Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=[O:2].[CH3:9][N:10]([CH3:27])[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](N)=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1)(=[O:13])=[O:12].O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:9][N:10]([CH3:27])[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:2])=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1)(=[O:13])=[O:12]
Reactant: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Reactant: CC(C)CCON=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1

Procedure:
Isoamyl nitrite (150 ml) was added to a stirred mixture of 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzamide (15.1 g) in acetic acid and concentrated sulphuric acid while maintaining the temperature at 70°-80° C. It was cooled, poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered to give 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzoic acid (11.2 g) as a white solid, m.p. 188.9°-189.4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[F:28])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccccc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:30]([C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(C#Cc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Yield: 60 %

Procedure:
The phenylethynyl group has several unexpected advantages over the ethynyl based analog. See the Hergenrother and Delfort references supra. When 4-fluoro-4'-phenylethynylbenzophenone was treated with phenol in the presence of an alkali metal base such as potassium carbonate in a polar aprotic solvent at 160° C., the expected 4-phenoxy-4'-phenylethynylbenzophenone was afforded in nearly quantitativeyield. However, when 4-ethynyl-4'-fluorobenzophenone was used in the same procedure, the result was a mixture of products with a total yield of 60%.Several variations in the procedure were tried, but the resulting product was not exclusively tile expected ethynyl arylene-ether. This indicates that when the phenylethynyl endcapping compound is used to terminate nucleophilic reagents, the reaction proceeds qualitatively to afford the phenylethynyl terminated reactive oligomers exclusively. If the ethynyl adduct is used, a variety of products results.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.[C:24]([Si:28]([CH3:43])([CH3:42])[O:29][C@H:30]1[C@H:37]2[C@H:33]([O:34][C:35]([CH3:39])([CH3:38])[O:36]2)[O:32][C@H:31]1[CH:40]=[O:41])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([Si:28]([CH3:43])([CH3:42])[O:29][C@H:30]1[C@H:37]2[C@H:33]([O:34][C:35]([CH3:38])([CH3:39])[O:36]2)[O:32][C@H:31]1[C@H:40]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1)[OH:41])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(C)O[C@@H]2O[C@@H](C=O)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@H](O)[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@@H]3O[Si](C)(C)C(C)(C)C)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene from step C (3.6 g, 11.1 mmol) in THF (60 ml) under N2 at −78° C. was added dropwise BuLi (2.5 M in hexanes, 4.4 ml, 11.1 mmol). After 30 minutes, aldehyde from step B (2.4 g, 64% clean, 5.1 mmol) in THF (20 ml) was added dropwise, and the reaction was stirred for 30 min at −78° C., allowed to warm to room temperature and stirred for 60 minutes, quenched with sat. aq. NH4Cl, diluted with Et2O, and washed with H2O and brine. The combined aqueous washes were back extracted with Et2O, which was washed by the same sequence. The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (120 g SiO2, 0-20% EtOAc:Hexanes, 75 minutes, 85 ml/min) to give clean (S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol (0.84 g, 1.5 mmol, 30%) plus the C5 epimer (0.83 g) and some mixed fractions (0.51 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][C:16]=2[C:22]([F:24])([F:23])[F:25])[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: O=Cc1ccc2[nH]nc(Br)c2c1
Product: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
3-Bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde was prepared from 3-bromo-1H-indazole-5-carbaldehyde and 4-chloro-2-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: O.[NH:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]([N+:22]([O-:24])=[O:23])([CH3:21])[CH2:17][CH2:18][CH:19]=[O:20]>C(O)(C)C>[OH:20][C:19](=[C:8]1[NH:2][C:3](=[O:4])[NH:5][C:6]1=[O:7])[CH2:18][CH2:17][C:16]([CH3:21])([N+:22]([O-:24])=[O:23])[CH3:15]
Reactant: CC(C)(CCC=O)[N+](=O)[O-]
Reactant: O=C1CNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(CCC(O)=C1NC(=O)NC1=O)[N+](=O)[O-]
Temperature: 85 °C
Yield: 80.2 %

Procedure:
Water (70 ml) was added to hydantoin (20.8 g, 210 mmol) and sodium carbonate (7.2 g, 70 mmol) and the mixture was dissolved by heating to 85° C. 4-Methyl-4-nitropentanal (20.0 g, 140 mmol) was dissolved in isopropyl alcohol (130 ml) and added. The mixture was refluxed under heating for 2 h and isopropyl alcohol was evaporated under reduced pressure. Water (20 ml) and concentrated hydrochloric acid were added to adjust its pH to 8. The precipitated crystals were separated and dried to give 5-(1-hydroxy-4-methyl-4-nitropentylidene)hydantoin (27.3 g). This compound (19.4 g, 78.9 mmol) was dissolved in pyridine (60 ml) and methanesulfonyl chloride (7.9 ml, 102.6 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 3 h. Water (50 ml) was added and the mixture was extracted three times with ethyl acetate (50 ml). The extract solutions were combined and washed 4 times with 1 mol hydrochloric acid (50 ml). After separation of layers, the organic layer was concentrated to dryness to give 5-(1-methanesulfonyloxy-4-methyl-4-nitropentylidene)hydantoin (20.5 g). To this compound (5.74 g, 17.8 mmol) were added tetrahydrofuran (80 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.7 ml, 17.8 mmol) and the mixture was stirred at room temperature for 4 h. Tetrahydrofuran was concentrated under reduced pressure and the residue was extracted with ethyl acetate (50 ml) and 0.5 M hydrochloric acid (80 ml). After separation of layers, ethyl acetate was concentrated to dryness to give 5-(4-methyl-4-nitropentylidene)hydantoin (4.0 g, 17.6 mmol, yield 61.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:9]=[N+:10]2[O-:31])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc3ccc(OC)cc3[n+]([O-])c2)cc1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of methyl 4-(7-methoxyquinolin-3-yl)benzoate (632 mg, 2.16 mmol), mCPBA (742 mg, 4.31 mmol) and DCM (10 mL) was stirred overnight. Saturated Na2CO3 solution was added and adjusted the pH >7, the organic layer was washed with water (50 mL×2), dried over NaSO4 and evaporated in vacuo to give the crude product as a yellow solid (540 mg, 81.0%).
Reaction SMILES: [CH:1]12[BH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[ClH:10]>CCOCC.CCCCCC>[Cl:10][B:9]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:1]1[CH2:2][CH2:3][CH2:4]2
Reactant: B1C2CCCC1CCC2
Reactant: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: ClB1C2CCCC1CCC2
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield following the method of Example 1 by treating 9-borabicyclo[3.3.1]nonane (9-BBN, Aldrich Chemical Company, Inc., Milwaukee, Wis.) with anhydrous HCl in ether. 11B NMR δ 79 ppm in hexane, bp 65° C. (0.3 mm).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([NH2:18])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:35]=[C:36]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])=[CH:23][C:22]=1[NH:35][C:36]1[N:16]([CH3:17])[C:14]2[CH:15]=[C:5]([O:4][CH2:3][CH:2]([F:1])[F:19])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:13]=2[N:18]=1
Reactant: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)n(C)c2cc1OCC(F)F

Procedure:
The sub-title compound was prepared from ethyl 2-(2,2-difluoroethoxy)-4-methylamino-5-amino-benzoate and N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethylpropionamide with DIC in DMF at r.t. in analogy to example 72a. The crude material was directly used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:25]#[N:26])=[C:16]4[S:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[C:17]=24)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.O[C@@H:28]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:29]([O:31]C)=[O:30]>C(Cl)(Cl)Cl>[C:25]([C:15]1[C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C@H:28]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:29]([OH:31])=[O:30])=[CH:7][CH:6]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)#[N:26]
Reactant: N#Cc1c2ccccc2c(-c2ccc(O)cc2)c2c1sc1ccccc12
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#Cc1c2ccccc2c(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)c2c1sc1ccccc12

Procedure:
Prepared from 11-(4-hydroxy-phenyl)-benzo [b]naphtho[2,3-d]thiophene-6-carbonitrile (Example 44) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp 145-148° C.: [a]D25=-2.03° (7.883 mg/mL CHCl3); NMR (CDCl3); δ8.31 (ddd, J=8, 1, 1 Hz, 1 H), 7.78 (ddd., J=8, 1, 1 Hz, 1 H), 7.70 (ddd, J=8, 8, 1 Hz, 1 H), 7.56 (ddd, J=8, 1, 1 Hz, 1 H), 7.47-7.37 (m, 6 H), 7.32 (ddd, J=8, 7, 1 Hz, 1 H), 7.20 (dd., J=8, 2 Hz, 1 H),7.14-7.05 (m, 4 H), 6.62 (ddd, J=8, 1, 1 Hz, 1 H), 5.06 (dd, J=7, 5 Hz, 1 H), 3.44 (d, J=5 Hz, 1 H), 3.42 (d, J=7 Hz, 1 H); MS (EI): [M+], 499 (100%); Anal. Calc. for C32H21NO3S: C, 76.93, H, 4.24, N, 2.80. Found: C, 75.77, H, 4.22, N, 2.70.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl.Cl.[CH3:18][N:19]([CH3:27])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (336 mg, 1.6 mmol) to afford the desired product (156 mg, 38%) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ 10.88 (br s, 1H), 8.94 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 5.07-4.92 (m, 1H), 2.67 (s, 3H), 2.34 (s, 6H), 2.39-2.32 (m, 2H), 2.31-2.22 (m, 1 H), 2.07-1.99 (m, 2H), 1.56-1.35 (m, 4H); ESI MS m/z 347 [M+H]+
Reaction SMILES: [C:1]1([S:7][CH:8]([CH:16]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)O)[CH:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O>O1CCOCC1>[C:25]1([S:24][CH:16]2[CH:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:17]2[C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC(c1cccs1)C(Sc1ccccc1)C(Sc1ccccc1)C(O)c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(SC2C(c3cccs3)OC(c3cccs3)C2Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 2,3-bis(phenylthio)-1,4-di(2-thienyl)-1,4-butanediol (54.0 g, 114.9 mmol) in 350 ml dioxane there is added 8.70 g conc. sulfuric acid in 4 almost equal portions with a 45 minutes interval between each addition. The rather thick suspension is stirred mechanically for 4 days at room temperature whereby a clear solution is obtained. The solution is poured into 500 ml water and the product is extracted with 2×300 ml toluene. The organic layer is washed with 2×250 ml water, then dried and rotary evaporated. A quantity of 50 ml ether, followed by 200 ml methanol as well as some seed crystals are stirred into the residue. The crystallized product is filtered off and washed with methanol. It weighs 21.83 g. The filtrate is rotary evaporated and the residue is chromatographed on an aluminum oxide column (16×3 cm) using a 1/1 mixture of toluene and hexane as the eluent, thus obtaining a fraction with an additional amount of the product. This fraction is rotary evaporated and the residue is dissolved in some ether. Methanol is added while stirring, whereupon 3,4-bis(phenylthio)-2,5-di(2-thienyl)-tetrahydrofuran crystallizes. It is isolated in the usual way and weighs 7.04 g. The total yield is 28.87 g (63.9 mmol, 56%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.Cl.[CH:18](OCC)=[O:19]>>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH:18]=[O:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(SC)cc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (0.84 g, 20.8 mmol) was added at room temperature to a solution of ethyl 4-methylthiophenylacetate (1.1 g, 5.2 mmol) in ethyl formate (20 mL). The mixture was stirred at room temperature for 1 hour and then cold 0.5 N HCl (20 mL) was added slowly. The crude reaction was then extracted with ether, and the organic layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated to yield 1.2 g of ethyl 4-methylthio-α-formyl-phenylacetate as a colorless oil, which was used in the next step without purification.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(O)cc1

Procedure:
2.50 g of optically active 1-trifluoromethylheptyl ester of p-benzyloxybenzoic acid was dissolved into 50 ml of ethanol, and then hydrogenolyzed under an atmosphere of hydrogen using 0.5 g of 5% Pd/C (palladium/carbon). After separating Pd/C by filtration, ethanol was distilled off to obtain 1.73 g of optically active 1-trifluoromethylheptyl ester of p-hydroxybenzoic acid.
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH:13]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:21][C:22](=[O:32])[NH:23][C:24]=2[CH2:25][O:26][CH2:27][CH2:28][N:29]=[N+]=[N-])=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[H][H].[Pd]>[C:40]1([CH:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:21][C:22](=[O:32])[NH:23][C:24]=2[CH2:25][O:26][CH2:27][CH2:28][NH2:29])=[O:18])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: [N-]=[N+]=NCCOCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCCOCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1

Procedure:
10 ml of ethyl acetate was added to a mixture of 180 mg (0.330 mmol) of 6-(2-azidoethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide and a catalytic amount of 10% palladium/carbon, and they were stirred at room temperature in hydrogen atmosphere under normal pressure overnight. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain the title compound.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH:33]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)[CH2:32][CH2:31]2>C1C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[C:33]([C:52]1[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1)[CH:32]=[CH:31]2
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2CCCCCCCCCCCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCCCCCC(=O)O)cc1

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.31 g.) and p-toluenesulphonic acid (0.005 g.) were successively added to a stirred solution of 12-[(1RS, 2RS)-6-methoxy-2-p-methoxyphenyl-1,2,3,4- tetrahydronaphth-1-yl]dodecanoic acid (0.29 g.) in benzene (30 ml.), and the mixture was stirred and heated under reflux for 2 hours whilst a stream of argon was bubbled through it. The mixture was cooled and filtered, the filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 2:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 12-(6-methoxy-2-p-methoxyphenylnaphth-1-yl)dodecanoic acid, which was a starting material for compounds described in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner as described in example 4 from 4-methoxy-3-methylbenzoic acid and pentan-3-amine. MS (M+H, 236).
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:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl.O>[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:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)c5ccc(Cl)cc5)cc4c3)c2cc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.110 g, 0.31 mmol) in 10 ml of CH2Cl2 was added K2CO3 (0.086 g, 0.62 mmol). The mixture was cooled to 0° C. and 4-chlorobenzoyl chloride (44 mL, 0.34 mmol) was added. The solution was stirred for 16 h and allowed to gradually warm up to RT. The reaction was diluted with water and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 485.0 (M+1). Mass Calc'd for C29H21ClN2O4: 484.937.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([O:28][C:29]([F:32])([F:31])[F:30])[CH:12]=[C:13]3[C:18]=2[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:14]3)=[CH:3][CH:2]=1>CC(O)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([O:28][C:29]([F:32])([F:30])[F:31])[CH:12]=[C:13]3[C:18]=2[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([OH:25])=[O:24])=[CH:14]3)=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccncc3)c2OC1C(F)(F)F
Solvent: CC(=O)O
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccncc3)c2OC1C(F)(F)F

Procedure:
The ester from Step 1 was hydrolyzed via a method similar to that described in Example 621c, Step 2 using HOAc in the acidification step to give the product as a pale yellow solid: ESHRMS m/z 430.0531 (M+H, C19H10F6NO4, Calc'd 430.0509); 1H NMR (dmso-d6, 300 MHz) 14.5 (brs, 1H), 8.64 (d, 2H, J=5.7 Hz), 7.58-7.48 (m, 5H), 6.08 (q, 1H, J=7.3 Hz).