Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[I-].[Na+].C[O-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[N:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: C[O-]
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nccn1CCN1CCOCC1
Temperature: 100 °C
Yield: 58 %

Procedure:
2-Nitroimidazole (0.55 g, 4.86 mmol), 4-(2-chloroethyl)morpholine hydrochloride (0.90 g, 4.86 mmol), sodium iodide (0.18 g, 1.21 mmol) and sodium methoxide (0.59 g, 10.0 mmol) are dissolved in DMF (25 mL). The mixture is heated at 100° C. under a nitrogen atmosphere for 14 h. The reaction mixture is cooled and solvent removed in vacuo. The residue is partitioned between ethyl acetate (30 mL) and sat. NaHCO3 (aq.) (30 mL). The aqueous layer is extracted with ethyl acetate (4×30 mL). The organic layers are combined, dried (MgSO4) and solvent removed in vacuo. The solid residue is purified by column chromatography, eluting with 3% methanol in dichloromethane to give a yellow oil (638 mg, 58%). 1H-NMR (400 MHz, d6-DMSO) =2.39-2.45 (m, 4H), 2.66 (t, 2H, J=6 Hz), 3.52 (t, 4H, J=4.8 Hz), 4.52-4.54 (t, 2H, J=6 Hz), 7.19 (s, 1H, Har), 7.68 (s, 1H, Har).
Reaction SMILES: [N+](=C)=[N-].[OH:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:22](O)(=O)C>C(OCC)C.O1CCOCC1>[CH3:22][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1Cc2cccc(Oc3ccccc3O)c2O1
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccccc1Oc1cccc2c1OC(=O)C2
Reaction time: 8 h

Procedure:
An excess of a solution of diazomethane in diethyl ether was added to a solution of 7-(2-hydroxyphenoxy)2,3-dihydrobenzofuran-2-one (4.9 g) in a mixture of diethyl ether (50 ml) and dioxane (50 ml), and allowed to stand overnight at room temperature. To the reaction mixture was added acetic acid (1 ml), and the organic solvent was distilled off. The oily residue was purified by column chromatography, and the crude crystals were crystallized from ethyl acetate to give 7-(2-methoxyphenoxy)-2,3-dihydrobenzofuran-2-one (2.3 g). mp 171°-172° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.Br[C:60]1[CH:66]=[C:65]([CH3:67])[C:63]([NH2:64])=[C:62]([CH3:68])[CH:61]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:68][C:62]1[CH:61]=[C:60]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)[CH:66]=[C:65]([CH3:67])[C:63]=1[NH2:64]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(C)c1N
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Bis(dibenzylideneacetone)palladium (2.88 g) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.69 g) were added to dry toluene (175 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (7.06 g), morpholine (8.7 mL) and 4-bromo-2,6-dimethylaniline (10.03 g) were added subsequently. The reaction mixture was heated to reflux for 16 hours under argon, cooled and filtered through silica (200 g). Brine (250 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was dissolved in diethyl ether (250 mL), filtered through silica (200 g) and concentrated in vacuo to furnish 8.5 g (41% yield) of the title compound as a dark oil. The product was used without further purification. GC-MS (m/z) 206 (M+); tR=6.90. 1H NMR (500 MHz, CDCl3): 2.18 (s, 6H), 3.02 (m, 4H), 3.85 (m, 4H), 6.62 (b, 2H).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:15])([CH3:14])[CH2:8][CH:7]2[CH3:16])C.Br.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:15])([CH3:14])[CH:8]=[C:7]2[CH3:16]
Reactant: CCOc1ccc2c(c1)C(C)CC(C)(C)N2
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CC1=CC(C)(C)Nc2ccc(O)cc21
Yield: 56.3 %

Procedure:
6-Ethoxy-2,2,4-trimethyl-3,4-dihydroquinoline [Ethoxyquin (70 g, 0.32 mole)], was added to 250 mL of 48% HBr, and the mixture was heated to reflux for about 1 hour. The solution was cooled and poured into water. The aqueous suspension was made basic (pH=14) by the addition of 50% aqueous NaOH. Concentrated HCl was added to adjust the pH to about 4, then the mixture was made slightly basic by the addition of saturated sodium bicarbonate solution. The mixture was extracted with EtOAc and the organic layers were dried (brine, MgSO4) and concentrated in vacuo. The thick dark oil was triturated with toluene and the insoluble residue was filtered. The crude solid was recrystallized from toluene to give the title compound as a light brown solid (mp 182°-184°, 34 g, 0.18 mole, 56%). An analytical sample was prepared by another recrystallization from toluene to provide light brown crystals, mp 182°-184°: IR (KBr) 3302, 2972, 2934, 1586, 1495, 1344, 1244, 1154, 880, 814 cm-1 ; 1H NMR (D-6 DMSO) δ 1.12 (s, 6H), 1.33 (s, 3H), 3.34 (s, 1H), 5.17 (br s, 1H), 5.26 (s, 1H), 6.28-6.42 (m, 3H); MS m/e 190 (MH+) .
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:39][C:40]1[NH:41][CH:42]=[CH:43][N:44]=1.Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:39][C:40]5[NH:41][CH:42]=[CH:43][N:44]=5)[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: ClCc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (26 mg, 0.05 mmol) in dry DMF (1 ml) was added sodium hydride (5 mg, 0.13 mmol) at 0° C. under nitrogen. After 1 hour at 0° C., 2-(chloromethyl)-1H-imidazole.HCl (10 mg, 0.07 mmol) was added and the resulting mixture was stirred for an additional 1 h at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O) to give the title compound (5 mg, 17%). 1H NMR (500 MHz, CDCl3): 7.83 (1H, s), 7.22-7.15 (7H,m), 7.14-7.13 (2H,m), 6.94 (2H,s), 6.22 (1H, br s), 5.14 (2H, s), 4.98 (1H, br s), 4.83 (2H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.75-1.70 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6]C(C)=[CH:4][CH:3]=1.[C:9]([OH:12])(=[O:11])[CH3:10]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+].C([O-])(=O)C.[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:10]([C:9]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccc(F)cc1
Yield: 86.6 %

Procedure:
The test described in Example 1 was repeated using 300 g of p-fluorotoluene, 660 g of acetic acid, 132 g of water, 6 g of cobalt acetate tetrahydrate, 5 g of sodium bromide and 5 g of sodium acetate. In a reaction time of 240 minutes, after conventional work-up, 330.5 g of p-fluorobenzoic acid (86.6% of the theory) was obtained, with a purity of 99.9%.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24](C(N)=O)[CH:23]=1>CS(C)=O.O>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:15][C:14]=1[F:20]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccncc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Potassium tert-butoxide (214 g) was dissolved in dimethyl sulfoxide (750 ml) and tetrahydrofuran (250 ml) under a nitrogen stream, and a solution of 4-amino-3-fluorophenol ½ naphthalene-2,6-disulfonate (242 g) and 4-chloropyridine-2-carboxamide (100 g) in dimethyl sulfoxide (1000 ml) was added dropwise to the solution with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 30 minutes, then in an oil bath at 90° C. (external temperature) for 2 hours. The reaction mixture was allowed to cool down to room temperature, and water (3000 ml) was added, and the reaction mixture was stirred for 2 hours. The precipitated solid was collected by filtration, and washed with water (500 ml, twice). The residue was suspended in water (2000 ml), stirred for 30 minutes, collected by filtration again, and washed with water (500 ml, twice). Drying by hot air at 60° C. gave the title compound (119 g, 75.3%).
Reaction SMILES: [SiH](CC)(CC)CC.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=O)=[C:12]([CH3:25])[CH:11]=1.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:12]([CH3:25])[CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)c(C)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cc2ccc(C)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Et3SiH (8.5 mL, 0.0531 mol) was added to a mixed solution of chloroform (8 mL) and acetonitrile (32 mL) of (4-methoxy-2-methyl phenyl)(4-methylphenyl)methanone and BF3.Et2O (4.5 mL, 0.0354 mol) was added dropwise while cooled on ice. The reaction mixture was warmed to room temperature and stirred at 50° C. for one hour. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate while cooled on ice, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography-(hexane:ethyl acetate=15:1) to obtain colorless oily 4-methoxy-2-methyl-1-(4-methylbenzyl)benzene (3.89 g, 97%).
Reaction SMILES: ClC1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)C=1.[CH3:12][O:13][CH2:14][O:15]CCC=C>C(Cl)Cl>[CH3:12][O:13][CH2:14][O:15][CH2:6][CH2:5][CH:4]1[CH2:8][O:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCOCOC
Solvent: ClCCl
Product: COCOCCC1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
m-Chloroperbenzoic acid (20.6 g, 95.6 mmol) was gradually added to a solution of 4-methoxymethoxy-1-butene (10.46 g, 90.1 mmol) in methylene chloride (250 ml) while cooling in an ice-bath, the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered, and the filtrate was washed with a 10% sodium sulfide aqueous solution and sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(2-methoxymethoxyethyl)oxirane (10.3 g, 86%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25].[Cl-].[NH4+]>CCCCCC.CS(C)=O>[CH3:8][O:7][C:5]([CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C(C(=O)OC)C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
30 mL of anhydrous dimethyl sulfoxide was added to 0.98 g of sodium hydride defatted with hexane, and to the resulting solution, 2.98 g of dimethyl malonate was gradually added at room temperature while stirring. After completion of the dropwise addition, the resulting mixture was stirred at 100° C. for 1 hour. This mixture was cooled to room temperature, and 3 g (14 mmol) of ethyl 4-fluoro-3-nitrobenzoate was added thereto, and the resulting mixture was stirred at room temperature for 30 minutes and then further stirred at 100° C. for 1 hour. After the reaction mixture was cooled, saturated ammonium chloride was added thereto, and the resulting mixture was subjected to extraction with ethyl acetate. The obtained ethyl acetate layer was washed sequentially with saturated brine and water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure, whereby ethyl 4-(di(methoxycarbonyl)methyl)-3-nitrobenzoate was obtained.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11].IC>O>[CH3:8][C:9]([CH3:4])([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)C(C)(C)C(C)=O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 0.1 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, and slowly added dropwise 0.12 mol 3-methyl-2,4-pentandione at room temperature. Upon completion, the mixture was stirred for 0.5 hours, then 0.12 mol iodomethane was slowly added dropwise. After stirred at room temperature for 10 hours, 20 ml water was added to dissolve solid. The mixture was extracted with ethyl acetate. The solvent was removed. Distillation was carried out under reduced pressure, and cut fraction 82-84° C./1 kPa was collected. The yield was 98%.
Reaction SMILES: [C:1]1([CH2:6][SH:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N1C(=O)C2=CC=CC=[C:12]2[C:11]1=[S:20])C>>[CH2:11]([S:20][S:7][CH2:6][C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCN1C(=O)c2ccccc2C1=S
Reactant: SCc1cccs1
Product: CCSSCc1cccs1

Procedure:
Starting from thenylmercaptan and N-ethylthiophthalimide there is obtained ethyl-thenyl-disulphide. nD20 =1.6044.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].CN(C)C=O.[H-].[Na+].I[CH2:31][CH3:32]>O>[CH3:1][O:2][C:3]([C:5]1([N:15]([CH2:31][CH3:32])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)OCC(C)C)CCc2ccccc2C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OCC(C)C)C1(C(=O)OC)CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cooled solution of ester from Example 53D (101 mg, 0.33 mmol) and anhydrous N,N-dimethylforamide (1.5 mL) under N2 was added 60% dispersion sodium hydride (35 mg, 0.825 mmol) and then stirred for 15 minutes. Iodoethane (40 μL, 0.495 mmol) was added. The reaction was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column (20% ethyl acetate/hexane) to provide the titled compound as a clear, colorless syrup (51 mg, 46%). 1H NMR (δ, CDCl3): 7.07–7.15 (m, 4H), 3.90 (dd, 2H), 3.71 (s, 3H), 3.35–3.5 (m, 2H), 3.00–3.08 (m, 2H), 7.75–2.8 (m, 2H), 2.55–2.6 (m, 1H), 2.19–2.3 (m 1H), 1.88–2.0 (m, 1H), 1.14 (t, 3H), 0.95 (d, 6H). MS (DCI/NH3): 334.2 (M+1).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14][C:13]([OH:23])=[CH:12][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.ClCCl>[Cl:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14][C:13]([OH:23])=[C:12]([I:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Cl)c(-c2cccc(F)c2)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1cc(-c2cccc(F)c2)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
N-Iodosuccinimide (261 mg, 1.16 mmol) was added to a mixture of 6-chloro-3′-fluorobiphenyl-3-ol (Preparation 100, 270 mg, 1.21 mmol) and concentrated sulphuric acid (24 μL, 0.43 mmol) in acetic acid (3 mL) and dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane (10 mL) and washed with sodium metabisulfite (0.5M, 10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with heptane:dichloromethane (70:30) to give the title compound (193 mg, 46%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH2:28]([N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1)[CH3:27]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cc3ccc(OC(F)(F)F)cc3)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Yield: 79.2 %

Procedure:
Compound 8 (77 mg, 0.229 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (43.3 mg, 0.252 mmol), potassium carbonate (95 mg, 0.687 mmol) and anhydrous dimethylformamide (5 mL) were charged to a small, argon purged flask fitted with a magnetic stirbar and resulting solution heated in an oil bath at 65° C. for 2 hours. After cooling to room temperature the mixture was diluted with H2O and ethyl acetate, transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude solid. The crude product was purified via chromatography on silica gel (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) to yield compound 9 (79 mg, 79.2%) as a yellow solid. 1H NMR (DMSO-d6) δ 0.77 (t, 6H, J=7.1 Hz), 2.39 (q, 4H, J=7.2 Hz), 2.50 (m, 2H), 4.19 (t, 2H, J=6.5 Hz), 4.31 (s, 2H), 6.40 (s, 1H), 7.33-7.41 (m, 4H), 7.58 (d, 1H, J=9.1 Hz), 7.99 (dd, 1H, J=9.0, 2.2 Hz), 8.48 (d, 1H, J=2.3 Hz).
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[CH:14]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:15])=O)(C)(C)C.[O:29]=[C:30]1[O:34][CH:33]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40]C=2)[CH:32]([NH:44][C:45](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:46])[CH2:31]1>>[CH2:36]([O:35][CH:33]1[CH:32]([NH:44][C:45]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:28])[CH:14]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:25])[CH3:26])=[CH:20][CH:19]=2)[CH3:15])=[O:46])[CH2:31][C:30](=[O:29])[O:34]1)[C:37]1[CH:38]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(NC(=O)c1ccc(N(C)C)cc1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N(C)C)cc1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 45 %

Procedure:
Prepared from 1-[2-(4-dimethylamino-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 60 mg (45% yield). 1H-NMR (500 MHz, CDCl3): δ 1.04 (d, 0.75H), 1.35 (d, 2.25H), 1.80-2.50 (m, 5H), 2.75-3.20 (m, 8H), 3.5H), 4.80-4.95 (m, 1.5H), 5.52 (d, H), 5.75-6.00 (m, 0.5H), 6.60-6.90 (m, 3H), 7.10-7.50 (m, 4H), 7.50-7.80 (m, 2H); retention time on analytical HPLC: 10.46 min; LC-MS: m/z=523 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([O:21]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:26](CCN)CC)C.C(N(C(C)C)CC)(C)C>CCOCC>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([NH2:26])=[O:21])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCN(CC)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: NC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 18 h

Procedure:
A mixture of 10 g (0.033 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) of diethylaminoethylamine and 39 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The reaction was stripped, the residue taken up in about 300 mL of ether and washed twice with water. The ether layer was extracted twice with a total of 150 mL of cold water containing 20 mL of 10% HCl. The combined water extracts were washed once with ether, colled, made basic with solid sodium carbonate, extracted several times with methylene dichloride, dried over sodium sulphate, treated with decolorizing carbon, filtered and stripped. The oily red residue was crystallized from ether to yield 6.86 g of N-[2-diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp 80°-83° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:14]=[CH:13][CH:12]=[C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOC(=O)COc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(-c2cccc(CO)c2)c1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a solution of ethyl (3-bromophenoxy)acetate (488 mg) in DME (10 mL) was added 3-(hydroxymethyl)phenylboronic acid (429 mg), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride (77 mg) and 2M Na2CO3 aqueous solution (5 mL) at ambient temperature. The reaction mixture was stirred at 80° C. for 7 hours. The resulting mixture was cooled to ambient temperature and diluted with EtOAc. The mixture was washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=100:0-97:3) to give ethyl {[3′-(hydroxymethyl)-3-biphenylyl]oxy}acetate.