Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N+:18]([O-])([OH:20])=[O:19]>>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccccc1
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc([N+](=O)[O-])cc1
Temperature: -2 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1,3-Dihydro-5-methyl-6-phenyl-2H-imidazo[4,5-b]pyridin-2-one (Example 4c, 8.06 g) was added in small portions to 80 ml 90% nitric acid cooled to -2° C. The reaction mixture was stirred at 0° C. for 2 hours and then poured portionwise into ice-water. The solid product was collected, washed with water and ether, and dried in high vacuum at 110°-130° C. to give 9.3 g (97%) of 1,3-dihydro-5-methyl-6-(4-nitrophenyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. above 300° C. Further purification was accomplished by repeated recrystallization from aqueous dimethylformamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14]([O:16]C)=O.[F:23][C:24]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:26]C(O)=O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14](=[O:16])[CH2:26][CH2:25][C:24]([F:34])([F:23])[C:30]([F:33])([F:32])[F:31]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsilyl)amide (1.0M, 10 mL, 10 mmol) was added dropwise to a −78° C. THF (20 mL) solution containing methyl 2-bromo-5-chlorobenzoate (0.836 g, 3.35 mmol) and 3,3,4,4,4-pentafluoropentanoic acid (0.644 g, 3.35 mmol, intermediate from Step A). After stirring for 15 minutes at −78° C. the solution was warmed to 0° C. and stirred for an additional 2 hours. The reaction was quenched with an excess of aqueous 1N HCl(ca 20 mL) and stirred overnight at room temperature. The solution was concentrated to remove the majority of the THF. The solution was then diluted with EtOAc and washed with 1N NaHCO3 (twice) and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (liquid). 1H NMR (500 MHz, CH3 CN-d3): δ 7.64 (d, J=8.6 Hz, 1H); 7.56 (d, J=2.6 Hz, 1H); 7.40 (dd, J=8.5, 2.7 Hz, 1H); 3.23 (t, J=7.3 Hz, 2H); 2.61-2.50 (m, 2H). m/z=365.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:23]1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:23]1[NH:22][C:30]2[C:25]([C:24]=1[CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a pink solid. MS: 465.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccccc3C(F)(F)F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccccc3C(F)(F)F)c21
Temperature: 10 °C
Yield: 79.4 %

Procedure:
In 100 ml of dry THF was dissolved 4.31 g of 3,4-dihydro-9-(2-trifluoromethylbenzylamino)acridin-1(2H)-one and the mechanically stirred solution was cooled to 10° C. under nitrogen. To it was added 5.8 ml of 1M LiAlH4 in THF dropwise over 15 minutes. Within 0.5 hour of addition the reaction was complete by TLC, so it was quenched with 1 ml of saturated ammonium chloride and the salts were filtered. The filtrate was evaporated to a solid which was dissolved in dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was refluxed and pentane was added to effect crystallization. The crystals were collected from the cooled mother liquor to yield 3.44 g of solid, mp 158°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:5][C:4]=1[CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19]C)=[O:18]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:5][C:4]=1[CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(CC(=O)OC)c1cc(C(=O)CC)c(OC)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(CC(=O)O)c1cc(C(=O)CC)c(OC)cc1OC

Procedure:
The methyl 3-(2,4-dimethoxy-5-propionylphenyl)octanoate prepared as described in step (i) above was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as crystals, melting at 92.5-94° C. (from ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cu][C:15]#[N:16].[OH-].[Na+]>CN(C)C(=O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1)#[N:16]
Reactant: Brc1ccc(-c2ccncc2)nc1
Reactant: N#C[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-c2ccncc2)nc1
Yield: 83 %

Procedure:
By the same method as in Example 1,5-bromo-2,4′-bipyridine was prepared. The resulting 5-bromo-2,4′-bipyridine (7.0 g) was dissolved in N,N-dimethylacetamide (15 ml), followed by addition of copper (I) cyanide (2.8 g), for agitation at 140° C. for 3 hours. After the reaction solution was cooled, aqueous 25% NaOH solution (10 ml) was added to deposit a crystal, which was filtered and recovered, to obtain the object substance (4.5 g; yield of 83%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([F:19])[N:13]=1.C(=O)(O)[O-].[Na+]>COC(C)(C)C.C(OCC)(=O)C>[F:11][C:12]1[C:17]([NH:18][CH:5]=[O:7])=[CH:16][CH:15]=[C:14]([F:19])[N:13]=1
Reactant: Nc1ccc(F)nc1F
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: COC(C)(C)C
Product: O=CNc1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (6 ml) was added to formic acid (6 ml), followed by stirring at room temperature for 20 minutes. Then, a solution of 2,6-difluoro-3-aminopyridine (2.06 g) in tert-butyl methyl ether (7 ml) was added so that the reaction solution was maintained at room temperature. The reaction solution was further stirred at room temperature for four hours. Ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.42 g). The property values of the compound are as follows.
Reaction SMILES: N.[Li].[CH:3]#C.C([SiH2]O[C:11]([CH3:31])(C)[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)(C)(C)C>CS(C)=O.C1COCC1>[CH2:11]([CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)[C:31]#[CH:3]
Reactant: C#C
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Agent: N
Agent: [Li]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C#CCC1CCC(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 3-neck 250 mL-flask equipped with a gas inlet tube and dry-ice condenser was cooled to −78° C. and charged with liquid ammonia (40 mL). To the reaction mixture was added lithium wire (600 mg, 86.4 mmol) generating a deep blue solution. The mixture was allowed to stir for 1 hour. Acetylene, passed through a charcoal drying tube, was added to the ammonia until all the lithium had reacted and the solution turned colorless, at which time the flow of acetylene was stopped, the acetylene-inlet tube and condenser removed and the flask outfitted with a thermometer. DMSO (20 mL) was added and the ammonia evaporated with a warm water bath until the mixture reached a temperature of 30° C. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5° C. and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added. The temperature was maintained at 5° C. The mixture was allowed to stir at 5° C. for 0.5 hours. Then the solution was gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black reaction mixture was poured slowly over ice (300 g) and extracted with ether (4×100 mL), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield a yellow oil. The oil was subsequently dissolved in THF (200 mL) and changed to a brownish color upon addition of TBAF hydrate (11.20 g, 35.5 mmol). The solution was allowed to stir for 24 hours 2 under N2 atmosphere. After stirring, the reaction was quenched with water (200 mL) and extracted with ether (3×100 mL). The ether extracts were combined and concentrated in vacuo. The crude product was purified by chromatography, on a silica gel column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g, 93%) as a yellow oil. 1H NMR (CDCl3) δ 3.45 (d, J=6.2, 2H), 2.10 (d, J=6.2, 2H), 1.9 (s, 1H), 1.94-1.69 (m, 4H), 1.52-1.34 (m, 2H), 1.16-0.83 (m, 4H); 13C NMR (CDCl3) δ 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:25][CH:26]=C)[CH2:5][C@@H:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:29](O)(=[O:31])C.CSC>CO.C(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:25][CH:26]([O:31][CH3:29])[N:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5]1)=[O:28]
Reactant: CC(=O)O
Reactant: C=CC[C@H](C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(OC)N(C(=O)OCc2ccccc2)[C@@H](C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ozone gas was bubbled through a stirred, cold, (−78° C.) solution of (2R,4R)-4-allyl-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester (5.0 g, 12.8 mmol) in 100 mL of 10:1 methanol/methylene chloride, and 0.73 mL of acetic acid until a blue color persisted. Nitrogen gas was then bubbled through the solution until the blue color dissipated. The mixture was warmed to ambient temperature and dimethyl sulfide (2.8 mL, 3.83 mmol) was added. The mixture was stirred for 48 hours, diluted with methylene chloride, and washed with 10% aqueous sodium carbonate, brine, and the mixture was dried over sodium sulfate. Filtration and concentration of the filtrate provided (2R,4S)-6-methoxy-piperidine-1,2,4-tricarboxylic acid 1-benzyl ester 2-tert-butyl ester 4-methyl ester as a clear oil, which was used in the subsequent step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]=[C:8]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)C>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1

Procedure:
To a stirred suspension of 10% palladium on carbon (45 mg) in methanol (5 mL) was added a solution of 3-(benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acid tert-butyl ester 29-7b (220 mg) in ethanol (5 mL) and the mixture was subjected to an atmosphere of hydrogen for 48 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 9:1 ethyl acetate/methanol to give 29-8b as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:18])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[N:6]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>COCCOC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]([CH3:10])[C:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:25](=[O:28])[CH2:26][CH3:27])[S:3][CH:4]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CN(C(=O)Cc1csc(N)n1)c1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Solvent: COCCOC
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CC(=O)N(C)c2ccc(Cl)cc2)cs1
Yield: 52.2 %

Procedure:
A 300 ml reaction flask was charged with 6.0 g (0.021 mole) of 2-amino-4-[N-4-chlorophenyl-N-methyl(carbamoylmethyl)] thiazole, 100 ml of 1,2-dimethoxyethane and 2.6 g (0.03 mole) of pyridine. The propionyl chloride (2.8 g, 0.03 mole) which was dissolved in 15 ml of 1,2-dimethoxyethane was added portionwise and the reaction solution was heated at 65° for two hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was extracted with water and dried over sodium sulfate. After evaporating most of the ethyl acetate, hexane was added. There was obtained 3.7 g (51%) of product, M.P. 153°-5°. N.M.R. (CDCl3) ∂1.2-1.4 (CH3), 2.3-2.5 (CH2), 3.3 (NCH3), 3.5 (0=CCH2), 6.5 (hetero-aromatic) 7.2-7.4 (aromatic).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:3][C:4]([CH3:7])=[CH:5][CH:6]=3)=[C:18]([F:25])[CH:17]=2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: Cc1ccc(Br)s1
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(-c3ccc(C)s3)c(F)c2)cc1

Procedure:
A mixture of 5.0 g (28.2 mmol) of 2-bromo-5-methylthiophene, 7.70 g (28.3 mmol) of 4′-ethyl-3-fluoro-4-biphenylboronic acid, 1.70 g (1.47 mmol) of tetrakis(triphenylphosphine)palladium(0) and 30 ml of 2 N sodium carbonate solution in 90 ml of toluene/ethanol (1:2) is refluxed for 3 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=97:3). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(4′-ethyl-3-fluorobiphenyl-4-yl)-5-methylthiophene as a colourless solid (m.p. 102° C.).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:13](=[O:16])(O)[O-].[Na+].I[CH3:19]>CO.CN(C=O)C>[CH3:13][O:16][C:5](=[O:6])[C:4]1[C:3](=[C:2]([OH:1])[CH:12]=[CH:11][CH:10]=1)[C:8]([O:7][CH3:19])=[O:9]
Reactant: O=C([O-])O
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: CI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cccc(O)c1C(=O)OC
Temperature: 55 °C
Yield: 76.9 %

Procedure:
A stirred mixture of 3-hydroxyphthalic anhydride (20.5 g, 125 mmol) in methanol (100 mL) was heated to reflux for three hours. The solvent was evaporated in vacuo, and the residue was suspended in sodium bicarbonate (29.4 g, 350 mmol) in DMF (250 mL), followed by addition of iodomethane (19 mL, 300 mmol) and heating at 55° C. for four hours. The mixture was cooled to room temperature, solvent evaporated in vacuo, and the residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (2×200 mL), dried, concentrated in vacuo, and then purified by flash column chromatography (Silica Gel, EtOAc/Hexane, 0% gradient to 100% 30 min) to give 3-hydroxyphthalic acid dimethyl ester (20.2 g, 77% yield). The product was used in the next step without further purification.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH:33]=O)[CH:28]=1>>[Br:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:28]=1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)ccn1
Agent: [Br-]
Product: COCCCCc1cc(Br)ccn1

Procedure:
Analogously to residue 1a, 2,4 mmol of (3-methoxypropyl)triphenylphosphonium bromide [111088-69-8] and 1.6 mmol of 4-bromopyridine-2-carbaldehyde [131747-63-2] are reacted. The title compound (E,Z mixture) is identified on the basis of the Rf value.
Reaction SMILES: CS([O:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)=O.O[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]3[CH:40]=[CH:39][C:30]4[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=4[CH:28]=3)[CH:20]=2)=[C:14]([CH3:41])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:6]1([O:5][C:12]2[CH:13]=[C:14]([CH3:41])[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]5[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=5[CH:28]=4)[CH:20]=3)=[C:16]([CH3:18])[CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)OC1CCCC1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCCC5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Cyclopentyl methanesulfonate 10c (50 mg, 0.28 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (60 mg, 0.14 mmol), and cesium carbonate (100 mg, 0.30 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 10 mL of water and extracted with ethyl acetate (20 mL×2). The organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) successively, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by elution system B to obtain the title compound (S)-methyl 2-(6-((4′-(cyclopentyloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 10d (40 mg, yield 30.0%) as a colorless slime.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH2:5][CH2:6][OH:7].[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2>C(O)C>[OH:7][CH2:6][CH2:5][N:4]([CH2:1][C:10]1[C:9]([OH:8])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)[CH3:3]
Reactant: CNCCO
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C=O
Solvent: CCO
Product: CN(CCO)Cc1c(O)ccc2[nH]ccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Paraformaldehyde (0.060 g, 2 mmol) and 2-methylamino ethanol (0.15 g, 2.0 mmol) was suspended in ethanol (10 mL) and heated at 50° C. for 20 minutes. The solution was cooled to room temperature and 5-hydroxyindole (0.27 mg, 2.0 mmol) was added. The solution was stirred under an atmosphere of N2 at room temperature overnight. The solution was evaporated to give the title compound (441 mg) that was used in the next step without further purification. MS m/z 221 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]([OH:54])([CH2:52][CH3:53])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]([OH:54])([CH2:52][CH3:53])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CC)CC)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CC)CC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogen carbonate (0.74 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.086 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.18 g, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-])=O.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:24])=[N:20][C:21]=1[O:22][CH3:23].N1C=CC=CC=1.[O:31]1CCOC[CH2:32]1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:24]2[C:32](=[O:31])[NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10]2(=[O:12])=[O:11])=[N:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(N)nc1OC
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1OC

Procedure:
The title compound (0.30 g, 0.89 mmol) was prepared in three steps from 2-nitrobenzenesulfonyl chloride (1.05 g, 4.72 mmol), 5,6-dimethoxypyridin-2-amine (0.80 g, 5.19 mmol) and pyridine (1.15 mL, 14.2 mmol) in 1,4-dioxane (19 mL) using the methods of (IntA19).