Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C(=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([C:12]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=3)[N:1]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NC(=O)c1cc(F)ccc1N
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(-c2nc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A suspension of 2-amino-5-fluorobenzamide (1.00 g, 6.49 mmol), methyl 4-formylbenzoate (1.06 g, 6.49 mmol) and sodium disulfite (1.26 g, 6.62 mmol) in N,N-dimethylacetamide (13 ml) is heated to 150° C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford 4-(6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-benzoic acid methyl ester as yellow solid; HPLC/MS 2.08 min (C), [M+H] 299.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]>Cl>[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[CH:12]=1)(=[O:9])=[O:10])[CH3:7]
Reactant: CCS(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [K+]
Product: CCS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Potassium nitrate (4.46 g, 44.12 mmol) was added portion wise to a solution of ethylphenyl sulfone in concentrated HCl (25 mL) at room temperature; then the mixture was heated to reflux for one hour. After cooling, the mixture was poured onto ice and the precipitate was collected by filtration. The solid was washed with cold water (2×50 mL) and dried. 1H NMR (CDCl3) δ ppm 1.28 (3H), 3.45 (2H), 7.80 (1H), 8.21 (1H), 8.30 (1H), 8.85 (1H); MS (DCI) m/z 216 (M+H).
Reaction SMILES: [NH2:1][C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:4].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8]1)=[O:4])(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(N)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC(C(=O)OCC1CCN(C(=O)OC(C)(C)C)CC1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2-amino-2,2-diphenylacetyloxy)-methyl)piperidine-1-carboxylate (prepared as in Preparation intermediate 12 with diphenylglycine replacing cyclohexylmandelic acid) (0.50 g, 1.18 mmol) in DCM (1.5 mL) was added a solution of acetic anhydride (0.122 mL, 1.30 mmol) in DCM (0.5 mL). The reaction mixture was heated at 40° C. for 18 hours. The reaction mixture was allowed to cool to RT and further acetic anhydride (0.06 mL, 0.65 mmol) added. The reaction mixture was heated at 40° C. for a further 18 hours. The reaction mixture was allowed to cool to RT, quenched with water, and the mixture was stirred at RT for 1 hour. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate and DCM. The organic phase was removed and the aqueous phase extracted with further DCM. The combined DCM extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The product was isolated (0.541 g, >100%). The crude product was used without further purification in the next step.
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: COc1ccc(C(=O)N[PH](=O)C2(NC(=O)OCc3ccccc3)CCCN(N)C2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)N[PH](=O)C2(N)CCCN(N)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Palladium black (20.0 mg) was added to a solution of (3S, P (SR))-3-benzyloxycarbonylamino-1-amino(4-methoxybenzoylamino)phosphinyl-2-piperidone (112.5 mg, 0.2243 mmol) in ethanol (15 mL), and the resulting mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2Cl.[CH3:20][NH:21][CH3:22].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[N:21]([CH3:22])[CH3:20]
Reactant: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 60 °C

Procedure:
6-Bromo-4-chloro-2-(3-fluorophenyl)-quinoline (20 g, 59.4 mmoles) was placed in a 500 mL three-neck round-bottom flask equipped with magnetic stirrer, nitrogen inlet, gas outlet, condenser and heating bath and dissolved in 150 mL of N-methylpyrrolidinone. 250 mL of a 40% aq. solution of dimethylamine was added with stirring. The mixture was warmed to 60° C. for 48 hrs. At the end of this time the mixture was cooled, added to 3 L of water in a 4 L Erlenmeyer flask and the mixture stirred until solids formed. The solids were collected by vacuum filtration and dried in a vacuum oven. The product was recrystallised from ethanol in a −20° C. freezer to give 19.6 g (95%) yield of the desired product.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:21][C:22]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[CH2:24][CH2:23]2)[C:5](=[O:20])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:19][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([N:6]2[CH:7]=[CH:2][N:3]=[C:4]([NH:21][C:22]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[OH:31])[CH2:24][CH2:23]3)[C:5]2=[O:20])[C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Temperature: 75 °C
Yield: 94.6 %

Procedure:
To 3-[5-bromo-2-oxo-3-[[1-[2-(phenylmethoxy)phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 259a, 9.2 g) in ethanol (400 mL) was added ammonium formate (14.04 g) and 10% Pd/C (1.693 g). The reaction was heated at 75° C. for 1 h, filtered through celite washing the celite with further warm ethanol (100 mL) followed by dichloromethane (2000 mL) and the combined filtrates were evaporated, diluted with dichloromethane (1000 mL) and washed with water, dried (MgSO4) and evaporated to give the subtitle compound (6.16 g).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:22])[NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:2]=[CH2:3].B.C1C[O:27]CC1.[OH-].[Na+].OO>C1COCC1>[OH:27][CH2:3][CH2:2][CH2:1][O:4][C:5](=[O:22])[NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]
Reactant: C=CCOC(=O)Nc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: CC(=O)NCCc1c[nH]c2ccc(NC(=O)OCCCO)cc12
Reaction time: 2 h

Procedure:
[3-(2-Acetylamino-ethyl)-1H-indol-5-yl]-carbamic acid allyl ester (1 mmol) is dissolved in THF (27 mL) and borane-THF (2 mmol) added dropwise. After 2 h, sodium hydroxide (4 mL of 3 M) and hydrogen peroxide (4 mL of 30%) are added and the solution stirred an additional 1 h. The solution is concentrated to half its volume, 10 mL water is added and it is extracted with ethyl acetate (4×25 mL). The combined extracts are washed with brine, dried, the solvent removed in vacuo, and the product chromatographed on silica gel with 5% methanol in chloroform as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](O)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 70 °C
Yield: 278.2 %

Procedure:
To a solution of 0.65 g (2.2 mmol) of 4-fluoro-2,6-dinitrophenol in 30 mL dimethylformamide was added 1.4 mL (15 mmol) of phosphorous oxychloride. The mixture was heated to 70° C. overnight, cooled to room temperature and quenched with ice. The mixture was diluted with water and the precipitate was collected giving 1.35 g (82%) of the title compound as a cream colored solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](=[O:23])[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:14][C:13]1[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][C:6]3=[O:12])=[CH:11][C:2]=2[O:1][C:21]=1[C:20](=[O:23])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: N#Cc1cc2c(cc1O)CCCC2=O
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)c2oc3cc4c(cc3c2N)C(=O)CCC4)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 24 %

Procedure:
To a solution of 3-hydroxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile from method II-6 (45 mg, 0.24 mmol) and 3-methoxyphenacyl bromide (60 mg, 0.26 mmol, 1.1 eq) in anhydrous N,N-dimethylformamide (2 mL) was added potassium carbonate (66 mg, 0.48 mmol, 2 eq). The reaction mixture was shaken at 90° C. for 17 h. The mixture was cooled to room temperature and poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice. Combined the organic layers and evaporated in vacuo. The crude product was washed with methanol and gave 19 mg (24%) of 3-Amino-2-(3-methoxy-benzoyl)-7,8-dihydro-6H-naphtho[2,3-b]furan-5-one as a yellow solid. 1H-NMR (DMSO-d6) δ 8.72 (s, 1H), 7.68 to 7.42 (m, 5H), 7.18 to 7.14 (m, 1H). 6.33 (s, 1H), 3.84 (s, 3H), 3.07 (t, J=6.0 Hz, 2H), 2.65 (t, J=6.6 Hz, 2H), 2.50 (m, 2H); MS LC-MS (MH+=336.2); Rf=0.62, 50% ethyl acetate-hexane.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[C:14]([CH3:29])[C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([N:3]([C:12]1[CH:13]=[C:14]([CH3:29])[C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(c1cc(C)c(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1cc(C)c(C)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A mixed solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4,5-dimethyl-1H-indol-7-yl]thiophene-2-sulfonamide (85 mg), methanol (10 mL) and tetrahydrofuran (15 mL) was added sodium borohydride (10 mg) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr. Aqueous citric acid solution was added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The obtained mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (84 mg, yield 99%) as pale-yellow crystals, melting point 189-190° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C:8]1[O:9][CH:10]=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C(Br)(Br)(Br)[Br:21]>O1CCCC1.[Cl-].[NH4+]>[Br:21][C:10]1[O:9][C:8]([C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:12][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ncco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ncc(Br)o1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-Butyl-dimethyl-silanyloxymethyl)-oxazole) (0.35 g, 1.643 mmol) in dry tetrahydrofuran (8 mL) is added n-Butyl lithium (0.26 g, 4.107 mmol) drop wise under nitrogen atmosphere at −78° C. then stirred at −40° C. for 2 hours. The reaction mixture is again cooled to −78° C. then added carbontetrabromide (1.36 g, 4.107 mmol) and stirred to room temperature for 14 hours. Reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting 2% Ethyl acetate in hexane to afford the crude title compound (0.18 g), which is used in the next step without purification. LC-MS (m/z): [M+H]=294.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>C1COCC1>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:6][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24])=[O:5]
Reactant: C=C(C)OC(=O)Cl
Reactant: COC(C)(C)C(N)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
A −78° C. solution of 2-methoxy-2-methylpropanamide (0.25 g, 2.134 mmol) in THF (6 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M in THF, 2.77 mL, 2.77 mmol) stirred for 0.5 h. A solution of isopropenyl chloroformate (0.257 mL, 2.347 mmol) in THF (1 mL) was added drop-wise and the mixture was stirred at −78° C. for 1 h. The mixture was warmed to RT, stirred for 1 h, quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (2-methoxy-2-methylpropanoyl)carbamate (440 mg, 102%). MS (ESI) m/z: 202.1 (M+H+).
Reaction SMILES: COC(=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C[C:41]1([CH3:49])[O:48][C:46](=[O:47])[CH2:45][C:43](=[O:44])O1.Cl.C(N=C=NCCCN(C)C)C>CO.O1CCCC1.[OH-].[Na+].C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.O.C1(C)C=CC=CC=1.C(O)C>[O:44]=[C:43]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:10]=1)[CH2:45][C:46]([O:48][CH2:41][CH3:49])=[O:47]
Reactant: COC(=O)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(=O)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixed solution of methyl(4-((2-phenoxybenzyl)oxy)phenyl)acetate (150 mg) in methanol (2.5 ml) and tetrahydrofuran (1.5 ml), 0.43 ml of 5N aqueous sodium hydroxide was added, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with chloroform. The combined organic layers were washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a colorless oil. To a solution of the crude product in chloroform (2 ml), 64 mg of Meldrum's acid, 84 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 110 mg of 4-dimethylaminopyridine were added, and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with chloroform and water, washed with 5% aqueous citric acid and a saturated saline solution sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: chloroform/methanol (98:2)) to afford a colorless oil. To a solution of the resultant oil (100 mg) in toluene (2 ml) was added 0.12 ml of ethanol, and the reaction solution was heated to reflux for 5 hours. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (90:10-70:30)) to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN
Product: CCCCCCC/C=C/C(=O)NCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and ethylamine as starting materials to give the aimed compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]I)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][O:9]3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CI)cc1
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c(-c2ccccc2)coc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc12

Procedure:
10.5 g of 7-hydroxy-isoflavone in 200 ml of anhydrous acetone are boiled for 2 hours with 11.8 g of p-nitrobenzyl iodide in the presence of 5.7 g of anhydrous potassium carbonate under reflux condenser. On distilling off about half of the volume of acetone, the residue is poured onto 1000 ml of water. The precipitating crude product is subjected to suction and recrystallized from glacial acetic acid, affording light yellow plates of 7-p-nitrobenzyloxy-isoflavone, m.p. 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C(C(O)=O)=CON=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1conc1-c1ccc(Cl)cc1
Agent: O=C(O)c1conc1-c1ccc(F)cc1
Product: OCc1conc1-c1ccc(Cl)cc1
Yield: 46.1 %

Procedure:
As described for example 13e, 3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid (40.0 g, 178.9 mmol) was converted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid, to the title compound (17.3 g, 46%) which was obtained as a light green solid. MS: m/e=210.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(C3CCOCC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCOCC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 4.8 %

Procedure:
A mixture of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.131 mmol), 3-cyanophenylboronic acid (40 mg, 0.222 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (15 mg) in 1,4-dioxane (3 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.54 mg, 5%). 1H-NMR (CDCl3): 1.54 (m, 2H), 1.62 (m, 1H), 1.88 (m, 1H), 2.10 (m, 1H), 2.48 (m, 1H), 3.39 (m, 3H), 3.42 (m, 3H), 4.03 (m, 3H), 6.90 (m, 1H), 7.45 (m, 2H), 7.58 (m, 2H), 7.62 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18]([OH:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[C:18]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(O)c3cccnc3)sc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3cccnc3)sc21
Yield: 94.4 %

Procedure:
A solution of 5-bromo-3-methyl-1-(2-methylpropyl)-6-[1-hydroxy-1-(pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.50 g, Example 39 step b)), 4-methylmorpholine-N-oxide (0.21 g), powdered 4A sieves (0.58 g) and tetra-n-propylammoniumperruthenate (0.02 g) in dry dichloromethane (40 ml) was stirred for 1 hour at room temperature. The suspension was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane to give the subtitle compound as a cream solid (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([C:9](Cl)=[O:10])[O:5][C:6]=1[CH2:7][Cl:8].[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([C:9](=[O:10])[N:14]([CH3:15])[CH3:13])[O:5][C:6]=1[CH2:7][Cl:8]
Reactant: O=C(Cl)n1oc(CCl)c(Cl)c1=O
Reactant: CNC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1oc(CCl)c(Cl)c1=O
Temperature: 25 °C
Yield: 62.5 %

Procedure:
254 mg of 4-chloro-2-chlorocarbonyl-5-chloromethyl-4-isoxazolin-3-one were dissolved in 5 ml of benzene, and then a solution of 48 mg of dimethylamine and 107 mg of triethylamine in 2 ml of benzene were added, with stirring, at room temperature. The mixture was stirred for a further 10 minutes, after which it was washed, in turn, with 2 ml of 0.1N sulphuric acid and water (twice, 5 ml each time). The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off. The residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. The solvent was distilled from the eluate and the residue was recrystallized from diisopropyl ether, to give 159 mg (yield 62.8%) of the title compound in the form of crystals, melting at 107°-108° C.