Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=CC=1C(O)=O.I[C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([I:23])[CH:22]=1.[C:25]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCOCC1.[Cu](I)I>[I:23][C:21]1[CH:22]=[C:17]([CH:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:25]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH:18]=[C:19]([CH3:24])[CH:20]=1
Reactant: Cc1cc(I)cc(I)c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: I[Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(I)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
Copper iodide (332 mg, 1.74 mmol), cesium carbonate (5.6 g, 17.4 mmol), and picolinic acid (429 mg, 3.49 mmol) were added to a dried flask under a nitrogen atmosphere. A solution of 3,5-diiodotoluene (3 g, 8.7 mmol) in dioxane (10 mL) was added, followed by the addition of di-tert-butyl malonate (1.3 mL, 8.7 mmol). The atmosphere inside the flask was removed under vacuum and replaced with nitrogen gas; this process was repeated a total of three times. The reaction mixture was then heated to 80° C. and stirred for 24 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted twice with diethyl ether (50 mL). The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluted with ethyl acetate in hexanes to provide the title product as an orange oil (0.62 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])(=[O:3])[CH3:2].[CH3:11][N:12](C)C(Cl)=O.C([Si](C)(C)C)#N.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc[n+]1[O-]
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-acetylpyridine-N-oxide (0.098 mol) in 200 ml of methylene chloride was added dimethylcarbamyl chloride (0.1 mol) and the reaction mixture was allowed to react at room temperature under nitrogen for 24 h. Additional dimethylcarbamyl chloride (0.1 mol) was added followed by cyanotrimethylsilane (0.22 mol), and the resulting mixture was allowed to react at 20° C. for 2 days. An additional 4 ml (0.03 mol) of cyanotrimethylsilane was then added, and the mixture was stirred at room temperature for another 24 hours. A solution of 200 ml of 10% K2CO3 was added to the reaction mixture and the resulting mixture was stirred for 45 min. The aqueous layer was extracted with 100 ml methylene chloride twice, the organic layers were combined and dried (K2CO3). After stripping the solvent, 16.9 g of crude product was isolated. The crude product obtained was chromatographed over Florisil” to isolate the desired products and the by-products with elution by the series of solvents: 2-acetyl-6-cyanopyridine (3a) (2 g, 50% CH2Cl2/hexane), 2-cyano-6-(1-cyano-1-trimethysilyloxy)ethylpyridine (3b) (0.81 g, CH2Cl2), 2-cyano-6-(1-cyano-1-dimethylcarbamoyloxy)ethylpyridine (3c) (1.67 g, 25:72 EtOAc/CH2Cl2), 2-(1-cyano-1-hydroxy)ethylpyridine (3d) (0.42 g, 50:50 EtOAc/CH2Cl2), and 2-(1-cyano-1-dimethylcarbamoyloxy)ethylpyridine-1-N-oxide (3e) (1.8 g, EtOAc). The products exhibited the following properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1>CCO.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(F)cc(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of ethyl (E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g, 63.33 mmol) and 10% palladium-carbon (1.4 g, 0.66 mmol, 50%, wet) in EtOH (300 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give ethyl 3-(3-fluoro-5-methoxyphenyl)propanoate (13.9 g, 61.4 mmol, 97%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO.O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([OH:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 95 %

Procedure:
N-[4-(trifluoromethyl)phenyl]-3-oxopentanoic acid amide 1.30 g (5.0 mmol) produced in Example 1 and ((S)-BINAP)RuBr2 50.0 mg (0.057 mmol) (BINAP denotes 2,2′-bisdiphenylphosphino-1,1′-binaphthyl. It was prepared according to the method described in Tetrahedron Asymmetry, 1994,5,675) were mixed with 20 mL of a methanol-water (10/1 in volume) solution. Hydrogen replacement was carried out three times and after the reaction solution was heated to 60° C., reaction was carried out under hydrogen pressure (3.0 kg/cm2) for 12 hours. After releasing hydrogen, the solution was concentrated under reduced pressure and purifying on silica gel chromatography was carried out to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide as a white solid (1.23 g, isolated yield: 95%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=90/10: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=12.0 minutes, (R) antipode=9.3 minutes) to be 84.7% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 1.00 (3H, t), 1.5-1.7 (2H, br), 2.50 (1H, dd), 2.59 (1H, dd), 2.75 (br, 1H), 4.06 (1H, m), 7.57 (2H, d), 7.64 (2H, d), 8.21 (1H, br)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11]([CH3:28])[S:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])(=[O:14])=[O:13]>C(Cl)Cl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][S:12]([N:11]([CH3:28])[CH3:10])(=[O:13])=[O:14])(=[O:23])=[O:24])=[O:27])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: CN(C)S(=O)(=O)Oc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OS(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a suspension of 0.37 g (0.003 mole) 2-amino-4,6-dimethylpyrimidine in 5 ml methylene chloride was added 1.2 g (0.004 mole) 2-(dimethylaminosulfonyloxy)-benzenesulfonyl isocyanate. The reaction exothermed (18°-26° C.) and was stirred at room temperature for 3 hours. The resultant white precipitate was filtered to give 0.9 g of a white solid, m.p. 195°-196° C. The infrared spectrum shows absorption bands at 1705, 1380, 1180 cm-1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C([C:31]2[C:35]3[S:36][CH:37]=[CH:38][C:34]=3O[N:32]=2)C=CC=1.S1C=CC=C1CN.C(=O)([O-])[O-].[K+].[K+]>>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:32][CH2:31][C:35]2[S:36][CH:37]=[CH:38][CH:34]=2)=[N:13]1
Reactant: ClCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: NCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(OCCCNCc2cccs2)cc(-c2noc3ccsc23)c1
Yield: 94 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 2-thiophenemethylamine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.35 g, 94% Yield) as an oil. Purity by LC/MS (APCI)=100% area, [M+H]+=371 m/e.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-quinazolinone (1 g, 3.5 mmol, from Step D), thionyl chloride (5 mL) and DMF (5 drops) was heated at reflux for 4 h. After cooling excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene to afford the intermediate, 4-chloro-6-methoxy-7-benzyloxyquinazoline, as a yellow solid (652 mg, 62%). MS(ES) 301 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:35]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH2:36]2)=[CH:8][C:9]=1[N:10]([C:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]2[CH:21]=[C:20]([Si](C)(C)C)[N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:35]2[CH2:36][CH2:37][C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)=[CH:8][C:9]=1[N:10]([C:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[C@H:11]1[CH2:12][CH2:13][C@H:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2cc([Si](C)(C)C)nn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2ccnn2)CC1
Reaction time: 24 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohexyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (1.1 g, 1.8 mmol) in THF (4.4 ml) was added TBAF 1.0 M in THF (0.270 ml, 2.70 mmol). The reaction mixture was stirred for 24 h and treated with water and saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) to give 5-(4,4-Dimethyl-cyclohexyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.534 g, 55%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:8][C:9]=1[CH2:10][C:11](O)=[O:12])[CH2:2][CH2:3][CH3:4].O>O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[S:8][C:9]=1[CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
1.15 g crude [4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetic acid were dissolved in 50 ml tetrahydrofuran and cooled in an ice bath to 0° C. At 0° C. 9.3 ml 1 M solution of borane tetrahydrofuran complex were added. The reaction mixture was warmed to 55° C. and stirred for one hour at this temperature. The reaction mixture was cooled in an ice bath and 50 ml water was added. The organic layer was added. The tetrahydrofuran was removed in vacuo and the residue extracted three times with portions of 80 ml ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvent removed in vacuo to provide 1.1 g crude 2-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as brown oil. This material was used without purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[O:30]1[CH:34]=[C:33](C2C=C(C=CC=2)N)[N:32]=[CH:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:33]3[N:32]=[CH:31][O:30][CH:34]=3)[CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(-c2cocn2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2cocn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(oxazol-4-yl)aniline in step 1. MS: 394.28 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]2[CH:19]=[CH:18][N:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O:22][CH2:23][CH3:24]>>[OH:22][CH:23]([C:24]1[CH:7]=[CH:6][CH:5]=[CH:9][CH:10]=1)[C:16]1[C:7]2[S:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=2[CH:19]=[CH:18][N:17]=1
Reactant: CCOCC
Reactant: COCOc1c(-c2ccccc2)sc2cnccc12
Product: COCOc1c(-c2ccccc2)sc2c(C(O)c3ccccc3)nccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 3-methoxymethoxy-2-phenyl-6-azabenzo[b]thiophene in 5 mL of dry ether was added and the solution was kept at -60° C. for 3 hours. The reaction was quenched with 0.5 mL of benzaldehyde and allowed to warm to room temperature. The mixture was partitioned between ether and water and the aqueous layer was washed with ether. The combined extracts were dried and concentrated to an oil. Chromatography on silica gel (30% ethyl acetate-hexane) afforded 0.62 g (44%) of a colorless oil, NMR (200 MHz, CDCl3) δ3.4 (s, 3H), 5.0 (s, 2H), 5.95 (s, 1H, --OH), 7.2-7.8-(m, 12H), 8.52 (d, J=6 Hz, 1H), Mass Spec m/e 377 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][O:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:23]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:42]4[CH:43]=[N:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4ccc(OC)nc4)cc3c2C)C2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution (5 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]methyl)amino}propanoate (0.25 g) synthesized in the above-mentioned (3) in N,N-dimethylacetamide were added (6-methoxypyridin-3-yl)boronic acid (0.14 g), potassium carbonate (0.13 g) and tetrakistriphenylphosphine palladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and filtered-through celite and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.15 g, 58%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.12 g, 85%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=0.92 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].[Br:17]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:17][C:10]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:2]([Cl:1])[C:3]([OH:16])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(Cl)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C(F)(F)F)c(Cl)c1O
Temperature: 15 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate (6.30 g) in DMF (65.0 mL) was added N-bromosuccinimide (4.41 g), and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.00 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:27]2[CH2:29][CH2:28]2)[CH:7]=1)=[O:5])C>Cl.C(O)C>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][N:18]1[C:11]1[N:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]2[CH:27]2[CH2:28][CH2:29]2)=[CH:13][C:12]=1[F:17]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4ccccc4C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4ccccc4C3)c(F)cc2c1=O
Yield: 76.8 %

Procedure:
150 mg of 7-(2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was dissolved in a mixture of 10 ml of 10% hydrochloric acid and 10 ml of ethanol. The mixture was heated under reflux for 2 hours. The precipitates deposited were collected by filteration, and washed with water and ethanol in this order to obtain 107 mg of 7-(2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:18])([F:17])[F:16])[N:6]=[CH:5][C:4]=1[C:19]([O:21]CC)=O)#[N:2].[CH3:24][NH2:25]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:17])([F:18])[F:16])[N:6]=[CH:5][C:4]=1[C:19]([NH:25][CH3:24])=[O:21])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1C#N
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1C#N
Temperature: 0 °C

Procedure:
A solution of 1.23 g of 5-cyano-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester and 8 ml of 40% aqueous monomethylamine in 20 ml of DMF was stirred at approximately 25° C. for 16 hours. The reaction mixture was poured into 150 ml of ice water and the precipitated solid was collected by filtration. The isolated material was recrystallized from ethanol to provide 535 mg of 5-cyano-1-[2-(trifluoromethyl)-4-chlorophenyl]-N-methyl-1H-pyrazole-4-carboxamide. mp=162.5°-164° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>N1C=CC=CC=1>[CH3:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 49.4 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and trimethylacetyl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 2,2-dimethyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]-furan-2-yl]propionamide (0.74 g). Mp 189-190° C.; MS (FAB) m/z 300 ([M+H]+); Anal. Calcd. for C19H25NO2: C, 76.22; H, 8.42; N, 4.68; Found: C, 76.57; H, 8.38; N, 4.62.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C@@H:19]([C:24](O)=[O:25])[CH2:18][CH2:17]2.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[OH:12][C@H:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:1][C:24]([C@H:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([I:13])[CH:15]=2)[O:20]1)=[O:25]
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC[C@H](O)COc1ccccc1)[C@H]1CCc2cc(I)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution containing (2S)-1-amino-3-phenoxy-2-propanol (Example 53, 11.97 mmol, 1.0 eq.), (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 11.97 mmol, 1.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.98 mmol, 2.0 eq.), 1-hydroxybenzotriazole hydrate (23.94 mmol, 2.0 eq.), and triethylamine (23.94 mmol, 2.0 eq.) in CH2Cl2 (200 mL) was stirred at room temperature for 3 hours. To the resulting solution was added water and two-phase mixture was extracted with CH2Cl2. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=2:1). The product was obtained as a white solid in 77% yield. MH+=454.1, retention time (LC-MS)=3.03 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2].[CH2:22](O[Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:20][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C[Si](C)(C)OCc1ccccc1
Product: CCOC(=O)C(OCc1ccccc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 37.9 %

Procedure:
2.5 g of oxo-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetic acid ethyl ester (example 15.1.a) were reacted with 1.5 g of benzyloxytrimethylsilane according to the procedure given in example 15.1.b) to give 1.2 g of (RS)-benzyloxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetic acid ethyl ester as slightly yellow oil.