Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[CH:10]1[C:16](=[O:17])[CH:15]2[CH2:18][CH:12]([CH2:13][CH2:14]2)[C:11]1=[O:19])[CH3:2].[Cl-].[Li+].C([Mg]Cl)(C)C.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1.ClCCl>[O:17]=[C:16]1[CH:10]([C:4]2[CH:5]=[C:6]([B:27]([OH:30])[OH:28])[CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:11](=[O:19])[CH:12]2[CH2:18][CH:15]1[CH2:14][CH2:13]2
Reactant: COB(OC)OC
Reactant: CCc1ccc(I)cc1C1C(=O)C2CCC(C2)C1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(B(O)O)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a solution of 3-(2-ethyl-5-iodophenyl)bicyclo[3.2.1]octane-2,4-dione (0.65 g, 1.77 mmol) in anhydrous tetrahydrofuran (15 ml) at −10° C. is added iso-propyl magnesium chloride lithium chloride complex (10.6 ml, 10.6 mmol, 1M in tetrahydrofuran) dropwise over 10 minutes. The reaction mixture is stirred at this temperature for 1.5 hours, then cooled to −78° C., at which point trimethyl borate (1.39 ml, 12.4 mmol) is added dropwise to maintain a temperature below −60° C. After re-cooling to −78° C. the mixture is further stirred for 5 minutes, then additionally at room temperature for 1 hour. The solution is quenched with 2M hydrochloric acid and extracted with ethyl acetate (×3). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give an orange-coloured gum. This crude product is dissolved in a minimum amount of dichloromethane then precipitated with iso-hexane to afford 3-(2,4-dioxo-bicyclo[3.2.1]oct-3-yl)-4-ethylphenylboronic acid (0.46 g, 90%) as a cream-coloured solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([NH:15][NH2:16])=[O:14])[CH:12]=[C:6]2[C:5]=1[NH:17][C@@H:18]1[CH2:22][CH2:21][C@@:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[C:19]1([CH3:33])[CH3:32])(=[O:3])[NH2:2].[C:34](N1C=CN=C1)(N1C=CN=C1)=[S:35].[CH3:46]CN(CC)CC.CI>C1COCC1>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:46]([S:35][CH3:34])=[N:16][N:15]=3)[CH:12]=[C:6]2[C:5]=1[NH:17][C@@H:18]1[CH2:22][CH2:21][C@@:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[C:19]1([CH3:33])[CH3:32])(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C1(C)C
Reactant: CCN(CC)CC
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A solution of tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (3.29 g, 7.16 mmol) and 1,1′-thiocarbonyldiimidazole (1.659 g, 9.31 mmol) in THF (25 mL) was heated to 70° C. for 2 hrs. The reaction mixture was added Et3N (2.59 mL, 18.61 mmol) and MeI (0.582 mL, 9.31 mmol) and stirred at RT for 16 hrs which was concentrated and added 150 mL of water which was stirred for 30 minutes. The solid was collected to give the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (2.35 g, 64% yield). LC/MS (M+H)+=516.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([CH3:28])[C:25]([O:26][CH3:27])=[C:17]([CH3:16])[CH:18]=2)=[CH:7][N:6]=1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C)cc(C(=O)Nc2cnc(Cl)nc2Cl)cc1C
Yield: 118.5 %

Procedure:
A solution of 3.2 g of 5-amino-2,4-dichloropyrimidine in 50 ml of ethyl acetate was added to a mixture of 25 ml of a saturated aqueous solution of sodium hydrogencarbonate and 25 ml of water. A solution of 4.9 g of 3,5-dimethyl-4-methoxybenzoyl chloride was added at room temperature over a period of 15 min, and the mixture was mixed intensively for 4 h. Then the layers were separated and the aqueous layer was extracted twice with ethyl acetate. After drying over sodium sulfate and filtration the solvent was removed in vacuo to give 7.54 g of raw product. The raw product was triturated with 25 ml of isopropanol. After filtration and washing with 10 ml of isopropanol 2.74 g of the title compound were obtained as a white solid.
Reaction SMILES: [C:1]([O:6]C([O-])=O)(=O)[O:2][CH2:3][CH3:4].[NH2:10][C:11]([NH2:13])=[O:12]>C(Cl)(Cl)Cl>[C:1]([NH:10][C:11](=[O:12])[NH2:13])([O:2][CH2:3][CH3:4])=[O:6]
Reactant: CCOC(=O)OC(=O)[O-]
Reactant: NC(N)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(N)=O
Reaction time: 48 h

Procedure:
0.65 ml (0.72 g, 0.00443 moles) of ethyl pyrocarbonate are added to a solution of 1.0 g (0.00285 moles) of 1-(1',3'-bis/2",6"-dimethylphenyl/-4'-methyl-imidazolidine-2'-ylidene)-urea, prepared as described in Example 72, in 10 ml of dry chloroform, and the mixture is allowed to stand at room temperature for 48 hours. Thereafter the solvent and the excess of the reactant are distilled off under reduced pressure. The oily residue is dissolved in 10 ml of diethyl ether, the insolubles are filtered off, and the filtrate is concentrated to a final volume of about 2 ml. Next day the separated crystalline product is filtered off, washed with a small amount of diethyl ether and dried. 0.5 g (41.7%) of 1-(1',3'-bis/2",6"-dimethylphenyl/-4'-methyl-imidazolidine-2'-ylidene)-3-carbethoxy-urea are obtained; m.p.: 123°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:17]([Cl:19])=[O:18]>>[ClH:19].[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:15]=2[O:14][CH3:13])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: COc1ccc(C(=O)Nc2cccc3c2CCN(C)C3)c(OC)c1
Product: Cl
Reaction time: 2 h

Procedure:
To a solution of 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.25 g, 1.54 mmol) in ethyl acethate (5 ml) was added 2,4-dimethoxybenzoyl chloride (0.263 g 1.54 mmol). The mixture was stirred under argon for 2 h before the precipithate was filtered off and dried to afford the title compound as white solid.
Reaction SMILES: BrBr.[Cl:3]Cl.[CH3:5][O:6][C:7](=[O:14])[CH2:8][CH2:9][C:10]([CH2:12]Br)=[O:11]>>[CH3:5][O:6][C:7](=[O:14])[CH2:8][CH2:9][C:10]([CH2:12][Cl:3])=[O:11]
Reactant: COC(=O)CCC(=O)CBr
Reactant: ClCl
Agent: BrBr
Product: COC(=O)CCC(=O)CCl
Yield: 35 %

Procedure:
In connection with this it is remarkable, that the 5-chlorolevulinic acid methyl ester can be also selectively produced by means of low temperature crystallisation from the chlorination mixture, which you get from the bromination mixture of levulinic acid or levulinic acid methyl ester in methanol and the subsequent bromine/chlorine exchange, in a gentle manner as already described for the 5-bromolevulinic acid methyl ester. As in the case of the 5-bromolevulinic methyl ester you proceed in the same way by using the same solvents and solvent mixtures and temperatures between −20° C. and −40° C. You get the 5-chlorolevulinic acid methyl ester in 35–38% yield and >98 purity. Impurities are the 3-chlorolevulinic acid methyl ester and the unconverted levulinic acid methyl ester. The 5-chlorolevulinic acid esters of the alcohols with chain lengths of C2–C4 can not be produced by low-temperature crystallisation because no crystallisation occurs under these conditions. The same is valid for the corresponding bromination mixtures of the 5-bromolevulinic acid esters which are produced from alcohols with chain lengths of C2–C4.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[O:13]1[C@H:17]2[O:18][CH2:19][CH2:20][C@H:16]2[C@@H:15]([OH:21])[CH2:14]1.Cl.[NH2:23][C@@H:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:25]([OH:28])[CH2:26][Cl:27].N[C@@H](CC1C=CC=CC=1)[C@H](O)CCl>C1COCC1.C(OCC)(=O)C>[O:13]1[C@H:17]2[O:18][CH2:19][CH2:20][C@H:16]2[C@@H:15]([O:21][C:1](=[O:2])[NH:23][C@@H:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:25]([OH:28])[CH2:26][Cl:27])[CH2:14]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)CCl)O[C@H]1CO[C@H]2OCC[C@H]21

Procedure:
1,1′-carbonyldiimidazole (162.15 g, 1 mol) was added to THF (0.5 L), following by solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (135.2 g, 1.04 mol) in 0.3 L of THF and the mixture was stirred for a further hour. (2S,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane hydrochloride (229 g, 0.97 mol) was added and the mixture heated at 55-60° C. approximately 5-6 hours under TLC control (for complete disappearance of (2S,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane). After completion of reaction the solution was cooled and transformed to the next step. For the preparation of analytical sample, 10 ml of solution was diluted with 50 ml of ethyl acetate, washed with water (40 mL), diluted hydrochloric acid (40 ml), 5% aqueous sodium hydrogen carbonate (40 mL) and water (50 mL). The solution was dried over sodium sulfate and evaporated to dryness. MS: m/z 356 (MH+). NMR spectrum corresponded to the structure of the desired product.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>C(Cl)Cl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2]
Reactant: COC(CN)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(CNC(=O)n1ccnc1)OC
Yield: 69 %

Procedure:
A suspension of 1,1'-carbonyldiimidazole (162.15 g) in CH2Cl2 (500 ml) was stirred on an ice-bath. 2,2-Dimethoxyethanamine (105.14 g) was added dropwise and the resulting reaction solution was stirred for 16 hours. The reaction mixture was cooled on ice, stirred for 30 minutes, and was allowed to crystallize. The precipitate was filtered off, stirred for 15 minutes in ethylacetate (250 ml) at RT, then cooled on an ice-bath for 30 minutes. The precipitate was filtered off, washed twice with DIPE (50 ml), then dried, yielding 137.4 g (69%) of N-(2,2-dimethoxyethyl)-1-H-imidazole-1-carboxamide (interm. 26).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CCCCCC.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:30])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1>O1CCCC1.C(O)(=O)C>[C:1]([CH2:2][C:23]([C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[Cl:15])([OH:30])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1)#[N:3]
Reactant: CC#N
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 44.5 %

Procedure:
Acetonitrile (2.25 g, 0.055 mole) was dissolved in dry tetrahydrofuran (100 ml) and the resulting solution was cooled to -70° C. under nitrogen in an acetone/dry ice bath. A solution of n-butyllithium in hexane (39 ml, 1.55 molar, 0.060 mole) was added dropwise over five minutes. After stirring for about 45 minutes at -70° C., 2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)acetophenone (12.8 g) in dry tetrahydrofuran (100 ml) was added dropwise over a 15 minute period. Stirring was continued at -70° C. for about one hour and then glacial acetic acid (20 ml) in tetrahydrofuran (20 ml) was added dropwise. The cooling bath was then removed. The reaction mixture was allowed to warm to 0° C., quenched in water (400 ml), and solid sodium carbonate was added to raise the pH to 8.0. After extraction with ethyl acetate (3×75 ml), the combined organic extracts were washed with saturated brine (3×50 ml), dried (Na2SO4) and evaporated to a pale yellow solid. This solid was washed well with ethyl ether to give the title compound (6.61 g, 44.5%), identical to the product of Example 1 as confirmed by n.m.r. and i.r. spectroscopy.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][OH:17].[OH-].[Na+]>O>[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][O:17][CH2:1][CH2:2][OH:3]
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 5 °C
Yield: 60.5 %

Procedure:
At 20° C., 264.3 g (6.0 mol) of ethylene oxide are passed into a solution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime in 2 l of water over a period of 85 minutes. The solution is cooled to 5° C. and 70 g (1.06 mol) of sodium hydroxide pellets are added, on which the temperature increases to 10° C. The mixture is stirred without further cooling for another 165 minutes and the precipitate that has formed is filtered off with suction, washed with 500 ml of ice-water a little at a time and dried at 40° C. in a vacuum drying cabinet. 143.0 g (61% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime]3-(O-methyl-oxime) are obtained as a mixture of two stereoisomers.
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.C([O:23][C:24](=O)[CH:25]([Cl:27])[Cl:26])C>CO>[Cl:26][CH:25]([Cl:27])[C:24]([NH:1][C@H:2]([CH2:12][F:13])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:23]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol (5.0 g, 20.0 mmol) in methanol (100 mL) is added triethylamine (9.56 mL, 67.8 mmol) and ethyldichloroacetate (6.22 mL, 50.8 mmol) and the mixture heated to reflux for 16 hours. After allowing to cool to room temperature, the solvent is removed under reduced pressure the resultant oil purified by column chromatography eluting from neat heptanes to 80% ethylacetate/heptanes to give the title compound (5.94 g). m/z (Cl) M+H 405.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[N:12]=[CH:11][C:10]=1[C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1(NC(C2C=NN(C3C=CC(C(OC)=O)=CC=3)C=2SC2CCCC2)=O)CCCCC1>>[CH:26]1([NH:25][C:24]([C:10]2[CH:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[C:9]=2[S:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: SC1CCCCC1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Agent: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCC2)cc1
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCCC2)cc1

Procedure:
Methyl 4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate was prepared from cyclohexylthiol and methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate #15) by the same process used for Intermediate #96.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=1.O>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Brc1ccccc1-c1cccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2-c2cccs2)cc1
Temperature: 100 °C

Procedure:
A vigorously stirred solution of 3.4 g (14 mmol) of 1-bromo-2-(2-thienyl)benzene and 3.77 g (15 mmol) of 4-methylphenyltrimethylstannane in 50 mL of dimethylformamide under a nitrogen atmosphere was treated with 427 mg of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 100° C. for 4.5 hours. The reaction mixture was cooled, poured into 250 mL of water and the resultant mixture extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in hexane/ether (100:5) and chromatographed on silica gel, eluting with hexane/ether (100:5) to give 2.25 g of he product. 1H NMR (200 MHz, CDCl3): 2.33 (s, 3H), 6.48 (dd, 1H), 6.83 (dd, 1H), 7.08 (m, 4H), 7.16 (dd, 1H), 7.35 (m, 3H), 7.46 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].Cl>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14](=[O:15])[NH:13][CH:10]([CH3:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: CC(C)N=C=O
Reactant: Oc1ccc(Cl)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1ccc(Cl)cc1F
Temperature: 60 °C
Yield: 91.4 %

Procedure:
To 5 g (34 mmol) 4-Chloro-2-fluorophenol and 416 mg (3.41 mmol) 4-dimethylaminopyridine in 18 ml THF are added 3.7 ml (37.5 mmol) isopropyl isocyanate and the mixture is heated for 20 hours at 60° C. After cooling down to room temperature 2 M HCl is added and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield 7.2 g isopropylcarbamic acid 4-chloro-2-fluorophenyl ester as the crude product. To 7.2 g (31 mmol) isopropylcarbamic acid 4-chloro-2-fluorophenyl ester and 5.1 ml tetramethylene diamine in 300 ml diethyl ether are added 5.9 ml (32.5 mmol) (trimethylsilyl)(trifluoromethan)sulfonate at room temperature. After 30 minutes the mixture is cooled to −70° C., 10.2 ml tetramethylene diamine and 27 ml of a 2.5 M n-BuLi solution are added successively. After one hour at −70°24 ml DMF in are added at −70° C. and the mixture is stirred another hour at −70° C. 130 ml ethanol and 36 ml of a 2 M aqueous NaOH are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is set acidic by addition of 100 ml 2 M aqueous HCl and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel to yield 1.1 g 5-chloro-3-fluoro-2-hydroxybenzaldehyde. 1.1 g (6.1 mmol) 5-chloro-3-fluoro-2-hydroxybenzaldehyde and 1.56 g (11.3 mmol) potassium carbonate are stirred vigorously in 11 ml DMF while 0.7 ml methyliodide are added. Stirring is continued for 18 hours and water is added. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 10%) to yield 570 mg 5-chloro-3-fluoro-2-methoxybenzaldehyde. 1H-NMR (CDCl3); δ=4.10 (d, 3H), 7.35 (dd, 1H), 7.59 (m, 1H), 10.35 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.[CH3:20][O-].[Na+].IC>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:20])[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a suspension of 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (2.2 g, 8.65 mmol) in methanol (44 ml) was added sodium methoxide (940 mg, 17.4 mmol) at room temperature under an atmosphere of nitrogen gas, followed by stirring. After 15 minutes, iodomethane (1.6 ml, 25.7 mmol) was added thereto, followed by stirring as it was for 22 hours. After concentrating the reaction mixture, water was added to the residue. Then, the precipitates were collected by filtration and washed with water, to give the crude crystals of the title compound (1.98 g). The crude crystals were suspended in ethanol, and then the precipitates were collected by filtration and washed with ethanol, to give the title compound (1.54 g, 66%) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]1.I[CH3:26]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:19](=[O:20])[N:18]([CH3:26])[C:17]([C:21]([F:22])([F:23])[F:24])=[N:16]1
Reactant: CI
Reactant: CC(C)Oc1cc(-n2nc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-n2nc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
Under a dry nitrogen atmosphere 0.1 g (0.0038 mole) of dry sodium hydride was added to a stirred solution of 1.3 g (0.0035 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-trifluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one in 30 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 20 minutes and 0.6 g (0.0038 mole) of iodomethane was added. After complete addition the mixture was warmed to 65° C. and stirred at that temperature for one hour. The mixture was allowed to cool to room temperature and stir for approximately 18 hours. Most of the solvent was removed by distillation under reduced pressure to leave a liquid residue. This residue was partitioned between water and diethyl ether. The organic phase was washed first with a 2N sodium hydroxide solution followed by water. The organic solution was dried over an anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 g of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-trifluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one as a solid (mp 96°-98° C.), Compound 35.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]([O:23][CH2:24][CH2:25][OH:26])[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[NH:38][N:37]=[N:36][N:22]=3)[CH:18]=[C:17]([O:23][CH2:24][CH2:25][OH:26])[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C#N)cc2OCCO)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(-c3nnn[nH]3)cc2OCCO)c1

Procedure:
In analogy to Example 140, by reacting 4-tert-butyl-N-[5-cyano-3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-phenyl]-benzenesulphonamide and sodium azide in N,N-dimethylformamide there was obtained 4-tert-butyl-N-[3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-5-(1H-tetrazol-5-yl)-phenyl]-benzenesulphonamide as a white foam.