Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].[CH2:13]=[O:14]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:13][OH:14])=[C:5]2[OH:12]
Reactant: Oc1ccnc2ccc(Cl)cc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2ccc(Cl)cc2c1O

Procedure:
6-Chloro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide at 55° for 24 hours to give the novel compound 6-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p.>300°.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[CH3:10][C:11]([CH3:13])=O.C(O)=O.C(O)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C([O-])(=O)C.[Na+]>Cl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]2[CH:6]3[CH2:5][CH2:13][CH:11]2[CH2:10][C:3](=[O:4])[CH2:7]3)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)=O
Reactant: COc1ccc(CCN)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(CCN2C3CCC2CC(=O)C3)cc1OC
Temperature: 10 °C
Yield: 66.9 %

Procedure:
Following a general procedure previously described (P. Doster et al. Eur. I. Med. Chem. 1984, 19, 105), 8.2 g (62 mmol) 2,5-dimethoxytetrahydrofuran were heated at 80° C. in 75 ml of 0.1N aqueous HCl for 1 h. After cooling to 10° C., 10 g (68.4 mmol) acetone dicarboxylic acid, 12.4 g (68.5 mmol) 2-(3,4-dimethoxyphenyl)ethylamine, 6.13 g (74.7 mmol) sodium acetate and 5.7 ml 12N aqueous HCl were added wile stirring. Stirring was maintained overnight at room temperature. The aqueous mixture was neutralized and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO4 and concentrated. The filtrate was concentrated and the residual oil was purified by chromatography on silica gel using ethyl acetate as eluent, affording 12 g of an oil pure by TLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
To a solution of methyl 3-(6-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}pyridin-3-yl)propanoate (0.170 g, 0.45 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.017 g, yield 10%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:7]([C:1]1[CH:6]=[CH:5][C:4]([C:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:16])=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1ccc(C(=O)CCC(=O)O)cc1
Yield: 83 %

Procedure:
Cumene 10d (99%, 4.8eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 120 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11d were obtained in 83% yield. 1H-NMR: 7.92 (d, 2H, Ar--H); 7.32 (d, 2H, Ar--H); 3.30 (t, 2H, CH2CH2COOH); 2.97 (sept., 1H,CH(CH3)2); 2.81 (t, 2H, CH2CH2COOH); 1.27 (d, 6H, CH(CH3)2).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH2:27])[CH3:23]>N1C=CC=CC=1>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH:27][C:13]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1)=[O:21])[CH3:23]
Reactant: CCOC(CN)OCC
Reactant: O=C(Nc1ccc(-n2cncn2)cc1)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOC(CNC(=O)Nc1ccc(-n2cncn2)cc1)OCC
Temperature: 50 °C
Yield: 97.9 %

Procedure:
A mixture of phenyl 4-(1H-1,2,4-triazol-1-yl)phenylcarbamate (13 g), 2,2-diethoxyethyl amine (7.4 g) and pyridine (3.67 g) was heated at 50° C. for 3 hours. The resultant was cooled and the precipitated crystals were washed with a mixture of diisopropyl ether and petroleum ether (1:1, 100 ml×2) to give 1-(2,2-diethoxyethyl)-3-[4-(1H-1,2,4-triazol-1-yl)phenyl]urea (14.5 g) as a colorless crystalline
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Br:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Br:10][C:3]1[C:2]([F:1])=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:5]([CH:4]=1)[CH:6]=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
4-Fluoro-3-bromo-benzaldehyde (3.00 g, 14.78 mmol) was added to a stirred solution of concentrated nitric acid (67%, 2.02 mL, 29.55 mmol) in concentrated sulfuric acid (18 mL) at 0° C. After the addition was complete, the ice bath was removed and the reaction was allowed to stir for 3 hours at room temperature. Then, the mixture was poured into ice and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:9 ethyl acetate:hexanes to give 2.66 g (73%) of 5-bromo-4-fluoro-2-nitro-benzaldehyde as a solid. 1H NMR (400 MHz, d6-DMSO): δ 10.14 (s, 1H), 8.31 (d, J=8 Hz, 1H), 8.25 (d, J=7 Hz, 1H).
Reaction SMILES: [NH2-].[Na+].[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.Cl[CH2:20][CH:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>C1(C)C(C)=CC=CC=1>[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:20][CH:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:7]=2[CH:6]=1
Reactant: ClCC1CN2CCC1CC2
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)N(CC1CN3CCC1CC3)c1ccccc1S2
Temperature: 25 °C

Procedure:
19.8 ml of a 50% suspension of sodium amide in xylene were added to a suspension of 68.3 g of 2-methoxyphenothiazine in 700 ml of anhydrous xylene. The mixture was agitated and heated to reflux. After 41/2 hours, 272 ml of an 8.5% solution of 3-chloromethyl-quinuclidine in xylene were added over a period of an hour and reflux was maintained for 16 hours. After cooling to room temperature, the reaction mixture was worked up as in Example 2. After recrystallisation of the crude product in a mixture of ether and isopropyl oxide, 2-methoxy-10-(3-quinuclidinylmethyl)-phenothiazine, m.p. 135°-136° C, was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:16]3[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(4-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as an orange solid (0.080 g). The filtrate was concentrated in vacuo, and purification of the residue on a isolute silica column using 1 to 5% methanol in ethyl acetate as eluant gave an additional 0.055 g of the product (total yield: 68%); 1H-NMR (500 MHz, DMSO-d6) 2.53 (br s, 4H, piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 6.97 (s, 2H, NH2), 7.34 (d, J=5.88 Hz, 2H), and 8.51 (d, J=4.48 Hz, 2H) (pyrid-4-yl protons), 8.16 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.00 min—393, 395 [(M+H)+, Br isotopic pattern].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14].C(OCC)C>CCCCCC>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)C=CC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 358.4 %

Procedure:
3-Acetylpyridine (100 g, 0.19 mol) was added to dimethylformamide dimethylacetal (156.5 g, 1.27 mol), and the mixture was reacted under reflux for 23 hours. After the reaction mixture was cooled to 0° C., a mixture of diethyl ether and hexane (3:2, v/v) (500 ml) was added and the whole mixture was stirred for 4 hours. The resulting solid was filtered and washed with a mixture of diethyl ether and hexane (500 ml, 3/2, v/v) to give 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (120 g).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([CH2:2][CH2:3][N:7]([CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(CCC(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
Acrylic acid (36.03 g; 0.5 mol) was added to N-methylaniline (53.58 g; 0.5 mol) and an exothermic reaction took place after which reaction was virtually complete. The mixture was stood overnight at room temperature and then diluted with water and made alkaline by the addition of sodium carbonate. The mixture was washed with dichloromethane and then the aqueous layer was cautiously acidified to pH 4.5 by the addition of concentrated hydrochloric acid SG 1.18. The resulting mixture was extracted into dichloromethane and washed with water The organic extract was dried (MgSO4) and the solvent removed by evaporation under reduced pressure to give a pale brown oil (57.32 g; 64%).
Reaction SMILES: [Br:1][CH:2]([CH3:8])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[C:9](OC(=NC(C)C)NC(C)C)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[Br:1][CH:2]([CH3:8])[C:3](=[O:7])[C:4]([O:6][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5]
Reactant: CC(Br)C(=O)C(=O)O
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: ClCCl
Product: CC(Br)C(=O)C(=O)OC(C)(C)C
Yield: 47.7 %

Procedure:
A solution of 1.6 g (8.85 mmol) of 3-bromo-2-ketobutyric acid and 7 g (4 equivalents) of O-t-butyl-N,N'-diisopropylpseudourea in 14 ml methylene chloride is stirred overnight at room temperature. After filtration, the solution is washed with NaHCO3 and brine, dried and evaporated to an oil which is chromatographed on silica gel with benzene as eluant to give 1 g (45%) of t-butyl 3-bromo-2-ketobutyrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:41])[O:14][CH2:15][CH:16]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[Cl:39])=[O:29])[CH2:17][C:18]([CH3:26])([CH3:25])[CH2:19][O:20][P:21]([OH:24])([OH:23])=[O:22])=[CH:5]2.[OH-].[Na+:43]>CO>[P:21]([O-:24])([O-:23])([O:20][CH2:19][C:18]([CH3:25])([CH3:26])[CH2:17][C@H:16]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[Cl:39])=[O:29])[CH2:15][O:14][C:13](=[O:41])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:22].[Na+:43].[Na+:43]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)COP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)COP(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a solution of S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-dimethyl-5-(phosphonooxy)pentyl 6-fluoroisoquinolin-3-ylcarbamate (340 mg, 0.55 mmol) in MeOH (30 mL) was added NaOH (0.1 N, 10.8 mL, 1.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and concentrated. The residue was dissolved in small amount of water and lyophilized to give sodium (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl phosphate (343 mg, 94.1%) as white solid. LRMS (M-2Na++3H+) m/z 615.5.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].ClC1[N:14]=[C:13]2[CH:15]([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17]C2=CC=1>CO>[O:1]=[C:5]1[NH:14][C:13]2[CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:2]=2[CH:3]=[CH:4]1
Reactant: C1CCOC1
Reactant: COC(=O)C1CCc2ccc(Cl)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCc2ccc(=O)[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a 15 mL mixture of tetrahydrofuran, methanol, and a 1.0 N aqueous LiOH solution in a 3:1:1 ratio was added 0.242 g (1.14 mmol) of methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate from Step C above. The resulting mixture was stirred at ambient temperature for 1 h. The solution was evaporated in vacuo and the resulting light brown residue was purified by reverse phase HPLC (YMC Pack Pro C18, 100×20 mm I D column, 0-60% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in water gradient) to give the title compound as a brown oil (184 mg, 90%). LC-MS: m/z (E/S) 180.0 (MH)+.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:17][S:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=[O:27].[K+].[K+]>CN(C=O)C.O>[C:20]1([S:18]([CH2:17][S:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:27])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(CCl)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)ccc1SCS(=O)(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
A mixture of methyl 2-mercapto-5-trifluoromethylbenzoate (0.94 g, 0.0040 moles), chloromethylphenylsulfoxide (0.70 g, 0.0040 moles) and K2CO3 (1.66 g, 0.012 moles) in DMF (10 ml) was stirred vigorously at 50° for 45 minutes. The reaction was cooled, diluted with water (30 ml), and the resulting precipitate collected, water and hexane washed, and dried under vacuum to afford 1.05 g (70%) of methyl 2-phenylsulfonylmethylthio-5-trifluoromethylbenzoate. Rf (Et2O:Hexane, 1:1+1% Acetic Acid)=0.15.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:24]=[CH:23][C:10](/[CH:11]=[N:12]/[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][O:16][C:17]3=[O:22])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.[O-:34][CH2:35][CH3:36].[Na+].C(O)C>C(OCC)(=O)CC>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]2[C:35](=[O:34])[C:36]3[C:18]([C:17]([O:16][CH2:15][CH3:14])=[O:22])=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][CH:11]2[C:10]2[CH:23]=[CH:24][C:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:8][CH:9]=2)=[CH:28][CH:27]=1
Reactant: CC[O-]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCN(CC)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(Cl)cc1)C(c1ccc(CN(CC)CC)cc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A mixture of (E)-4-(4-((diethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (500 mg, 1.55 mmol) and 4-chlorobenzaldehyde (218 mg, 1.55 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (107 mg, 4.66 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the crude of the title compound (268 mg, yield 35%). LC-MS (ESI) m/z: 491 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#CCO)c2)c1F)c1[nH]cnc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (100 mg, 0.203 mmol), dichlorobisthiphenylphosphinepalladium(II) (14.22 mg, 0.020 mmol), copper(I) iodide (1.929 mg, 10.13 μmol) and TEA (0.141 ml, 1.013 mmol) in THF (5 ml) was added propargyl alcohol (22.72 mg, 0.405 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(3-hydroxy-1-propyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (18 mg, 0.038 mmol, 19% yield).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([Cl:23])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (2.1 g) and phosphorus pentachloride (1.6 g) in benzene (20 ml) was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure to give crystals of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g). A solution of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g) in benzene (20 ml) was added to a mixture of aluminum chloride (2.4 g) in benzene (20 ml). The mixture was stirred overnight at ambient temperature and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with diluted hydrochloric acid and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of hexane and ethanol to give crystals of 3-(2,4-difluorophenoxy)-4-nitrobenzophenone (2.3 g).
Reaction SMILES: [CH3:1][O:2][N:3]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:4]1[NH:5][C:6](=[O:31])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:15]([OH:16])[C@@:14]3([C:29]#[CH:30])[F:28])[C:11]=2[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:62]1[CH:67]=[CH:66][CH2:65][CH2:64][CH2:63]1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][N:3]([C:32]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:4]1[NH:5][C:6](=[O:31])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23])[C@@H:15]([O:16][CH:63]4[CH2:64][CH2:65][CH2:66][CH2:67][O:62]4)[C@@:14]3([C:29]#[CH:30])[F:28])[C:11]=2[N:12]=1
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(F)[C@H](OC2CCCCO2)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 13 (0.8 mmol), in anh THF (20 ml/mmol), at room temperature, was added p-toluen sulfonic acid (0.12 mmol) and dihydropyran (2 ml/mmol). The reaction mixture was stirred at room temperature for 3 days and neutralized with TEA. The mixture was diluted with DCM, washed twice with H2O. The organic phase was dried over Na2SO4, filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound. Molecular Formula C43H52FN5O6Si. Scan ES+ 780 (M+H)+