Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1Cl)([O-:21])=[O:20]>C1(C)C=CC=CC=1.O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][C:27]=1[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([O-:21])=[O:20]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Sc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A mixture of 2-mercaptopyridine (1.7 g), potassium t-butoxide (1.7 g) and N,N-dimethylformamide (3 ml) in toluene (15 ml) was stirred at room temperature for 30 minutes. To the mixture was added 4'-nitro-3'-chloroacetophenone (1.5 g) and the resulting mixture was stirred overnight. Water was added and the insoluble material was filtered, washed with toluene and dried to give crystals of 4'-nitro-3'-(2-pyridylthio)acetophenone (1.1 g).
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:12]4[N:11]=[N:10][CH:15]=[CH:14][CH:13]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: NCc1cccnn1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnn1
Yield: 17 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridazin-3-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 17% yield: mp 187-189° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=4.2 Hz, 1H), 7.59-7.56 (m, 1H), 7.49-7.45 (m, 1H), 7.03-7.00 (m, 1H), 4.88 (d, J=5.4 Hz, 2H), 4.14-4.09 (m, 2H), 3.73-3.67 (m, 2H), 3.19 (d, J=7.1 Hz, 2H), 2.62 (s, 3H), 0.97-0.92 (m, 1H), 0.60-0.54 (m, 2H), 0.27-0.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.0, 159.4, 158.1, 155.2, 152.8, 150.7, 126.9, 126.2, 117.4, 48.6, 43.7, 42.2, 42.1, 17.4, 8.9, 3.4; MS (ES+) m/z 373.2 (M+1).
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](OCC)(=[O:17])[CH2:14][CH2:15][CH3:16].Cl>C1(C)C=CC=CC=1.O>[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: CCCC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)CC(=O)CCc1ccccc1
Reaction time: 9 h

Procedure:
Sodium (7.3 g) was added in small portions to a solution of 4-phenyl-2-butanone (46.8 g, 0.31 mol) and ethyl butyrate (110 g, 0.95 mol) in toluene (120 ml) at 20°-60° C. under nitrogen, and stirring was continued for 9 h under reflux. After standing overnight, the reaction mixture was taken up in H2O (300 ml), neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residual reddish orange oil (84 g) was distilled under reduced pressure to afford the title compound as a pale yellow oil which was an ca 3:7 mixture of Keto/Enol as seen by the methylene singlet at δ3.52 ppm and the methine singlet as δ5.45 ppm in the 1HNMR spectrum; yield: 15.4 g; bp. 166°-168° C./2 mmHg.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]([OH:13])[CH2:7][C:8](OCC)=[O:9])(=[O:3])[CH3:2].O.[NH2:15][NH2:16]>CO>[C:1]([NH:4][CH2:5][C@H:6]([OH:13])[CH2:7][C:8]([NH:15][NH2:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@@H](O)CNC(C)=O
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A 5.00 g (26.4 mmol) of ethyl (R)-4-acetylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 20 ml of methanol, and 2.00 g (39.6 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred overnight. After the mixture was cooled to room temperature, 20 ml of methanol was added thereto and crystallization was carried out at 10° C. to give 3.90 g (84%) of the title compound. Melting point: 177.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:11][CH2:12][CH3:13])C=CC=CC=1.[CH3:30][O:31][C:32]([CH3:40])([CH3:39])[CH2:33][CH2:34][CH2:35][C:36](=O)[CH3:37].O>CN(C)C=O>[CH2:16]1[CH2:15][O:14][C:10]([CH2:11][CH2:12][CH:13]=[C:36]([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])([CH3:40])[CH3:39])([CH3:9])[O:17]1
Reactant: CCCC1(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Reactant: COC(C)(C)CCCC(C)=O
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)CCCC(C)=CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
8.15 g of potassium tert.-butylate were added to a solution of 38 g of triphenyl 2,2-ethylenedioxy-pentyl phosphonium bromide in 400 ml of dimethylformamide cooled to 0° C. and then 12.75 g of 6-methoxy-6-methyl-2-heptanone were added. The mixture was stirred for 4 hours at 0° C. and was then poured into water. The mixture was extracted with petroleum ether (b.p.= 40°-75° C.) and the extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The yellow oil was chromatographed over silica and was eluted with a 8-2 benzene-ethyl acetate mixture to obtain 9.15 g of 2,2-ethylenedioxy-10-methoxy-6,10-dimethyl-5-undecene in the form of a colorless oil which was a mixture of the E and Z isomers with respect to the double bond in the 5-position. A supplementary chromatography under pressure and elution with a 9-1 benzene-ethyl acetate mixture gave a separation of the E and Z isomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]>[Cl:1][C:2]1[N:7]=[C:6]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1nc2c(c(Oc3ccccc3)n1)CCC2
Temperature: 27.5 °C
Reaction time: 13 h
Yield: 52.4 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.45 g, 2.4 mmol), phenol (0.28 g, 3 mmol), cesium carbonate (0.97 g, 3 mmol) and copper powder (0.01 g) in anhydrous dimethylformamide (5 mL) was stirred at about 20 to 35° C. for 6 to 20 hours. The reaction was quenched by addition of water. The organics were extracted with EtOAc and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.31 g, 54%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10](=[O:19])[CH:11]=[CH:12][C:13]2=[O:18]>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][C:4]([O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10](=[O:19])[CH:11]=[CH:12][C:13]2=[O:18])=[O:5]
Reactant: O=C1C=CC(=O)c2c(O)cccc21
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Product: O=C(CCCl)Oc1cccc2c1C(=O)C=CC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of triethylamine (1.4 ml) and 1.27 g. of 3-chloropropionylchloride in 5 ml. of DCNM was added to a solution of 1.73 g. of 5-hydroxy-1,4-naphthoquinone. The reaction mixture was stirred for 2 hours at room temperature. The solution was filtered and concentrated to a small volume and chromatographed on a silica gel column (ethylacetate-cyclohexane-DCM) to give 741 mg. of desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[CH3:10][C:11]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12].N1C=CN=C1.[Na+].[Cl-]>CN(C)C=O.O>[CH3:13][C:11]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1)([CH3:10])[CH3:12]
Reactant: N#CC1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(C#N)CC1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution maintained at 10° C., under nitrogen, of 11 g (87.8 mmoles) of 4-hydroxycyclohexanecarbonitrile (prepared according to Praefcke K. and Schmidt D., Z. Naturforsch (1980) 35b, 1451-4) in 50 ml of N,N-dimethylformamide, there is added dropwise 26.6 g (96.8 mmoles) of 1,1-dimethylethyldiphenylsilyl chloride, then by portions, 13.1 g (190 mmoles) of imidazole. Stirring is continued at room temperature during 3 days, before pouring the reaction mixture in water saturated with NaCl. The product is extracted with a hexane-ether (1:1) mixture. The organic phase is washed with a N HCl solution, then with water saturated with NaCl, before drying and concentration. The residue is purified by chromatography on a column of silica in dichloromethane to give 26.5 g (yield=85.9%) of a colorless thick oil.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34]CF)[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1.[F:39][CH2:40][CH2:41]CN=[N+]=[N-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34][CH2:41][CH2:40][F:39])[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:37][CH:38]=1
Reactant: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCF)nn3)cc21
Reactant: [N-]=[N+]=NCCCF
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCCF)nn3)cc21

Procedure:
is prepared according to the procedure for compound 12, with the exception that 3-fluoropropylazide is used in place of the 2-fluoroethylazide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:38][O:39][C:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:40]3([O:39][CH3:38])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC1=CCCCC1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
To a solution of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-hydroxymethyl-1H-imidazole (14) (33 mg, 0.1 mmol) prepared in accordance with the method as described in WO 96/10019 and p-toluenesulfonic acid pyridinium (27.6 mg, 0.11 mmol) in toluene (1.5 mL) was added 1-methoxycyclohexene (112 mg, 1.00 mmol) under ice-cooling, and stirred at room temperature for 6 hours. A drop of triethylamine was added to the reaction mixture, and the mixture was filtered to remove the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on an alumina column (eluate: toluene) to give the compound 15 (37.0 mg, 70%) as oil. Rf 0.16 (Al2O3 60, Type E, toluene).
Reaction SMILES: [H-].[Na+].C[OH:4].Br[C:6]1[C:7](=O)[O:8][C:9]2C(C=1C)=C[CH:12]=[C:11]([OH:17])[CH:10]=2.CN([CH:22]=[O:23])C>Cl>[CH3:22][O:23][CH2:12][C:11](=[O:17])[CH2:10][C:9]([O:8][CH2:7][CH3:6])=[O:4]
Reactant: Cc1c(Br)c(=O)oc2cc(O)ccc12
Reactant: CN(C)C=O
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
NaH (7.71 g, 192.7 mmol) was suspended in DMF (110 mL). The solution of MeOH (2.64 g, 82.5 mmol) in DMF (55 mL) was added drop wise at 0° C. After that, the mixture was stirred at 0° C. for 30 min. The solution of compound 1 (9.54 g, 57.9 mmol) in DMF (55 mL) was added dropwise at 0° C., then the reaction mixture was allowed to warm slowly to RT and stirred for 16 h. The reaction mixture was diluted with 1N HCl (400 mL), extracted with MTBE (250 mL×3). The combined organic layer was washed with H2O (200 mL×5), dried over Na2SO4, filtered, concentrated, purified by silica gel column (PE:EA=10:1) afforded ethyl 4-methoxy-3-oxobutanoate (1.4 g, 15.1%) as light yellow oil.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O.C(OCC)(=O)C>[OH:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1
Reactant: CCOC(=O)[C@@H](Cc1cccc(C#N)c1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@@H](CO)Cc1cccc(C#N)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
The process is performed as in Example 2, starting with 3.3 g of ethyl (2R)-2-acetylamino-3-(3-cyanophenyl)propanoate and 1.23 g of sodium borohydride in 50 cm3 of ethanol and working at a temperature in the region of −30° C. After stirring for 16 hours at a temperature in the region of 20° C., the reaction medium is evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. and the residue obtained is then stirred in a mixture of 100 cm3 of water and 100 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place and the aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and then washed with twice 50 cm3 of water, dried over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. 2.13 g of N-[(1R)-2-hydroxy-1-(3-cyanobenzyl)ethyl]acetamide are obtained in the form of a white solid. (αD20=+7.5±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32](OCC)[O:33]CC)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 100.9 %

Procedure:
In a substantially similar manner to that of Example 2-(6), was treated a mixture of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (1.5 g) in acetone (15 ml) and 6N hydrochloric acid (1.5 ml) to give a reddish brown oil which was crystallized and washed with n-hexane to give crystals (1.30 g) of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([O:14][C:15](C)=O)[CH2:7]2.[CH3:18]I>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH3:18])([O:14][CH3:15])[CH2:7]2
Reactant: CC(=O)OC1Cc2cc(Br)ccc2C1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC1(C)Cc2cc(Br)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
640 mg of 60% of sodium hydroxide was added at room temperature to 20 ml solution of dimethylformamide with 850 mg of 5-bromo-2-methylcarbonyloxy-1-indanone obtained in the above 1). After stirring for 10 min at room temperature, 3.5 ml of methyl iodide was added and the mixture was stirred for 1 hour at room temperature. Then, 2 ml of dimethylformamide containing 5% water was added and further stirred for 1 hour at room temperature.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@H:7]1[CH2:12][N:11](CC2C=CC(OC)=CC=2)[CH2:10][C@@H:9]([OH:22])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@H:7]1[CH2:12][NH:11][CH2:10][C@H:9]([OH:22])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C[C@@H](O)C[C@@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A suspension of 329 (25.5 mmol) and 10% Pd/C (1 mol %) in MeOH (250 mL) was fitted with a balloon of hydrogen and allowed to stir at room temperature for 4 h. At that time, a vacuum was applied to remove any remaining hydrogen, the vessel was purged with nitrogen, diluted with MeOH (100 mL) and filtered through a pad of Celite on a fritted funnel. The resulting solution was concentrated to give 5-(R)-(tert-Butyl-dimethyl-silanyloxy)-piperidin-3-(R)-ol (330) as a colorless oil (25.0 mmol, 98% yield). 1H NMR (400 MHz, CD3OD) δ=0.13 ppm (s, 3H), 0.14 (s, 3H), 0.929 (s, 9H), 1.84 (br t, 2H, J=5 Hz), 2.71–2.78 (m, 2H), 2.97–3.05 (m, 2H), 4.04–4.09 (m, 1H), 4.19–4.24 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:22]([CH2:24][NH2:25])[CH:23]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:22]([CH:23]=1)[CH2:24][NH:25][C:14]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (299 mg, 1.30 mmol), 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine (293 mg, 1.40 mmol), EDC (376 mg, 1.96 mmol) and HOAt (89 mg, 0.65 mmol) in DMF (7 mL) was stirred at room temperature for 16 h. Water and saturated aqueous K2CO3 were added and the mixture was extracted with EtOAc. The organic layer was washed with brine and the combined aqueous layers were extracted once with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to a yellow oil. Silica gel chromatography (65% EtOAc-hexanes) afforded the title compound as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.46 (dd, J=1.8, 8.4 Hz, 1 H), 7.29–7.26 (m, 1 H), 6.84 (br m, 1 H), 4.74 (br m, 1 H), 4.29–4.16 (m, 2 H), 4.04 (br m, 1 H), 2.76–2.70 (m, 1 H), 2.24–2.04 (m, 1 H), 1.64–1.32 (br m, 5 H), 1.48 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22](OC)OC)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:35][O:36][NH2:37].C(OCC)(=O)C>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22]=[N:37][O:36][CH3:35])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)OC
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CON=CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 69.4 %

Procedure:
In a solution of 152 mg of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2-dimethoxyethyl) -2-methyl benzoic acid amide (Compound of the present invention No. 5-083) synthesized similarly to Synthetic Example 5 in 14 ml of methanol-water (6:1) mixed solvent, 38 mg of methoxyamine hydrochloride was added, and stirred under reflux with heat for 8 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, diluted by adding 80 ml of ethyl acetate, washed with water (30 ml×2), and dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethylacetate-hexane (1:1), and 102 mg of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[CH2:23]([NH:30][C:31](=[O:32])[N:5]([CH2:4][C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[Br:1])[CH2:6][CH3:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (2.35 g, 8.33 mmol) in CH2Cl2 (24 mL) was added triethylamine (1.8 mL, 12.5 mmol), followed by benzyl isocyanate (1.22 mL, 10.0 mmol), and the reaction was stirred at room temperature for 50 minutes. The mixture was worked up with CH2Cl2 and H2O, and the combined organic layers were dried, filtered, and concentrated. The residue was dissolved in CH2Cl2 and filtered to remove solids, and the filtrate was purified by silica gel chromatography to give 3-benzyl-1-(2-bromo-5-trifluoromethyl-benzyl)-1-ethyl-urea.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[C:17]([CH:19]=[C:20]([O-])[CH3:21])#[N:18].[Na+].[NH2:24][C:25](=[CH:27][C:28](=[O:34])[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:26].C(O)(=O)C>CC(O)C>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]2[C:27]([C:28](=[O:34])[CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])=[C:25]([CH3:26])[NH:24][C:20]([CH3:21])=[C:19]2[C:17]#[N:18])=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Reactant: CC(N)=CC(=O)CCC(C)C
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc(F)c(F)c3c(=O)cc(C)oc23)C(C(=O)CCC(C)C)=C(C)N1

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 69.25 mg (0.45 mmol) of 2-amino-7-methyloct-2-en-4-one (example 14, stage a) and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 88.1 mg (46.36% of theory) of the title compound are obtained as yellow crystals.