Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[N:12]=[CH:11][C:10]([C:16]([O:18]CC)=O)=[C:9](Cl)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>C(O)CCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[NH:12][CH:11]=[C:10]3[C:16](=[O:18])[N:29]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)[N:30]=[C:9]3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CN(C(=O)OCC)CC2
Solvent: CCCCO
Product: CCOC(=O)N1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
A mixture of 3 g of ethyl 6-ethoxycarbonyl-4-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate (Example 1c) and 1.4 g of p-chlorophenylhydrazine in 100 mL of n-butanol is stirred and heated at reflux under nitrogen atmosphere for 20 hours, then cooled. Solid is collected and washed successively with n-butanol, then with ether. Solid is then dried in a vacuum oven at 80° for 24 hours obtaining 8-ethoxycarbonyl-2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridine-3(5H)-one, mp 357°-359°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[C:5]=1[OH:18])[CH:2]=[CH2:3]>ClCCl.CC#N.CC#N.Cl[Pd]Cl>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:6]1[C:5]([OH:18])=[C:4](/[CH:1]=[CH:2]/[CH3:3])[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCc1cccc(-c2c(Cl)cccc2Cl)c1O
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: C/C=C/c1cccc(-c2c(Cl)cccc2Cl)c1O
Yield: 96.1 %

Procedure:
A mixture of 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol (2.922 g, 10.47 mmol) and bis(acetonitrile)dichloropalladium (II) (136 mg, 0.523 mmol) in anhydrous dichloromethane was heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was then concentrated to a small volume under reduced pressure and directly pre-adsorbed onto silica gel. Purification by flash chromatography using a solvent gradient of 2 to 7.5% ethyl acetate in hexane gave 2.81 g (96%) of 2′,6′-dichloro-3-[(1E)-prop-1-enyl]-1,1′-biphenyl-2-ol as a colorless syrup. HRMS: calcd for C15H12Cl2O, 278.02652. found (EI, M+), 278.0262.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[I:11]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10]
Reactant: ClI
Reactant: N#Cc1ccc(N)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(F)c(N)c(I)c1
Reaction time: 1 h

Procedure:
A 25 ml of two-neck round bottom flask was filled with argon gas and the solution of 4-amino-3-fluoro-benzonitrile (300 mg, 2.204 mmol, 1 equiv.) in methylenechloride was put into the flask. To the solution was added iodomonochloride (393.6 mg, 2.424 mmol, 1.1 equiv.) and stirred for 1 hour. After confirming the completion of the reaction with TLC, to resulting solution was added saturated sodium thiosulphate solution and stirred. The reaction solution was extracted with methylenechloride, washed with water(twice) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethylacetate=3/1) to yield a brown liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C@@H:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][C@H:60]([NH2:68])[CH2:61][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.C(OCC)C>[CH2:45]([O:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][CH:60]([NH:68][C:4](=[O:6])[CH:3]([N:2]([CH3:1])[CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:61][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:55][CH:54]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1)N(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
(S)-2-Dimethylamino-4-methyl-pentanoic acid (55.3 mg, 0.347 mmol) was dissolved in dry DMF (3 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added in succession N,N-diisopropylethylamine (0.180 mL, 1.04 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (132 mg, 0.347 mmol, Novabiochem, La Jolla, Calif.). The resulting reaction mixture was stirred at that temperature for 30 minutes, (S)-2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine (153 g, 0.347 mmol, Example 3, Step D) was then added. After an additional 60 minutes stirring at 0° C., the reaction mixture was mixed with 60 mL of diethyl ether, and the resulting mixture was successively washed with saturated aqueous NaHCO3 solution and brine and then dried over Na2SO4. The solution was concentrated in vacuo, an oil was obtained. The crude product was purified by chromatography (silica gel, 10% methanol in chloroform) to give the title compound as a white solid (90 mg, 55%); mp 113-114° C.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]([CH:22]=[O:23])=[CH:12][C:11]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C1COCC1.[Ag-]=O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:13]([C:22]([OH:1])=[O:23])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Reactant: [OH-]
Agent: O=[Ag-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
At ambient temperature, to a stirred mixture of silver (I) oxide (0.570 g, 2.46 mmol) in H2O (9.8 mL) was added NaOH (0.983 g, 24.6 mmol) and the reaction was heated at 50° C. After 0.5 h, to the reaction was added a solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carbaldehyde (1.78 g, 4.92 mmol) in THF (9.8 mL) and the reaction was heated at 90° C. for 1h. To the reaction was added silver (I) oxide (0.570 g, 2.46 mmol), NaOH (0.983 g, 24.6 mmol) and H2O (10.0 mL). The reaction was heated at 90° C. for 16 h. The reaction was filtered through a celite pad, rinsing with hot H2O (3×). The filtrate was washed with ether (3×), acidified with 2N HCl (pH 2) and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated to give 1.73 g (93%) of the title compound. 1H NMR (DMSO-d6) δ2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H), 3.01 (s, 3H), 4.39 (s, 2H), 7.39-7.52 (m, 6H), 7.59-7.62 (m, 4H), 7.89 (s, 2H), 13.07 (s, 1H).
Reaction SMILES: [Si](O[C@@H]([C@H:11]1[C:44](=O)[N:13]2[C:14]([C:33](OCOC(=O)C(C)(C)C)=O)=[C:15](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:16](C)[C@@H:12]12)C)(C(C)(C)C)(C)C.S[C@@H:47]1CNC(=S)C1>C(#N)C>[CH:44]([N:13]([CH2:12][CH3:16])[CH:14]([CH3:15])[CH3:33])([CH3:11])[CH3:47]
Reactant: S=C1C[C@H](S)CN1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Yield: 104 %

Procedure:
In 1 ml of acetonitrile was dissolved 20 mg of pivaloyloxymethyl (1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-diphenylphosphoryloxy-1-methylcarbapen-2-em-3-carboxylate, 4.3 mg of (4S)-4-mercaptopyrrolidin-2-thione obtained in the above (3) and 4.1 mg of N,N-diisopropylethylamine were added thereto under nitrogen gas at -20° C., and the mixture was stirred for 2 hours while gradually elevating a temperature thereof to 0° C. The reaction mixture was poured into a 0.1M phosphate buffer (pH 7) and extracted with ethyl acetate. After the extract was washed and dried, the solvent was removed under reduced pressure. The residue was purified by thin layer chromatography (solvent; ethyl acetate:n-hexane=5:5) to obtain 7 mg of pivaloyloxymethyl (1R,5S,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[(4R)-pyrrolidin-2-thion-4-ylthio[-1methylcarbepen-2-em-3-carboxylate as colorless crystal.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:30]=[C:31]([O:35][CH3:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1cccc(Br)c1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cnc(OC)nc4OC)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12m and 3-bromoanisole
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].[CH3:13][Si](C)(C)Cl.C(N(CC)CC)C.Cl.[C:26]([C@@H:31]([NH:35][C@H:36]([C:38](Cl)=[O:39])[CH3:37])[CH2:32][CH2:33][CH3:34])([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH3:34][CH2:33][CH2:32][C@H:31]([NH:35][C@H:36]([C:38]([N:1]1[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C@H:4]2[C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:39])[CH3:37])[C:26]([O:28][CH2:29][CH3:30])=[O:27].[CH3:8][C:9]([NH2:1])([CH3:4])[CH3:13]
Reactant: CCC[C@H](N[C@@H](C)C(=O)Cl)C(=O)OCC
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (7.44 g) in dichloromethane (80 mL) at 20-25° C., trimethylchlorosilane (5.84 mL) and triethylamine (6.4 mL) were added and it was stirred at 20-25° C. for two hours. After two hours triethylamine (5.54 mL) was added, the suspension was cooled to −15° C., a suspension of N—((S)-1-carbetoxybutyl)-L-alanylchloride hydrochloride (11 g) in dichloromethane (80 mL), cooled to −15° C., was poured thereto and the stirring was continued at a temperature from 0° C. to −5° C. for two hours. The reaction solution was heated to 0° C., the precipitated triethylamine hydrochloride was filtered off and washed with dichloromethane (20 mL), water (66 mL) in which NaOH (1.6 g) had been dissolved was added to the filtrate and the pH was adjusted to 4.2 with a 20% NaOH solution. The organic phase was separated and the aqueous layer was washed two more times with dichloromethane (40 mL). The combined dichloromethane layers were evaporated, the residue was dissolved in isopropyl acetate (250 mL), the undissolved part was filtered off, and t-butylamine (4.4 mL) was added to the filtrate. The precipitated crystals were dissolved at the boiling point of the solution, the clear solution was cooled to 10-20° C. and it was continued with stirring for two hours. After two hours, the precipitated crystals were filtered off, washed with isopropyl acetate (30 mL) and dried at 35-40° C. in an air dryer. 15.3 g of perindopril erbumine in alpha form with a purity of more than 99% were obtained; the content of single impurities was not above 0.1%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[CH:8]([CH2:10][CH2:11][C:12]([O:14]C)=O)=O.[C:16](O)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:16]([O:1][CH2:2][CH2:3][N:4]1[C:12](=[O:14])[CH2:11][CH2:10][CH:8]=[N:7][CH2:6][CH2:5]1)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: COC(=O)CCC=O
Reactant: NCCNCCO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCN1CCN=CCCC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 104.2 g (1 mole) of N-hydroxyethylethylenediamine and 116.1 g (1 mole) of methyl 3-formylpropionate. At 130° C., 18 g of water and 32 g of methanol were distilled off. After adding 340.5 g (1 mole) of behenic acid, esterification was carried out at 210° to 220° C. to obtain 4-behenoyloxyethyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[C:55]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1O)([CH3:58])([CH3:57])[CH3:56].C[OH:67]>C(Cl)Cl>[Br:1][C:62]1[CH:63]=[CH:64][C:59]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:60][C:61]=1[OH:67]
Reactant: CO
Reactant: [Br-]
Reactant: CC(C)(C)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Br)c(O)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Dissolve tetrabutylammonium tribromide (48.1 g, 100 mmol) and 2-tert-butylphenol (15 g, 100 mmol) in CH2Cl2(180 mL) and MeOH (120 mL) at 0° C., and stir overnight. Evaporate the solvent, and partition residue between Et2O (150 mL×3) and water (200 mL). Combine organic layers, and wash with 1M HCl (aqueous, 200 mL) and brine (100 mL), dry over MgSO4, filter, and rotary evaporate to give 23 g (100%) of 2-bromo-5-(1,1-dimethylethyl)phenol as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=8.5 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.87 (dd, J=8.5, 2.3 Hz, 1H), 5.57 (s, 1H), 1.31 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 153.15, 151.81, 131.37, 119.22, 113.48, 106.88, 34.68, 31.20.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.[CH3:30][C:31]([CH3:33])=[O:32].[Cl-].[NH4+]>C1COCC1>[C:26]([C:9]1[CH:8]=[C:7]([C:31]([OH:32])([CH3:33])[CH3:30])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(C)O)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of n-BuLi (1.6 M in n-hexane, 10.6 mL, 6.62 mmol) in THF (30 mL) was added a solution of tert-butyl 4-(4-bromo-2-tert-butylphenyl)piperazine-1-carboxylate (Example 85, 4.5 g, 11.3 mmol) in THF (15 mL) at −80° C. After stirred for 2 h at that temperature, it was added acetone (4 mL) and allowed to be warmed to room temperature. After 16 h, it was added saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=98:2 to 80:20) to provide tert-butyl 4-[2-tert-butyl-4-(1-hydroxy-1-methylethyl)phenyl]piperazine-1-carboxylate (3.1 g, 73%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:33])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:33])[N:15]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cccnc32)cc1
Temperature: 140 °C
Yield: 79.8 %

Procedure:
Cyclohexylamine (1.18 mL, 10.35 mmol) was added to a stirred solution of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (13) (1.80 g, 5.17 mmol) in xylene and heated at 140 ° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase washed by water and brine, then dried over Na2SO4 and evaporated to yield 1.68 g (82%) of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (29) as white solids. MP: 149° C.; 1H-NMR (DMSO-d6): δ 1.2-1.4 (m, 5H), 1.55 (m, 1H), 1.70 (m, 2H), 1.90 (m, 2H), 3.69 (s, 3H), 3.86 (m, 1H), 5.54 (s, 2H), 6.81 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.43 (m, 1H), 8.47 (dd, J=2.0, 8.0 Hz, 1H), 8.79 (dd, J=1.6, 4.8 Hz, 1H), 10.22 (d, J=7.2 Hz, 1H); EIMS m/z 408 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=O)[CH2:2][CH3:3].[C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:34])[CH:23]=1)(=[O:21])[CH3:20]>>[CH3:34][C:24]1[CH:23]=[C:22]([C:19](=[O:21])[CH:20]=[CH:17][C:5]2[S:6][C:7]3[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=3[C:4]=2[CH2:1][CH2:2][CH3:3])[CH:27]=[CH:26][C:25]=1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Reactant: CCCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Product: CCCc1c(C=CC(=O)c2ccc(C=CC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from the above-mentioned 3-propyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (112 mg, 0.411 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (90 mg, 0.41 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (107 mg, yield 55%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]([F:39])([F:38])[C:29]1[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:35]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:27])[F:38])[N:34]=2)=[O:36])[CH2:7]1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)n2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-trifluoromethyl-pyridine-2-carboxylic acid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.C(Cl)Cl.Cl>C1COCC1.O>[F:17][C:15]([F:16])([F:18])[C:12]1[N:11]=[CH:10][C:9]([CH2:8][CH2:7][C:6]([OH:19])=[O:5])=[CH:14][CH:13]=1
Reactant: COC(=O)CCc1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Lithium hydroxide monohydrate (330 mg) is added in one portion to a solution of 3-(6-trifluoromethyl-pyridin-3-yl)-propionic acid methyl ester (610 mg) in a mixture of THF (15 mL) and water (5 mL). The mixture is stirred for 20 h at RT. DCM and aqueous HCl (1.0 M) are added, the layers are separated and the aqueous layer is extracted twice with DCM. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to give the desired propionic acid as a beige solid.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C=O)C.[CH:32]1([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CC(C)=O.[OH-].[Na+]>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:42][C:40](=[O:41])[CH2:39][CH2:38][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: O=C(O)CCC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCC1CCCCC1

Procedure:
In 20 ml of acetone is dissolved 1.0 ml of cyclohexanepropionic acid, and 3.0 ml of 2N-NaOH is added, followed by addition of 1.2 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF. The mixture is refluxed for 8 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is chromatographed on a silica gel column. Following passage of 200 ml of n-hexane-diisopropyl ether (3:7), elution is carried out with 800 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.21 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:58]=[CH:57][CH:56]=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[CH:56][CH:57]=[CH:58][C:50]=2[Cl:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Yield: 69 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (69 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (103 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 15 min. Subsequently, 2-chloro-α-methylbenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 64%).