Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH3:6][NH:7][CH3:8].Cl.Cl[C:11]([N:13]1[C:19]2[S:20][C:21]([CH2:23][CH3:24])=[CH:22][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16][CH2:15][CH2:14]1)=[O:12]>O>[CH2:23]([C:21]1[S:20][C:19]2[N:13]([C:11](=[O:12])[N:7]([CH3:8])[CH3:6])[CH2:14][CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[CH:22]=1)[CH3:24]
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccccc1

Procedure:
To 50 ml of 25%(W/V) tetrahydrofuran solution of dimethylamine is added 7.1 g of 1-chlorocarbonyl-7-ethyl-5-phenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring, and stirred at room temperature for 2 hours. The reaction mixtureis transferred to water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is treated with ethanolic hydrogen chloride to give 7-ethyl-1-dimethylcarbamoyl-5-phenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloric as yellow crystals, melting at 237°-238° C with decomposition.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:55])[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]([NH:31][C:32]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH:38]=2)=[O:33])[CH:30]=1)=O)(C)(C)C.C(OC(C1(C2C(=O)N(COCC[Si](C)(C)C)C=C(NC(C3C=NN(CC4C=CC(C)=CC=4)C=3)=O)C=2)C=C2C(C=CC(CN3CCC(F)CC3)=C2)=N1)=O)(C)(C)C.NCCN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[F:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:25]2[C:26](=[O:55])[NH:27][CH:28]=[C:29]([NH:31][C:32]([C:34]4[CH:35]=[N:36][N:37]([CH2:39][C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)[CH:38]=4)=[O:33])[CH:30]=2)=[CH:10]3)[CH2:19][CH2:20]1
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(CN6CCC(F)CC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(Cn2cc(C(=O)Nc3cc(C4(C(=O)OC(C)(C)C)C=c5cc(CN6CCC(F)CC6)ccc5=N4)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2cc(C(=O)Nc3c[nH]c(=O)c(-c4cc5cc(CN6CCC(F)CC6)ccc5[nH]4)c3)cn2)cc1
Temperature: 120 °C

Procedure:
A 2-5 mL microwave vial was charged with intermediate (8g), 5-(4-fluoro-piperidin-1-ylmethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indolecarboxylic acid tert-butyl ester (96 mg, 0.125 mmol), tetrahydrofuran (3 mL), 1,2-diaminoethane (38 mg, 42 ul, 0.63 mmol) and finally tetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (0.63 mL, 0.63 mmol). The vial was heated under microwave irradiation at 120° C. for 20 mins. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (4×20 mL) and brine (4×20 mL). The organics were dried (Na2SO4) and concentrated in vacuo. The resultant yellow solid was purified via trituration using acetonitrile, to afford the title compound as a yellow solid, 42 mg, 63%.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH:23]([CH3:25])[CH3:24])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reaction time: 3 h
Yield: 83 %

Procedure:
20% palladium hydroxide (wet, 60 mg) was added to a solution of tert-butyl cis(±)-4-(benzylamino)-3-isopropoxypiperidine-1-carboxylate obtained in Example (147d) (120 mg, 0.345 mmol) in methanol (1.2 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the resulting residue, and the organic substance was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 74 mg of tert-butyl cis(±)-4-amino-3-isopropoxypiperidine-1-carboxylate as a colorless oily substance (83%). The resulting amine was dissolved in DMF (1 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 54 mg, 0.29 mmol) was added, and the mixture was cooled in an ice water bath. 1-Hydroxybenzotriazole (44 mg, 0.31 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (60 mg, 0.31 mmol) were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, sequentially washed with brine, water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol) to obtain 60.6 mg of the title compound as a colorless solid (50%).
Reaction SMILES: [P:1](Cl)([Cl:7])([S:3][CH2:4][CH2:5][CH3:6])=[O:2].[CH2:9]([OH:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[P:1]([Cl:7])([S:3][CH2:4][CH2:5][CH3:6])([O:11][CH2:9][CH3:10])=[O:2]
Reactant: CCO
Reactant: CCCSP(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCSP(=O)(Cl)OCC
Temperature: -10 °C
Reaction time: 2 h

Procedure:
S-Propyl dichlorothiophosphate (3.1 grams; 0.016 mole) was charged into a 300 ml glass reaction flask equipped with a mechanical stirrer. Methylene chloride (80 ml) was added and the solution was cooled to a temperature of -10° C. A solution of ethanol (0.737 grams; 0.016 mole) and triethylamine (1.62 grams; 0.016 mole) was then added dropwise with stirring while maintaining the temperature of the reaction mixture at about -5° C. After the addition was completed the reaction mixture was allowed to warm to room temperature and stirring was continued for a period of two hours to yield the desired product O-ethyl S-propyl chlorothiophosphate in solution.
Reaction SMILES: [CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3].[H-].[Na+].[CH3:48]I>CN(C=O)C>[CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:14][CH2:15][CH2:16][N:17]([CH3:48])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:2]=[CH2:3]
Reactant: C=CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(C/C=C/CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.6 g (0.936 mmol) of (E)-1-allyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 2a) in 8 ml of DMF there are added, with stirring, 0.075 g (1.875 mmol) of sodium hydride dispersion (approx. 60%) and, after 5 min., 0.117 ml (1.875 mmol) of methyl iodide. The reaction mixture is stirred for 15 h at room temperature; a further 0.075 g (1.875 mmol) of sodium hydride dispersion (approx. 60% ) and 0.117 ml (1.875 mmol) of methyl iodide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a, but using ethyl acetate-hexane (1:2) in the flash chromatography, yields the title compound, Rf value=0.36 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][C:46](Cl)=[O:47])[CH2:40][CH2:39]1)[CH2:36][CH3:37]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:46](=[O:47])[CH2:45][CH2:44][C@H:41]4[CH2:42][CH2:43][C@H:38]([CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40]4)=[CH:25][CH:26]=3)=[N:19][N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Reactant: CCC[C@H]1CC[C@H](CCC(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2nnc(-c3ccc(OC(=O)CC[C@H]4CC[C@H](CCC)CC4)cc3)s2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(4-n-Octyloxyphenyl)-5-(4-hydroxyphenyl)-1,3,4-thiadiazole (0.1 mole, 3.82 g) is suspended in 50 mL of absolute toluene and, after addition of 10 mL triethylamine and 100 mg 4-dimethylaminopyridine, treated with stirring with 0.011 moles (2.38 g) 3-(trans-4-n-propylcyclohexyl)-propionyl chloride. The mixture is stirred for 12 hours at room temperature and for 2 hours at 80° C. After being allowed to cool to room temperature, the reaction solution is diluted with 100 mL ether and washed once with 100 mL water, once with 100 mL 5% sodium bicarbonate solution and once again with 100 mL water. After drying over Na2SO4, the solvent is distilled off in a rotary evaporator. The residue is recrystallized from ethanol and methanol until the transition temperature is constant.
Reaction SMILES: [Cl:1][C:2]1[C:8]([SH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11](Cl)(Cl)=[S:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:8]([SH:9])=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(S)c(Cl)cc1F
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)c(S)cc1N=C=S
Temperature: 25 °C

Procedure:
2.00 g of 4-chloro-2-fluoro-5-mercaptoaniline was dissolved in chloroform, and 1.12 ml of thiophosgene was dropwise added at 0° C. After the dropwise addition, the temperature was raised to room temperature and then, the mixture was refluxed. After refluxing for six hours, chloroform was distilled off to obtain 2.47 g of the above-identified compound as brown oil.
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccsc2)cc1C=O
Temperature: 80 °C

Procedure:
3 g of 5-bromo-2-anisaldehyde (0.014 mol) are dissolved in 45 ml of 1,2-dimethoxyethane and 2.68 g of 3-thiopheneboronic acid (0.021 mol) are added, followed by addition of aqueous 2N sodium carbonate solution (4.44 g, 0.042 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.48 g, 4.19 10−4 mol). The reaction mixture is heated at 80° C. for 20 hours with stirring and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The resulting phase is dried over magnesium sulfate and then filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 94/6 cyclohexane/ethyl acetate). 2 g of a beige-colored solid are isolated.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.O>[C:16]([NH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(CN)C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
In a mixture of 10 ml of pyridine and 10 ml of water was dissolved 500 mg of β-amino-isobutyric acid, and 1.5 ml of benzyloxycarbonyl chloride was dropped thereinto with stirring at 0° C. After completion of the dropping, the resulting mixture was stirring of room temperature for 3 hours, after which the pyridine was removed under reduced pressure. Then, hydrochloric acid was added to the residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer obtained was washed successively with diluted hydrochloric acid, water and an aqueous sodium chloride solution, and then concentrated to obtain an oily substance. Subsequently, the oily substance was washed with a mixed solvent of ether and hexane to obtain 380 mg of the desired compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](O)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]cnc2c1
Temperature: -78 °C
Reaction time: 10 h

Procedure:
1H-benzo[d]imidazole-5-carboxylic acid (10 mmol, 1 eq.) was dissolved in 30 mL THF and cooled down to −78° C. 20 mL 1 M solution of lithium aluminium hydride (20 mmol, 2 eq.) were added slowly. After stirring at ambient temperature for 10 hours the reaction was quenched with methanol. The solvent was removed, 50 mL aqueous solution of sodium hydrogen carbonate was added and extracted with 50 mL ethyl acetat three times. The combined organic layers were dried over sodium sulfate, filtrated and the solvent was removed under reduced pressure. The product was purified by means of flash-chromatography using silica gel and a ethyl acetate/MeOH-gradient.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][CH:46]1[C:61](=[O:62])[N:48]2[C:49]([C:58]([OH:60])=[O:59])=[C:50]([CH2:53][S:54][C:55](=[O:57])[CH3:56])[CH2:51][S:52][C@H:47]12>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C.O.O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:45][CH:46]2[C:61](=[O:62])[N:48]3[C:49]([C:58]([OH:60])=[O:59])=[C:50]([CH2:53][S:54][C:55](=[O:57])[CH3:56])[CH2:51][S:52][C@H:47]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
A mixture of 9.9 g of 2-tritylamino-4-thiazolylacetic acid, 100 ml of tetrahydrofuran and 2.7 ml of N-methylmorpholine was stirred under an inert gas for 15 minutes at room temperature and was then cooled to -15° C after which 3.15 ml of isobutyl chloroformate were added. The mixture was stirred for 5 minutes at -10° to -15° C and then 6.5 g of the product of Step A, 65 ml of water and 3.15 ml of triethylamine were added over 2 minutes. The mixture was stirred for 11/2 hours at room temperature and the tetrahydrofuran was removed. The mixture was acidified and was extracted with methylene chloride. The mixture was vacuum filtered and the organic phase was washed and evaporated to dryness. The powdery residue was triturated with ether and dried to obtain 15.2 g of raw product. 6.7 g of of the said product were dissolved in methylene chloride and ethyl acetate was added thereto. The insoluble phase was removed and the solution was treated with carbon black and was vacuum filtered. The recovered product was rinsed and dried to obtain 5.1 g of 7-[2-(2-tritylamino-4-thiazolyl)-acetamido]-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])=[O:19]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1c(F)cccc1Cl
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1c(F)cccc1Cl

Procedure:
starting from ethyl 2-chloro-6-fluorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2-chloro-6-fluorobenzimidate and therefrom with methylhydrazine there is obtained 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 80°-84° C.;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:12](=[O:14])[CH3:13].C([O-])=O.[Na+].C([O-])(=O)C.[Na+]>CN(C=O)C.[Cl-].C([N+](CC)(CC)CC)C>[CH3:17][C:16]1([CH3:18])[C:2]2[C:3](=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[N:11]([C:12](=[O:14])[CH3:13])[CH2:15]1
Reactant: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: O=C[O-]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 80 °C

Procedure:
N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (4.5 g, Step B) was dissolved in 50 mL anhydrous DMF, 2.5 g tetraethyl-ammonium chloride, 1.2 g sodium formate, 3 g sodium acetate were added, the resulting mixture was bubbled with nitrogen gas for 10 minutes. Pd(OAc)2 (350 mg) was added and the mixture was heated at 80° C. under N2 overnight. After the mixture was concentrated in vacuo, it was extracted between saturated NaHCO3 solution and EtOAc, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 Hexane:EtOAc to afford a yellow gum. MS: 235 (M+1). Calc'd. for C12H14N2O3—234.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:23])[CH:7]([O:20][CH2:21][CH3:22])[CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([OH:19])=[CH:11][CH:10]=1)[CH3:4].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31].C(C1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl>CN(C)C=O.O>[CH2:3]([O:5][C:6](=[O:23])[CH:7]([O:20][CH2:21][CH3:22])[CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([O:19][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])=[CH:11][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Agent: CC(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)c2c1CCCC2)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
0.037 g (1.54 mmol) Sodium hydride was added in small portions below 30° C. and under argon to a solution of 0.30 g (1.03 mmol) [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester in 5.0 ml N,N-dimethylformamide. After 10 minutes, 0.384 g (1.54 mmol) 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) were added and the reaction mixture then stirred for 16 hours at ambient temperature. It was then diluted with water and extracted with ether. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.35 g (67%) of [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: Cl.[CH:2]([N:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]([CH3:8])[CH3:7])([CH3:4])[CH3:3].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[O:20]=[C:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[O:11][C:10](=[O:12])[CH2:9][N:5]([CH:6]([CH3:7])[CH3:8])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)N(CC(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)N(CC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.82 g (19.5 mMol) diisopropylamino-acetic acid hydrochloride (3), in 50 ml DMF, was added to 2.24 g (19.5 mMol) N-hydroxysuccinimide and 8.04 g (39 nMol) dicyclohexylcarbodiimide. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated in vacuum to dryness. After dissolving the residue in CH2Cl2, the solution was washed with NaHCO3, dried (sodium sulphate) and the solvent evaporated. The compound was then recrystallised from diisopropylether.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[O:25])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.8 %

Procedure:
A mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol (2.05 g), activated manganese dioxide (6.0 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (1.65 g, yield 81%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.