Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[NH2:18]/[C:19](/[CH3:28])=[CH:20]\[C:21]([O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:22].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>CC(O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]2[C:20]([C:21]([O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:22])=[C:19]([CH3:28])[NH:18][C:2]([CH2:16][CH3:17])=[C:3]2[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:5])[CH:35]=[CH:36][CH:37]=1
Reactant: CCC(=O)CC(=O)OCC=Cc1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CC(C)O
Product: CCC1=C(C(=O)OCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
465 mg (2.0 mmol) of (3-phenyl-2-propene-1-yl) 3-oxovalerate, 309 mg (2.0 mmol) of (2-cyanoethyl) 3-aminocrotonate and 0.227 ml (2.0 mmol) of 3-chlorobenzaldehyde were heated at 70° C. under stirring in 10 ml of 2-propanol overnight. The reaction mixture was further heated at 120° C. under stirring under atmospheric pressure for 3 hours to evaporate 2-propanol. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)/[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)/[C:37]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:39])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of triphenylphosphine (341 mg, 1.3 mmol) in methylene chloride (7 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (231 mg, 1.3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cycloheptyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (255 mg, 0.65 mmol). After 15 min at 0° C., the reaction mixture became clear. The clear solution was then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (193 mg, 1.95 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30) mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded the pure (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (133 mg, 43%) as an amorphous solid.
Reaction SMILES: [Na].C([C:4](CC)(C([O-])=O)[C:5]([O-])=[O:6])C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:17]=[CH:18][C:19](=[O:21])[CH3:20]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]2[CH2:4][C:5](=[O:6])[CH2:20][C:19](=[O:21])[CH2:18]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)CC(c2ccc(Cl)c(Cl)c2)C1

Procedure:
A solution of 1.3 g of sodium metal in 30 ml of ethanol is treated with 9 g of diethylmalonate and an ethanolic solution of 12.1 g of 3,4-dichlorobenzalacetone, heated under reflux for 15 min, cooled and concentrated to dryness in vacuo. The residue is treated with 400 ml of water containing 7 g of 80% potassium hydroxide pellets and heated under reflux for 2 hr. Insoluble material is removed and the filtrate is acidified with concentrated sulfuric acid, heated under reflux until carbon dioxide evolution ceases, cooled, filtered, washed with water and dried. Recrystallization from 2-propanol gives 5-(3,4-dichlorophenyl)-1,3-cyclohexanedione; mp 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.[N+](=[CH2:24])=[N-]>CO.O1CCCC1>[CH3:24][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1)=[O:10]
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
trans-1-(p-Methoxybenzyloxycarbonyl)-4-hydroxy-L-proline (5.0 g) was dissolved in 50 ml of methanol and 50 ml of tetrahydrofuran. An ethereal solution of diazomethane was added thereto under ice-cooling until nitrogen gas evolution stopped. The mixture was allowed to stand overnight and distilled to obtain trans-1-(p-methoxy-benzyloxycarbonyl)-4-hydroxy-L-proline methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2[OH:18].C1COCC1.[Li+].[OH-]>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:19])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:13]([OH:15])=[O:14])=[C:7]2[OH:18]
Reactant: CCOC(=O)c1c(O)c2cc(C)cc(F)c2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(F)c2ncc(C(=O)O)c(O)c2c1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
To a solution of ethyl 8-fluoro-4-hydroxy-6-methylquinolone-3-carboxylate (0.50 g) in 30 mL of 1:1 MeOH:THF is added 8 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 20 mL glacial acetic acid. The resulting precipitate is collected, washed with H2O, and dried to yield 0.382 g of 8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxylic acid as a white solid. To a solution of this acid (0.23 g) and 4-chlorophenylhydrazine (0.21 g) in 10 mL DMF is added triethylamine (0.16 m), EDC (0.24 g), and HOBt (0.16 g). The mixture is stirred at room temperature for 3 days. Upon diluting the reaction mixture with 100 mL H2O, an orange solid precipitates. The crude product is adsorbed onto silica and chromatographed eluting with 4% MeOH in CHCl2. Fractions homogenous by TLC are condensed and recrystallized from EtOAc/hexanes to yield 0.0181 g of the desired product as a white solid.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:6]([CH2:38][CH3:39])[CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([O:33]C)=[O:32])=[C:29]2[C:24]([C:25]3[CH:37]=[CH:36][O:35][C:26]=3[CH:27]=[N:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:5].C(O)=O>O1CCOCC1.O>[CH2:38]([N:6]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([C:25]3[CH:37]=[CH:36][O:35][C:26]=3[CH:27]=[N:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:39]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)O
Temperature: 90 °C
Yield: 51.4 %

Procedure:
Lithium hydroxide monohydrate (0.107 g) was added to a solution of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]-quinoline-6-carboxylate (Intermediate 6, 0.026 g) in a mixture of dioxane (1.7 mL) and water (0.8 mL). The resultant mixture was stirred and heated at 90° C. overnight. After cooling, the mixture was acidified by addition of formic acid and then evaporated to dryness. The residue was triturated with a mixture of methanol and DCM (10%) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-12%. The product was triturated with a mixture of DCM and diethyl ether (50%) and the solid was collected by filtration and dried in vacuo to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylic acid (0.013 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].[I:13]I>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: II
Reactant: Brc1ccc2cn[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Brc1ccc2c(I)n[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 6-bromo-1H-indazole (10 g, 50.8 mmol, commercially available) in dioxane (200 ml) was treated with 3N aqueous NaOH (100 ml). The vigorously stirred mixture was treated with iodine (27.1 g, 107 mmol), added portionwise over 5 minutes then stirred for 60 minutes. The reaction was quenched with 200 ml of 20% citric acid solution, followed by 160 ml of saturated NaHSO3 solution, then partitioned between ethyl acetate and water. The organic extract was dried with MgSO4 and concentrated to a solid which was triturated with ether and pentane to afford the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([O:32]CC3C=CC=CC=3)[CH:19]=2)[OH:17])[O:12][C:11](=[O:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:32])[CH:19]=2)[OH:17])[O:12][C:11](=[O:40])[CH:10]=1
Reactant: O=c1cc(OCc2ccccc2)cc(CC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=c1cc(O)cc(CC(O)c2ccc(O)c(O)c2)o1
Yield: 70 %

Procedure:
35.6 g (66.6 mmol) 4-benzyloxy-6-[2-[3,4-dibenzyloxyphenyl)-2-hydroxy-ethyl)]-2H-pyran-2-one (VI) was hydrogenated for 6 hours at room temperature under a hydrogen pressure of 44 mbar in 1200 ml ethanol using 10 g W2 Raney nickel. After taking up 4.4 l hydrogen the catalyst was removed by suction filtration and it was rewashed several times with tetrahydrofuran. The evaporated filtrates yielded 12.2 g (70%) VII after triturating with ether, melting point 153° C. (decomp.).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:19]=[CH:18][C:10]2[C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][O:13][C:9]=2[C:8]=1[CH2:20][CH2:21][CH3:22].[Br:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.CCOCC>[CH2:20]([C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=2[CH:18]=[CH:19][C:7]=1[O:6][CH2:26][CH2:25][CH2:24][Br:23])[CH2:21][CH3:22]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (50 mL) of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole as prepared in Example 4 step 2 (5 grams, 20.4 mmol) was added 1,3-dibromopropane (10 mL, 98.5 mmol), followed by cesium carbonate (10 grams, 30.7 mmol). The mixture was stirred at room temperature overnight. After aqueous ether work-up and silica gel chromatography (hexanes: 2.5% ethyl acetate), the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: Cc1cnc(C#N)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C2(N)CC2)nc1
Reaction time: 0.25 h

Procedure:
To a solution of 5-methylpyrimidine-2-carbonitrile (200 mg, 1.7 mmol, 1 eq) in dry THF under an argon atmosphere was added titanium isopropoxide (0.58 ml, 2.0 mmol, 1.2 eq) slowly at ambient temperature and the reaction mixture was stirred for 15 mins. Ethyl magnesium bromide (1M solution) in THF (4 ml, 4.0 mmol, 2.4 eq) was added via syringe slowly at ambient temperature. Then the reaction mixture was stirred for an hour. BF3.EtO (0.36 ml, 2.6 mmol, 1.5 eq) was added slowly through syringe to the mixture at 0° C. The mixture was allowed to attain ambient temperature and stirred for another one hour. 10 ml of water was added to the reaction mixture which was then filtered through Celite and the bed washed with water and ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) then extracted with DCM. The organic was washed with brine solution, dried over sodium sulphate and concentrated to give the crude product which was taken for coupling reaction without further purification. Yield: 125 mg (crude).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1.[CH3:23][C:24]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1>C(Cl)Cl>[CH3:23][C:24]1[N:29]=[C:28]([NH:30][C:1]([N:13]2[CH2:14][CH2:15][N:11]([CH:8]3[CH2:7][CH2:6][O:5][CH2:10][CH2:9]3)[C:12]2=[O:16])=[O:2])[CH:27]=[CH:26][C:25]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)on1
Reactant: O=C1NCCN1C1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3C)ccn2)on1
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
Phosgene (20% in toluene, 0.613 g, 1.24 mmol) was treated with a solution of Example B1 (0.063 g, 0.37 mmol) and pyridine (0.1 mL, 1.24 mmol) in DCM (2 mL), stirred for 15 min, then concentrated to dryness. The residue was dissolved in DCM (2 mL), treated with a solution of 6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.07 g, 0.25 mmol) and TEA (0.17 mL, 1.24 mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (75 mg, 63%). 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1 H), 8.55 (d, J=5.7 Hz, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 6.98 (s, 1 H), 6.96 (dd, J=5.7, 2.5 Hz, 1 H), 3.95-3.77 (m, 5 H), 3.48-3.35 (m, 4 H), 2.28 (s, 3 H), 2.24 (s, 3 H), 1.71-1.70 (m, 2 H), 1.60 (d, J=12.5 Hz, 2 H); MS (ESI) m/z: 479.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.Cl>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[C:21]([F:24])([F:22])[F:23])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(c2ccc(O)cc2C(F)(F)F)CN1Cc1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Oc1ccc(C2CN(Cc3ccccc3)CCO2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-6-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholin-3-one (26.18 g; 67.3 mmol) in THF (600 mL) was added dropwise BH3.THF in THF (235.4 mL; 1.00 mol/1; 235.4 mmol), at 0° C. The resulting mixture was stirred for 1 hour at 0° C. and thereafter 18 hours at RT. Subsequently, 1M aqueous HCl (550 mL) was added and the mixture stirred overnight at RT. The resulting mixture was partitioned between EtOAc and 2M aqueous NaOH (350 mL), the organic layers was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2) to afford 4-(4-benzyl-morpholin-2-yl)-3-trifluoromethyl-phenol
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][C:20](=[N:22][O:23][CH3:24])[CH2:19][C@H:18]1[C:25]([OH:27])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:28](=[N:31]O)([NH2:30])[CH3:29]>C(Cl)Cl.C1COCC1>[CH3:24][O:23][N:22]=[C:20]1[CH2:21][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[C@H:18]([C:25]2[O:27][N:31]=[C:28]([CH3:29])[N:30]=2)[CH2:19]1
Reactant: CC(N)=NO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc(C)no2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59 %

Procedure:
Diisopropylcarbodiimide (3.16 g, 25.17 mmol) was added to a solution of (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2, 6.50 g, 25.17 mmol) and acetamidoxime (Intermediate 7, 1.86 g, 25.17 mmol) in DCM (55 ml) and stirred overnight at room temperature (DCM-insoluble amidoximes were pre-dissolved in THF, to which was added a solution of DIC and Intermediate 2 in DCM). After filtering at the pump, and evaporation in vacuo, the residue was dissolved in pyridine (60 ml) and refluxed for one hour, then cooled and allowed to stand overnight, then evaporated in vacuo. The crude product was then dissolved in DCM (50 ml) and washed with sat. NaHCO3(aq) (2×50 ml) and then 1M HCl(aq) (2×50 ml), dried over magnesium sulphate and evaporated in vacuo (crude yield 70%). Silica gel chromatography, eluting with 15% ethyl acetate in hexanes gave the desired compound, tert-butyl (2S,4EZ)-4-(methoxyimino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyrrolidinecarboxylate (4.4 g, 60% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:22]>C(O)C>[NH2:22]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])=[O:6]
Reactant: N
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCC(C)(C)CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.07 g of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 15 ml of ethanol was cooled with ice-water. The solution was bubled gasous ammonia and then stirred at room temperature. The solution stood at room temperature overnight. To the solution was added ice-water, and then a precipitated white solid was removed. The solid was washed with water and dried under reduced pressure to yield 4.79 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].O1C=CN=C1>C(OCC)(=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: c1cocn1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccc(O)cc2)n1
Temperature: 115 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 25.0 g (182.3 mmol) of 4-hydroxybenzamide and 23.0 mL (182.3 mmol) of ethyl bromopyruvate was stirred and heated at 115° C. for 30 minutes. The mixture cooled to room temperature and sat under N2 atmosphere overnight. Ethyl acetate (100 mL) was added and the mixture stirred for 1 hour. The solid oxazole (36.99 g, 158.6 mmol) was collected by suction filtration in 87% yield: 1H NMR (CDCl3) δ10.21 (broad s, 1H), 8.82 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 4.29 (q, 2H), 1.29 (t, 3H); IR (cm-1) 3400, 3169, 1731, 1612, 1731, 1507, 1444; FDMS 233. Anal. (C12H11NO4) C, H, N.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[C:8](=C=O)[C@H:9]([OH:39])[C@@H:10]([NH:33]OC(C)(C)C)[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[Cl:44]CCl.CO>>[ClH:44].[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:39])[C@@H:10]([NH2:33])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C(=C=O)[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCCOCCOC)c1)C(C)C)NOC(C)(C)C
Reactant: ClCCl
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OC)c(OCCOCCOC)c1)C(C)C
Product: Cl

Procedure:
Analogously to Example 1, the title compound is prepared starting from 27 mg of N-tert-butoxy-carbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-{3-[2-(2-methoxy-ethoxy)ethoxy]-4-methoxy-phenyl}-octanoic acid (N-butyl)amide. This yields the tire compound: Rf (dichloromethane/methanol=1:1)=0.19; Rt (I)=18.93 minutes; FAB-MS(M+H)+ =511.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[N:15][CH:16]=2)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].[N:24]([O-])=[O:25].[Na+]>>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:24]=[O:25])=[CH:16][N:15]=1
Reactant: Cc1ccc(NCCc2ccc(C)nc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(N(CCc2ccc(C)nc2)N=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a three-necked bottle, 5-(2-p-methylphenylaminoethyl)-2-methylpyridine 4.5 g and 2N HCl 200 ml was added, heated to 30° C. and stirred to complete dissolution, then cooled with ice-water bath to 0-5° C., added dropwise with NaNO2 aqueous solution (13.8 g of NaNO2 dissolved in 50 ml of water). After dropwise addition, the temperature was elevated and the reaction was performed at room temperature for 1 h. To the reaction liquor, saturated NaHCO3 solution was slowly added dropwise until no gas generated. A great quantity of solid appeared, stirred for 1 h, suction filtrated, washed with water to obtain light yellow solid powder, dried and weighed to obtain 2-methyl-5-(N-nitroso-2-p-methylphenylaminoethyl)pyridine 4.3 g. Yield was about 85%.