pyrimidinone and 1.66 g of 4-(4'-trifluoromethylphenoxy)benzyl bromide and thereto was added 0.3 g of sodium hydride (55% in mineral oil). The mixture was stirred for 15 hours at room temperature. The resulting solution was poured into 50 ml of water and then extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 2.1 g of crystals. The crystals were recrystallized from a mixture of hexane and ethyl ether (3:1 ) to give 0.6 g of the intended product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.O>CO.O1CCCC1>[C:9]([O:8][CH2:7][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCCC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(COC(C)=O)COC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)OCCC(CCC1(CCO)CCCCC1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(acetoxymethyl)-2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane (340 mg) in methanol (5 mL) and tetrahydrofuran (3 mL) was added 3N hydrochloric acid (2.0 mL) at room temperature. After stirring the solution at room temperature for 5.5 hours, water was added thereto. The solution was concentrated under reduced pressure to distill off methanol and tetrahydrofuran, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=4:6) to give the title compound (110 mg).
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([CH2:10][CH3:11])[CH:4]=1.II.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20]>O1CCCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:19]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[OH:20])=[C:5]([CH2:10][CH3:11])[CH:4]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: O=Cc1ccco1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(O)c1ccco1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Magnesium turnings (1.16 g, 0.048 mol) are stirred under a nitrogen atmosphere for 30 minutes, followed by dropwise addition of 4-bromo-2-ethyl-1-iodobenzene (15.0 g, 0.048 mol) as a solution in anhydrous tetrahydrofuran (40 ml), until the magnesium is just covered. A crystal of iodine is added and the reaction heated to reflux. After initiation begins external heating is stopped and the remaining aryl halide solution is added at such a rate as to maintain a controlled reflux. Once addition is complete the reaction is heated at reflux for 1 hour and the mixture is then cooled to room temperature. A solution of furan-2-carbaldehyde (4.0 ml, 0.048 mol) in anhydrous tetrahydrofuran (10 ml) is then added dropwise, and the suspension is then stirred at room temperature for 20 hours. The reaction is quenched with saturated ammonium chloride (200 ml) and extracted with ethyl acetate (200 ml). The organic phase is separated, dried over anhydrous magnesium sulfate then evaporated under reduced pressure. The crude product is purified by flash column chromatography (1:4 ethyl acetate/hexane eluant) to afford (4-bromo-2-ethyl-phenyl)furan-2-yl methanol as a brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH:25][C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:21]([C:17]1[N:16]([C:11]2[C:12]([O:14][CH3:15])=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:36]#[N:37])[CH2:27][C:26](=[O:38])[NH:25][C:9]=3[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1-n1cccc1C(C)(C)C)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {4-(2-tert.-butyl-pyrrol-1-yl)-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-methoxy-phenyl}-carbamic acid tert.-butyl ester (Example M19) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (22 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH:32][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:27][CH:26]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Product: CC(=O)N1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)CC1

Procedure:
The title compound was prepared from 1-[4-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-piperazin-1-yl]-ethanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 434 (MH+); HPLC Rf: 3.52; HPLC purity: 99%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-:12].[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][OH:12])=[C:9]([CH:10]=1)[C:8]([OH:7])=[O:11]
Reactant: O=C1OCc2ccc(F)cc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)ccc1CO
Yield: 78.1 %

Procedure:
To a solution of 6-fluoroisobenzofuran-1(3H)-one (0.549 g, 3.61 mmol) in methanol (12 mL) and water (3 mL) at room temperature was added potassium hydroxide (0.350 g, 6.24 mmol). The mixture was heated at reflux for 1.5 hr. The mixture was concentrated under vacuum to a volume of about 3 mL. The residue was acidified with 1 M KHSO4 solution to pH 3-4. The insoluble material (inorganic salt) was removed by suction filtration and the filtrate was extracted with ethyl acetate (5×30 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.479 g, 2.82 mmol, 78% yield) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(OC(F)(F)F)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-5-trifluoromethoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-5-trifluoromethoxybenzaldehyde. Mass spectrum (ES) MH+=371.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.CO.O.O.[OH-].[Li+]>C1COCC1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1ccccc1-c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
Crude 4′-tert-butylbiphenyl-2-carboxylic acid ethyl ester (33 g, ˜117 mmol) was taken up in a mixture of THF (100 mL), methanol (50 mL) and water (40 mL). Lithium hydroxide monohydrate (7.36 g, 176 mmol) was added and the reaction mixture was allowed to stir at room temperature for 3 days. The mixture was extracted three times with diethyl ether. The aqueous phase was then acidified using aq. 6N HCl and extracted three times with EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated. The solid residue was triturated with hexane to afford the title compound as a white solid (18.7 g, 63%). 1H NMR (selected signals, DMSO-d6): 7.66 (dd, 1H), 7.53 (m, 1H), 7.41 (d, 2H), 7.25 (d, 2H), 1.29 (s, 9 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]2=[O:29])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[CH:19][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[C:21]1=[O:29])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(OCc2ccccc2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c3ncccc23)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 3-(8-benzyloxyquinol-5-ylmethylen)-2-oxindole (140 mg, 0.37 mmol) in acetone (10 ml) was added 2-bromoacetic acid ethyl ester (151 mg, 0.9 mmol) and anhydrous potassium carbonate (150 mg) and the reaction mixture was stirred for 8 h at 50° C. Then the mixture was concentrated under vacuum, the residue taken up with dichloromethane, the organic phase washed several times with water, dried and evaporated. The residue was crystallized from ethyl acetate to give 150 mg (87% yield) of title compound.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.CCOCC>[N:27]([CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26])=[N+:28]=[N-:29]
Reactant: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CN=[N+]=[N-])c1
Reaction time: 24 h
Yield: 94.4 %

Procedure:
To a stirred solution of 187 mg (0.5 mmol) of the compound obtained from Example 9 in 5 ml of DMF was added 98 mg (1.5 mmol) of sodium azide at room temperature. After 24 hours, the reaction mixture was diluted with ether, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a yellow oil, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 180 mg (yield 94%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=1)[O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:22]=[C:23]([NH2:25])[S:24][CH:2]=2)=[C:6]([CH3:21])[CH:7]=1
Reactant: Cc1cc(C)cc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(C)cc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)c1
Yield: 59 %

Procedure:
A mixture of 2-bromo-1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (8.15 g, 23.5 mmol) and thiourea (1.79 g, 23.5 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (4.50 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 6.76 (s, 1 H), 6.68 (s, 2 H), 6.64 (s, 2 H), 6.26 (s, 1 H), 2.29 (s, 6 H), 2.16 (s, 6 H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([OH:7])=O.[NH2:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:27]([O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C:16]([C:27]([O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:7]
Reactant: CO/N=C(\C(=O)O)C(=O)CCl
Reactant: C[Si](C)(C)CCOCOC(=O)C1=C(CSc2cnns2)CS[C@@H]2C(N)C(=O)N12
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CO/N=C(/C(=O)CCl)C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOCC[Si](C)(C)C)=C(CSc3cnns3)CS[C@H]12
Yield: 20.7 %

Procedure:
A solution of 4-chloro-2-(Z)-methoxyimino-3-oxo-butanoic acid (2.17 g, 4.77 mmol.), 2-(trimethylsilyl)ethoxymethyl 7-amino-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate (0.85 g, 4.77 mmol.), and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1.18 g, 4.77 mmol.) in 40 ml of methylene chloride was stirred at room temperature for 3 hours then worked up as described in Example 6 to afford 0.615 g of the ester. NMR (CDCl3) δ0.03 [S, 9H, --Si(CH3)3 ], 0.97 (t, 2H, J=7.5 Hz, --CH2Si--), 3.62 (pair of d, 2H, J=18 Hz, endocyclic --CH2S--), 3.75 (m, 2H, --OCH2 --), 4.17 (pair of d, 2H, J=3 Hz, exocyclic --CH2S), 4.18 (S, 3H, --OCH3), 4.63 (S, 2H, --ClCH2 --), 5.07 (d, 1H, J=4.9, 6H of 7ACA), 5.38 (pair of d, 2H, J=6.0 Hz, --OCH2O), 5.87 (dd, 1H, J=4.9 and 8.5 Hz, 7H of 7ACA), 7.22 (d, 1H, J=8.5 Hz, --NH--), 8.52 (S, 1H, thiadiazole H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO.O>CCCCCC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: Brc1ccc2c(c1)CNCC2
Yield: 59.6 %

Procedure:
A mixture of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydoisoquinoline (G. E. Stokker, Tetrahedron Letters 1996, 37, 5453) (43.4g, 0.14 mol), potassium carbonate (104.3g, 0.75 mol), methanol (1 L) and water (150ml) was heated at reflux for 1 h, then cooled and evaporated in vacuo. Residue was partitioned between water (1 L) and dichloromethane (4×200 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was dissolved in hexane. The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as an oil (17.7 g, 60%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C[C@@H]1CCCN1)[C:13]1C=CC=CC=1.CCOCC.C[Mg]I.[Cl-].[NH4+]>C1C=CC=CC=1>[OH:9][C@:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[CH:10]=[O:11]
Reactant: O=CC(=O)c1ccccc1
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C[C@@](O)(C=O)c1ccccc1
Temperature: -70 °C
Yield: 66.8 %

Procedure:
In 15 ml of benzene, were dissolved 714 mg of phenylglyoxal monohydrate and 828 mg of (S)-2-(anilinomethyl)pyrrolidine. The resulting solution was refluxed for one hour while removing the formed water by azeotropic distillation. Benzene was removed by distillation in vacuo and the residue was dissolved in 20 ml of ether. To the resulting solution cooled to -70° C., was added dropwise 1.5 equivalents of an ether solution of methylmagnesium iodide. After having been allowed to react for one hour at -70° C., the solution was admixed with 4 ml of saturated aqueous ammonium chloride solution and brought to room temperature. After separating the ether layer, the aqueous layer was neutralized with saturated aqueous sodium hydrogencarbonate solution and then extracted with ether. The ether layer was combined with the previously separated ether layer, admixed with 30 ml of 2% hydrochloric acid and allowed to react for 12 hours at 0° C. The ether layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the ether by distillation in vacuo, the residue was purified by means of a silica gel column chromatography to obtain 471 mg (67%) of (S)-(+)-2-hydroxy-2-phenylpropionaldehyde. [α]D =+244° (C=1.138, benzene); optical yield was 95%. The optical yield was determined by converting the substance into methyl atrolactate methyl ether of known optical rotation.