Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using the procedure described in Example 103A, 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl]urea from Example 95B (0.45 g, 1 mmol) was reacted with tert-butyl 4-hydroxypiperidine-1-carboxylate (0.242 g, 1.2 mmol) in the presence of Ph3P (0.393 g, 1.5 mmol), and di t-butyl azodicarboxylate (0.345 g, 1.5 mmol) in THF (10 mL) at room temperature overnight, to afford tert-butyl 4-(4-{3-[3-(5-tert-butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)piperidine-1-carboxylate as a crude product. LC-MS (ESI) m/z 633 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(F)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(c2ccc(F)cc2)CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of ethyl 4-(4-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylate (7.1 g, 28 mmol) and KOH (3.2 g, 56 mmol) in 100 mL EtOH/H2O (4:1) was refluxed for 4 hours, M−1=223. The mixture was cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 4.9 g of the product as a white solid. MS (m/z)=223 (M−1)−.
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:8]=1[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])([O-])=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][S:2][C:7]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:8]=1[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]
Reactant: CCCCOC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)c1ccc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
Sodium thiomethoxide (0.91 g; 13.0 mmol; 1.3 equiv) was dissolved in water (3.4 mL). Tetrabutylammonium bromide (0.48 g; 1.50 mmol; 0.15 equiv) was added. Butyl 2-nitro-4-trifluoromethylbenzoate (5b; 2.91 g; 10.0 mmol) was dissolved in toluene (5 mL) and added to the mixture. The reaction mixture was stirred at ambient temperature for 2.5 h to completely consume 5b according to thin layer chromatography (tlc) analysis. The reaction mixture was diluted with toluene and water and the layers were thoroughly mixed and then separated. The organic layer was dried over Na2SO4 and concentrated to afford 2.85 g (98%) of 6b which contained a small amount of tetrabutylammonium bromide. The crude product was flash chromatographed and eluted with 5% ethyl acetate in heptane to afford 2.32 g (79%) of pure 6b.
Reaction SMILES: [F:1][C:2]1[C:12]2[NH:11][CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.[Cl-].[Na+].O>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8](=[O:13])[CH2:9][CH2:10][NH:11][C:12]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]1=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCNc2c(F)cccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)CCNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-fluoro-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one from Example 1B (220 mg, 1.2 mmol) in DMF (4 ml) was added sodium hydride (60%, 48 mg, 1.2 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and was stirred for 10 min. Tert-butyl bromoacetate (190 μl, 1.2 mmol) was added and the mixture was stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was reduced in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc:pet ether 60:40); yield 240 mg, 67%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: O=C1CCNCC1
Reactant: Brc1cccc2cc[nH]c12
Agent: Cl
Solvent: O
Product: Brc1cccc2c(C3CCNCC3)c[nH]c12

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 0.95 g (4.8 mmol) of 7-bromoindol and 1.89 g (12.3 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 1.1 g (89% of yield) of the desired product were obtained.
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=O)[C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:11][C:4]1[C:5]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])=[CH:6][NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1c(C(=O)O)c[nH]c1C=O
Reactant: CN1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O

Procedure:
5-Formyl-4-methyl-1H-pyrrole-3-carboxylic acid (500 mg, 3.27 mmol) reacted with 1-methylpiperazine (0.43 mL, 3.92 mmol) to give 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9][CH2:10][CH3:11])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH2:10][CH3:11])=[O:20])=[CH:4][N:3]=1
Reactant: CCSc1cnc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)c1cnc(Cl)c(Cl)c1
Yield: 42 %

Procedure:
4 g (0.02 mol) of 2,3-dichloro-5-ethylthiopyridine were reacted with 3.47 g (0.02 mol) of m-chloroperbenzoic acid in 30 ml of methylene chloride by a method similar to Example 1, Precursor β. After the crude product had been purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate=2:1), 1.9 g of product of value were obtained in the form of white crystals. Yield: 42%. m.p.: 78-79° C.; 1H-NMR (d6 dimethyl sulfoxide): δ [ppm]=1.1 (t; CH3); 3.0 and 3.2 (2×m, CH2); 8.35 and 8.6 (2×s, pyr H).
Reaction SMILES: C(Cl)(=O)OCC.[CH3:7][C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([CH3:12])[C:9](O)=[O:10].C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>CC(C)=O.O>[CH3:7][C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([CH3:12])[C:9]([N:25]=[N+:26]=[N-:27])=[O:10]
Reactant: CC(C)(C(=O)O)c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)N=[N+]=[N-])c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
10.6 ml of ethyl chlorocarbonate were gradually added, keeping the temperature below 0° C., to a solution of 15.8 g of 2-methyl-2-(2-thienyl)propionic acid [prepared as described in step (ii) above] and 15.6 ml of triethylamine in 210 ml of acetone. The reaction mixture was stirred at 0° C. for 2 hours, after which 10 ml of an aqueous solution containing 10.3 g of sodium azide were added to the mixture at 0° C. The reaction mixture was then stirred at 0° C. for 2 hours, diluted with water, and extracted three times with diethyl ether. The combined organic extracts were washed with 1N aqueous hydrochloric acid, with an aqueous solution of sodium hydrogencarbonate, and with a satulated solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure to give 18.5 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1)C.[C:23]1([C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][C:26]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A) and 4-phenylphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce the title compound. MS(ES) for C28H28O4[M+NH4]+: 446.2.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>O1CCCC1>[CH3:21][S:22]([O:4][CH2:3][C:2]([CH3:1])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)[CH3:5])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)n1cc([N+](=O)[O-])cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COS(C)(=O)=O)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (13 g) obtained in Step G of Example 103 in tetrahydrofuran (100 mL) were added successively dropwise triethylamine (12 mL) and methanesulfonyl chloride (6.3 mL) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (18 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:5]=2.[C:21]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].N1CCCCC1>CO>[C:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10](/[CH:11]=[CH:22]/[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:23])=[C:2]([CH3:1])[NH:3]2)=[CH:8][CH:7]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1[nH]c2cc(C(=O)c3ccccc3)ccc2c1C=O
Reactant: CC(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1[nH]c2cc(C(=O)c3ccccc3)ccc2c1/C=C/C(=O)c1ccncc1
Reaction time: 24 h
Yield: 74.7 %

Procedure:
In a dried 100 mL round bottom flask under argon, compound 29 (50 mg, 0.19 mmol) was dissolved in anhydrous methanol (3 mL). 4-Acetyl-pyridine (21 μL, 0.19 mmol) and piperidine (19 μL, 0.19 mmol) were added and the reaction was refluxed. After 24 hours, the reaction was cooled, filtered and rinsed with cold hexanes and dried under vacuum, yielding 52 mg (74%) of pure yellow solid. 1H NMR (600 MHz, d6-DMSO): δ 12.350 (s, 1H, N—H), 8.832-8.222 (d, J=6.0, 2H, pyr-2,6H), 8.255-8.241 (d, J=8.4, 1H, indole-4H), 8.125-8.099 (d, J=15.6, 1H, C═CH), 8.008-7.999 (d, J=5.4, 2H, pyr-3,5H), 7.801 (s, 1H, indole-7H), 7.766-7.754 (d, J=7.2, 2 H, phenyl-2,6H), 7.683-7.642 (m, 2H, phenyl-4H, indole-5H), 7.585-7.563 (m, 3H, C═CH, phenyl-3,5H), 2.659 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 195.5, 188.2, 150.6, 148.5, 144.6, 138.7, 138.2, 135.4, 132.0, 130.6, 129.4, 129.2, 128.4, 123.1, 121.5, 119.9, 114.5, 114.1, 109.6, 12.3. Melting point: 267-270° C. TLC (ethyl acetate:hexanes 4:1) Rf=0.29. Elemental analysis calculated for C24H18N2O2 0.05H2O: C, 78.48; H, 4.97; N, 7.63. found: C, 78.08; H, 5.01; N, 7.50.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Cl:6][C:7]1[N:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10].Cl>O.CO>[Cl:6][C:7]1[C:8]([C:9]([NH:2][OH:3])=[O:10])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NO)c1cccnc1Cl
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of hydroxylamine hydrochloride (6.75 g) in water (25 ml) was added sodium hydroxide solution (7.65 g sodium hydroxide in 50 ml water) with stirring under ice cooling. To this stirring solution was added methyl 2-chloronicotinate (15.5 g) in methanol. After being stirred at room temperature for 2.5 hours, pH was adjusted to 3.5 with 6N-hydrochloric acid under ice cooling. After 1 hour, the title compound (11.0 g) was obtained by filtering the precipitated crystals and washing with water and, then, a methanol-ether mixture (1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:18]1([NH:24][CH2:25][CH:26]=[CH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH2:27][CH:26]([CH2:25][NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][N:15]2[CH3:16])=[CH:4][CH:3]=1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc(Cl)cc1
Reactant: C=CCNc1ccccc1
Product: CN1OC(CNc2ccccc2)CC1(Cn1ccnc1)c1ccc(Cl)cc1

Procedure:
Derivative 3 (R1 =4-Cl, R2 =R3 =H) is obtained by a procedure similar to that described in Example 1 by reacting 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (1: R1 =4-Cl) with N-phenyl-2-propen-1-amine (2: R2 =R3 =H). The product cis-/trans-diastereometric mixture is flash-chromatographed on neutral silica gel using chloroform-methanol (97:3 by volume) as eluent. Isomer A has a melting point of 159°-160° C. (ethyl acetate). Anal. Calcd for C21H23ClN4O: C, 65.87; H, 6.05; N, 14.63; Cl, 9.26. Found: C, 65.77; H, 6.20; N, 14.42; Cl, 9.48. Isomer B has a melting point of 172°-173° C. (ethyl acetate).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 36.2 %

Procedure:
A mixture of methyl thiosalicylate (0.93 g, 5.5 mmol), 2-cyano-6-methylthiopyridine (0.83 g, 5.5 mmol), triethylamine (1.17 ml, 8.3 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.57 g, 37%) as crystals.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A solution of 21.5 g (99.5 mmol) of methyl 2-chloro-3-nitrobenzoate in 300 mL of tetrahydrofuran (THF) was treated with drop wise addition of 300 mL (597 mmol) of methylamine (2M solution in THF) and was stirred overnight at room temperature. The reaction was concentrated to dryness, dissolved in dichloromethane, and washed with aqueous sodium bicarbonate and water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 20.8 g (100%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=1[Cl:12])[CH3:2].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=2)=[N:7][C:6]=1[Cl:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1Cl
Yield: 829.4 %

Procedure:
2,6-dichloronicotinic acid ethyl ester (0.22 g, 0.1 mmol) and 4-trifluoromethoxy-phenol (0.178 g, 0.1 mmol) were coupled using the procedure of Example 17(a) to afford 0.3 g of the required produCt. Percentage purity (LCMS): 64.0%.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CCCCOC(=O)c1ccc(I)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of butyl 4-iodobenzoate (3.5 g, 11 mmol), 4-trifluoromethylbenzene boronic acid (2.30 g, 12 mmol), potassium carbonate (4.77 g, 35 mmol), toluene (40 mL), and water (20 mL) was deaerated by sparging with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) was added, and the mixture was heated at reflux for 3 h and then cooled to ambient. The organic layer was separated, washed with brine, dried (MgSO4), passed through short column of silica gel, and concentrated to deposit a gold solid. The product was purified by recrystallization from aqueous isopropanol to provide 1.03 g (28% of theory) of a white powder. 1H NMR (CDCl3): δ 1.00 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 4.36 (t, 2H), 7.66 (d, 2H), 7.72 (s, 4H), 8.14 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10](=[O:28])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][C:29]([OH:33])=[O:32])=[CH:20][CH:19]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C=CC(=O)OC
Solvent: COCCOC
Solvent: CO
Product: O=C(O)CCC(CC=Cc1ccc(Cl)cc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred solution of 1,7-bis-(p-chlorophenyl)-4-phenyl-1,6-heptadien-3-one (16.10 g., 0.039 mole) in glyme (150 ml.), followed by addition of methyl acrylate (3.87 g., 0.045 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (20 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (25 ml.) and the solid (yellowish) that precipitates is filtered and air-dried; yield 16.5 g., m.p. 75°-173°C. Several recrystallizations from n-butyl chloride gives material with m.p. 178.5°-180°C.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:25]2[CH:24]=[CH:23][C:22]3[O:17][CH2:18][CH2:19][O:20][C:21]=3[CH:26]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCCO3)c2cc3c(cc21)OCO3
Yield: 32 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (240 mg) and 1,4-benzodioxan-6-carboxaldehyde (181 mg) by the procedure described in example 10 in 32% yield, mp: 185-187° C. 1H NMR (CDCl3): 6.86-6.75 (m, 3H), 6.67 (s, 1H), 6.30 (s, 1H), 5.91 (s, 1H), 6.89 (s, 1H), 5.18 (s, 1H), 4.99 (br s, 1H), 4.44 (m, 2H), 4.25 (s, 4H), 1.56 (d, J=6.8, 3H), 1.55 (d, J=6.8, 3H). Anal. calcd. for C20H20N2O5.(½)H2O: C, 63.65; H, 5.61; N, 7.42. Found: C, 63.37; H, 5.34: N, 7.07.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1N1CCCCC1
Temperature: 70 °C
Yield: 115.9 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 3-nitro-4-chloro-pyridine (10.0 g, 63.3 mmol), piperidine (16.2 g, 190 mmol) and ethanol (200 mL). After heating at 70° C. for 2 h, the solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (200 mL) and 10% aqueous potassium carbonate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 100% yield (15.2 g) of 159a as a yellow oil: 1H NMR (500 MHz, CDCl3) d 8.81 (s, 1H), 8.31 (d, 1H, J=6.0 Hz), 6.86 (d, 1H, J=6.0 Hz), 3.22 (t, 4H, J=4.5 Hz), 1.72 (m, 6H); MS (APCI+) m/z 208.4 (M+H).