Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18](O)=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.C1COCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(F)cc2F)cc1=O
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
2-(Aminooxy)ethanol (0.05 g, 0.6 mmol) in MeOH (1 ml) was added to 4-(2,4-difluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (0.15 g, 0.5 mmol) in MeOH (20 ml). THF was added dropwise until the reagents dissolved. The solution was stirred at RT for 30 min, after which DMT-MM (0.18 g, 0.6 mmol) was added. After stirring at RT for 60 h, the reaction had not gone to completion. Further 2-(aminooxy)ethanol (0.05 g, 0.6 mmol) and DMT-MM (0.18 g, 0.6 mmol) were added and the reaction mixture stirred for a further 2 h at RT. The solvent was then removed under reduced pressure and the residue dissolved in EtOAc. After washing with water ×2, sat. NaHCO3 and brine, the organic layer was dried (Na2SO4), concentrated and further purified by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) to give 4-(2,4-difluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.07 g, 39%) as a white solid; m.p. (EtOAc/Hexane) 232-238° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.62 (br s, 1H), 9.21 (br s, 1H), 8.11 (s, 1H), 7.51-7.38 (m, 2H), 7.17-7.11 (m, 1H), 5.30 (s, 1H), 4.76 (br s, 1H), 3.92 (t, J=4.8 Hz, 2H), 3.62 (t, J=4.8 Hz, 2H), 3.34 (s, 3H). LCMS (ACPI+) 340 (100%). Anal. Calcd for C15H15F2N3O4.0.25 H2O: C, 52.4; H, 4.5; N, 12.2. Found C, 52.6; H, 4.5; N, 12.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:22]3[N:23]=[CH:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:26]=3)([OH:21])[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.N1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([C:22]3[N:23]=[CH:24][NH:25][CH:26]=3)([OH:21])[CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)cc1OC
Yield: 81.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-(3′,4′-dimethoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.37 g) and pyridine hydrochloride (479 mg), the colorless amorphous title compound (660 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].[CH2:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]#[CH:18])[CH3:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[CH3:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[C:15]#[C:14][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](CC)(CC)CC)c(C)c1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-bromo-3-methylbenzoate (from the previous step) (1.0 eq.), triethyl(ethynyl)silane (1.1 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 60° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% ethyl acetate in hexane to give ethyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([S:13][CH:14]=[CH:15][C:16](Cl)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][NH:28][C:16](=[O:17])[CH:15]=[CH:14][S:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)C=CSc1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(C=CSc1ccccc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
Pyridine (2.7 ml) was added to THF (80 ml) solution of 3-(phenylthio)acryloyl chloride (3.0 g) and hydrochloric acid salt of O-benzylhydroxylamine (2.6 g) under ice-cooling and stirred at the same temperature for one hour and at room temperature for three hours. The reaction mixture was concentrated under reduced pressure. Chloroform (150 ml) was added to the residue, washed successively with 1N hydrochloric acid, pure water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 2:1) to obtain N-benzyloxy-3-(phenylthio)acrylamide (3.5 g) as colorless oil. N-benzyloxy-3-(phenylthio)acrylamide (1.0 g) was dissolved to acetonitrile (70 ml), carbon tetrabromide (2.3 g) and triphenylphosphine (1.8 g) were added thereto under ice-cooling, then heat refluxing for four hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 20:1) to obtain N-benzyloxy-3-(phenylthio)acrylimidoyl bromide (1.1 g) as light yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: Oc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)cc1Cl
Reaction time: 1 h

Procedure:
Concentrated nitric acid (10 ml) in acetic acid (30 ml) was added dropwise to a cooled solution of 3-chlorophenol (10 g) in acetic acid (10 ml). After 1 hour at -5°, the mixture was poured onto ice, extracted with ether, dried over sodium sulfate and evaporated. The residue was then pun fled by column chromatography eluting with hexane-ethyl acetate (85:15) to give the title compound (9 g). M.p. 120°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[NH2:21]>>[NH2:21][C:13]1[CH:14]=[C:15]([C:16]2[O:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:19]=[CH:20][C:12]=1[O:11][CH3:10]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: Cc1ccc(N)c(O)c1
Product: COc1ccc(-c2nc3ccc(C)cc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-amino-5-methylphenol (368 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 75 mg (10%). 1H NMR (CDCl3) δ 7.69–7.58(m, 4H), 7.35(bs, 1H), 6.92(d, J=7.9 Hz), 3.85(s, 3H), 2.51(s, 3H). MS 255 m/z (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=[C:11]([CH2:19][O:20][Si](C(C)C)(C(C)C)C(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH2:19][OH:20])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)nc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1ccc(CO)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-benzyloxy-3-propoxy-6-triisopropylsilanyloxymethyl-pyridine (860 mg, 2.0 mmole) is added 1M tetrabutylammonium fluoride solution in tetrahydrofuran (4.0 mL, 4.0 mmole) and the mixture stirred at room temperature for four hours. The reaction mixture is diluted with water and extracted with ether. The combined ether layers were combined and washed with water, dried over sodium sulfate, filtered, chromatographed on silica gel eluting with 1:1 hexanes/ether to give a white solid, 355 mg, (65%); m.p. 50-1° C., MS (ES+): m/z 274.1 (M+H).
Reaction SMILES: COC1C=CC(C[O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=CC=1>C(O)(=O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(COc2ccc(C=O)cc2OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reaction time: 48 h
Yield: 82.9 %

Procedure:
A solution of 4-[(4-Methoxyphenyl)methoxy]-3-(phenylmethoxy)benzaldehyde (25.93 g, 0.074 mol) in acetic acid (200 mL) was heated to reflux (150□C) and stirred for 2 days. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL). The organic solution was washed with water (200 mL) and 0.5M aqueous sodium hydroxide (5×200 mL). The basic extracts were combined, acidified to pH 1 with concentrated HCl and back extracted with ethyl acetate (2×300 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to a gummy solid, which was recrystallized from ethyl acetate and petroleum ether to give the product as a pale brown powder (14 g, 82%). 1H NMR (CDCl3) δ 9.84 (s, 1H, O═C—H), 6.26 (1H, s, OH), 5.20 (s, 2H, CH2Ph).
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:5][CH2:4]1>CO.N.[Ni]>[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:5][CH2:4]1
Reactant: O=C(OCC1CCC(=NO)CC1)N1CCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC1CCC(COC(=O)N2CCCC2)CC1
Reaction time: 12 h

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-oxo-cyclohexylmethyl ester (2 mmol) in ethanol (10 mL) was added hydroxylamine (10 mmol) and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester. Pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester was dissolved in a 2N ammonia methanol solution (10 mL) and then Raney nickel was added. After 12 hours stirring under hydrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester. To a solution of pyridine-2-yl-methanol (2 mmol) in THF (10 mL) was added CDI (2 mmol). After 2 h stirring at room temperature, pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester was added and the resulting mixture was stirred for additional 2 hours at 60° C. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (310 mg, 43% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1>C1C=CC=CC=1.C(OCC)C>[C:3]([O:7][C:6]([C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)=[O:8])([CH3:6])([CH3:4])[CH3:2]
Reactant: O=C(O)c1cc[nH]c1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1cc[nH]c1

Procedure:
0.50 g (4.50 mmol) pyrrole-3-carboxylic acid is suspended in 15 ml absolute benzene and boiled under reflux. A solution 4.07 g (18.0 mmol) 90% N,N-dimethylformamidedi-tert-butylacetal in 15 ml absolute benzene is added drop-wise within 30 min. Following another heating under reflux for 30 minutes and subsequent cooling, the reaction mixture is diluted with diethyl ether, washed with 5% sodium carbonate solution and saturated NaCl solution. Drying on sodium sulfate, filtration and concentration on the rotary evaporator leave as a crude product a yellow solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22].Cl>C(O)C.C(OCC)(=O)C.[Ni]>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[NH:15][C:21](=[O:22])[C:20]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)ccc1NC1CCCCC1
Reactant: O=C(O)C(=O)O
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c2cc(F)ccc2n(C2CCCCC2)c1=O
Yield: 49.9 %

Procedure:
A solution of 2.0 g (8.4 mmol) N-cyclohexyl-4-fluoro-2-nitroaniline in a mixture of 100 ml ethanol and 50 ml ethyl acetate was hydrogenated at atm. pressure by using Ra-Ni (1 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give an oil. A mixture of the oil, 2.8 g (23 mmol) oxalic acid dihydrate, 10 ml ethanol and 150 ml 4N hydrochloric acid was refluxed for 11/2h. After cooling to 25 C. the precipitate was filtered off and washed with water to give 1.1 g (50%) 1-cyclohexyl-6-fluoroquinoxaline2,3(1H,4H)-dione. M.p. 289.8° C., 1H-NMR (DMSO-d6) :12.0 (1H, broad s), 7.6 (1H, M), 7.0 (2H, M), 4.5 (1H, M), 2.6-0.9 (10H, M).
Reaction SMILES: [CH:1]1([C:7]([CH3:12])=[CH:8][C:9](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=CC[C@H]1O[C@@]1([C@@H]1[C@]2(OC2)CC[C@@H](OC(/C=C/C=C/C=C/C=C/C(O)=O)=O)[C@H]1OC)C.[N+:46]([C:49]1[CH:50]=[C:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[C:62]([F:65])([F:64])[F:63])[CH:52]=[CH:53][C:54]=1[NH2:55])([O-])=O>>[CH:1]1(/[C:7](/[CH3:12])=[CH:8]/[C:9]2[NH:55][C:54]3[CH:53]=[CH:52][C:51]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[C:62]([F:63])([F:64])[F:65])=[CH:50][C:49]=3[N:46]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=CC(=O)O)C1CCCCC1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: CO[C@@H]1[C@H](OC(=O)/C=C/C=C/C=C/C=C/C(=O)O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Product: C/C(=C\c1nc2cc(-c3ccccc3C(F)(F)F)ccc2[nH]1)C1CCCCC1

Procedure:
(E)-2-(2-Cyclohexyl-propenyl)-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole was prepared from the acid chloride of 3-cyclohexyl-but-2-enoic acid (prepared as described in YOUNG, S. T. et al., “Synthetic Studies in the Fumagillin Series”, J. Org. Chem., 1963, pp 928-932, Vol. 28) and 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (prepared as described in Example 3, STEP A) according to the procedures s described in Example 3, STEPS B, C and D.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:20]=3)[C:6](=[O:30])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][CH3:40].N1CCOCC1>CN(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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:20]=3)[C:6](=[O:30])[N:5]([CH2:38][CH2:39][CH3:40])[C:4]=2[N:3]=1
Reactant: CCCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCCc3nc(-c4ccccn4)no3)c(=O)c21
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: [K+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(CCCCc2nc(-c3ccccn3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (40 mg, 0.09 mmol) in DMF (3 ml) was treated with potassium carbonate (15 mg, 0.11 mmol) and 1-iodopropane (19 mg, 0.11 mmol). The mixture was heated at 40° C. for 3 h then at 70° C. for a further 3 h. The mixture was cooled and degassed by the successive application of vacuum and nitrogen gas. The mixture was then treated with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and morpholine (0.1 ml, 1.2 mmol) and then stirred overnight. The mixture was evaporated and partitioned between chloroform (2 ml) and water (2 ml). The aqueous phase was extracted with further chloroform (2 ml) and the combined organics evaporated and the residue dissolved in methanol (2 ml). The solution was applied to a 1 g aminopropyl SPE and eluted with methanol and then with 5% acetic acid in methanol. Product-containing fractions were pooled and evaporated and the product further purified by MDAP to reveal 8-chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1.4 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(Cl)Cl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCNc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCNc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 1.608 g (6.7 mmol) of 4,4-dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline (Compound 94) in 1.5 ml of triethylamine in a heavy-walled tube was degassed under argon and then treated with 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was degassed again under argon, treated with 2.09 g (21.2 mmol) of trimethylsilylacetylene and the tube was sealed. The mixture was heated at 50 degrees C. for 48 h. After cooling to room temperature methylene chloride was added to the reaction mixture and the mixture filtered. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 0.20 (9H, s), 1.20 (6H, s), 1.57-1.63 (2H, m), 3.16-3.25 (2H, m), 4.02 (1H, broad s), 6.24 (1H, d, J~8.2 Hz), 7.00 (1H, dd, J~8.2 Hz, 1.8 Hz), 7.26 (1H, d, J~1.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([OH:12])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:32]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44]CCC(C)C)[CH:39]=1)[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl.O.CN(C)C=O>[OH:44][C:40]1[CH:39]=[C:38]([O:37][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:43]=[CH:42][C:41]=1[C:10]([C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH:8]=1)=[O:12]
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1OCC(C)C
Reactant: CC(C)CCOc1cccc(OCCC(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OCCC(C)C)cc2O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
In 10 ml of methylene chloride is dissolved 1.00 g of 3-(3-ethoxy-3-oxopropyl)-4-isobutoxybenzoic acid. After adding 0.36 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide successively at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 0.95 g of aluminum chloride and 1.02 g of 1,3-diisopentyloxybenzene are successively added at 5-10° C., and stirred at the same temperature as above for 30 minutes and then at ambient temperature for 30 minutes. Then, 0.45 g of aluminum chloride is added at ambient temperature and stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 0.63 g of ethyl 3-[5-(2-hydroxy-4-isopentyloxybenzoyl)-2-isobutoxyphenyl]propanoate as a light yellow oily product. A 0.60 g portion of the oily product obtained above is dissolved in 12 ml of ethanol, 1.3 ml of 5 mol/L sodium hydroxide solution is added, and the mixture thus obtained is stirred at ambient temperature for 2 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.48 g of [5-(2-hydroxy-4-isopentyloxybenzoyl)-2-isobutoxyphenyl]-propanoic acid is obtained as a light yellow solid product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2Cl)(=[O:3])[NH2:2].[OH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1C(N)=O
Temperature: 150 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
After mixing 6-carbamoyl-4-chloro-7-methoxyquinoline (2.0 g, 8.4509 mmol), 5-hydroxyindole (1.68 g), diisopropylethylamine (2.2 ml) and N-methylpyrrolidone (2.2 ml), the mixture was heated and stirred at 150° C. for 5 hours. After cooling, the partly solidified reaction mixture was dissolved in dimethylsulfoxide and then adsorbed onto NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethanol, the suspension was diluted with diethyl ether and hexane, and the crystals were filtered out, washed with diethyl ether:hexane=1:5 and dried by aspiration to obtain the title compound (1.291 g, 3.8698 mmol, 45.79%) as light yellow crystals.