Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]4OCC[O:25]4)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCCC1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=[O:25])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cc(C2OCCO2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Temperature: 40 °C
Reaction time: 7 h
Yield: 103.4 %

Procedure:
A solution 2-((3,4-dichlorophenyl)amino)-8-(1,3-dioxolan-2-yl)-6-nitroquinazolin-4-ol (1.08 g) in tetrahydrofuran (35 mL) and dimethylsulfoxide (1 mL) was treated with 10% (v/v) hydrochloric acid (25 mL). The resulting mixture was stirred at 40° C. for 7 h, then was cooled to room temperature and stirred for 16 h. Evaporation of the tetrahydrofuran in vacuo provided a brown slurry, from which the product was isolated by filtration. The brown solids were washed with water (50 mL) and dried. The crude product was dissolved in tetrahydrofuran (3.75 mL), dried over MgSO4, filtered and evaporated to afford the title compound (1.0 g) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 10.57 (s, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.54 (bd, J=2.1 Hz, 1H), 8.03 (bd, J=2.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.49 (dd, J=2.1, 8.7 Hz, 1H). HPLC Method A: 7.73 min. MS (APCI−): m/z 377, 379.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11](Cl)(Cl)Cl)=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].[C:35](O)(=[O:37])[CH3:36]>[Zn].O>[CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:9][CH2:10][CH2:11][O:37][CH2:35][CH3:36])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(=O)O
Agent: [Zn]
Solvent: O
Product: CCOCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 1 h

Procedure:
5.9 g of zinc powder were introduced int a solution of 6.5 g of the product of Step D, 23.4 ml of acetic acid and 2.6 ml of water and the mixture was stirred for 1 hour and filtered. The filtrate was decanted and the organic phase was washed with water. The aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness to obtain 4.7 g of (S) α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3 (3-hydroxy-3-oxo-propynyl)-cyclopropane-carboxylate which was used as is for the next step.
Reaction SMILES: [S:1]1[CH2:10][C:2]1([CH3:11])[CH:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[C:6]1([CH3:9])[CH2:7][CH2:8][CH:3]([C:2]([SH:1])([CH3:10])[CH3:11])[CH2:4][CH:5]=1
Reactant: CC1=CCC(C2(C)CS2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=CCC(C(C)(C)S)CC1
Temperature: 0 °C
Yield: 69 %

Procedure:
0.637 g (3.8 mM) of the compound prepared according to letter (b) above in 12 ml of tetrahydrofuran (THF) were added under nitrogen atmosphere to a stirred boiling suspension of 72 mg (1.9 mM) of LiAlH4 in 3 ml of THF. The reaction mixture was refluxed for 1 further hour, then cooled at 0° C. and the excess of LiAlH4 decomposed by addition of water. The obtained mixture was then extracted with ether (3×) and the organic phase washed with water (3×), dried and evaporated. After fractional distillation of the crude residue, there were obtained 0.450 g (69% yield) of the desired 1-p-menthene-8-thiol, b.p. 40° C./0.133 Pa.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+].O>O1CCOCC1>[CH2:37]([O:36][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In 50 ml of dioxane was dissolved 10 g of 2'-deoxy-5'-O-trityl-5-fluorouridine. To the solution were added 2.9 ml of benzyl bromide and 14.6 g of particles of potassium hydroxide. The mixture was stirred at room temperature for 1 hour. Thereto was added 40 ml of water. The mixture was adjusted to a pH of about 3 to about 4 and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The sodium sulfate was separated by filtration and the solvent was distilled off, giving as an intermediate 16.0 g of 2'-deoxy-3'-O-benzyl-5'-O-trityl-5-fluorouridine.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([C:14]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=1[OH:16])[CH2:12][CH3:13]>OS(C(F)(F)F)(=O)=O>[OH:16][C:15]1[CH:17]=[CH:18][C:19]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:20]([OH:21])[C:14]=1[CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCc1c(O)cccc1O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)Cc2ccccc2)c1O

Procedure:
Using the procedure in Example 51, step 1, phenylacetic acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 1,3-dihydroxy-4-phenylacetyl-2-(n-propyl)benzene.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][C:21](OC)=[O:22].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:22][CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)CC1=C(C)c2ccccc2/C1=C\c1ccc(SC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSc1ccc(/C=C2/C(CCO)=C(C)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 3 (270 mg, 0.83 mmol) in dry THF (5 mL) at 0° C. was added a solution of diisobutyl aluminum hydride (1M) in toluene (2.1 mL, 2.1 mmol, 3.5 eq.). After 1 hour, the reaction mixture was added dropwise to a solution of 1N aqueous HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate-hexane to afford pure title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]1([O:18][CH2:17]1)[CH3:16]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([CH3:17])([OH:18])[CH3:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCNCC2)cn1
Reactant: CC1(C)CO1
Solvent: CO
Product: CC(C)(O)CN1CCN(c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To 1-(6-chloropyridin-3-yl)piperazine (0.600 g, 3.04 mmol) in methanol (1.5 mL) was added dropwise isobutylene oxide (0.274 mL, 3.04 mmol). The reaction was left to stir at room temperature overnight. An additional 0.15 equivalents of isobutylene oxide were added and the reaction was placed in a 55° C. oil bath overnight. Solvent was removed in vacuo. Silica gel chromatography (gradient elution 2 to 10% methanol in DCM) afforded compound 251 (0.450 g, 55.0% yield). 1H NMR (400 MHz, CDCl3) δ 0.95-1.50 (m, 7 H) 2.23-3.61 (m, 9 H) 7.12-7.24 (m, 2 H) 8.03 (br. s., 1 H) ppm.
Reaction SMILES: BrC[CH2:3][O:4][CH2:5]CBr.ClC1C=CC([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20](O)=[C:21](OC)[CH:22]=3)[N:17]=CN=2)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:5][O:4][C:3]1[N:13]=[CH:14][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: BrCCOCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 153.7 %

Procedure:
2-Bromoethyl ether (1.57 ml, 12 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.1 mmol), (prepared as described for the starting material in Example, 2), and potassium carbonate (1.73 g, 12 mmol) in DMF (10 ml). The mixture was stirred for 18 hours at ambient temperature and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (60/38/2). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(22-bromoethoxy)ethoxy)-4-(4-chloro-2-fuoroanilino) methoxyquinazoline (763 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[C:16]([F:15])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3)nc2n(CC)c1=O
Yield: 39.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.77 g (16.7 mmol) of 3-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.96 g (yield 40%) of Compound 128 as a pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH2:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[C:1]([C:4]1[C:5]([NH:17][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2C)c1N
Product: CC(=O)c1c(C)[nH]c(-c2ccccc2C)c1NCc1ccc(Cl)cc1

Procedure:
The title compound (M.p. 167°-70° C) is prepared from 4-acetyl-3-amino-5-methyl-2-(o-tolyl)-pyrrole (m.p. 258° C), obtained substantially in the same way as compound A), by transforming into the corresponding p-chlorobenzylidene derivative (m.p. 215° C) by reaction with p-chlorobenzaldehyde and subsequent catalytic hydrogenation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=4[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:26]([OH:27])[C:30]([F:33])([F:32])[F:31])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of 9-chloro-1-(4,6-dimethoxy-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (433 mg, 1.12 mmol) and trimethyl(trifluoromethyl)silane (495 μL, 3.35 mmol) in tetrahydrofuran (6.0 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 112 μL, 0.112 mmol) at 0° C. After 30 min, hydrochloric acid (1.0 M, 2.5 mL) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale yellow solid (445 mg, 0.972 mmol, 87%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br-].[CH:18]1([Zn+])[CH2:21][CH2:20][CH2:19]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1COCC1>[CH:18]1([C:2]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=2[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:21][CH2:20][CH2:19]1
Reactant: [Zn+]C1CCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCC1
Temperature: 45 °C
Yield: 98 %

Procedure:
A 1-L three-neck, round bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet was charged with (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (27.2 g, 89.1 mmol), THF (181.2 mL) and bis(tri-tert-butylphosphine)palladium (3.4 g, 6.68 mmol). Cyclobutylzinc bromide (267.2 mL, 134 mmol) was added and the reaction is heated at 45° Celsius for 22 hours. The reaction was cooled to room temperature and quenched with 1M HCl. The aqueous phase is extracted with MTBE and the combined organic extracts were washed with water, saturated aqueous thiourea, 1M HCl brine, dried over sodium sulfate and concentrated to dryness to provide (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane as a light yellow oil (24.5 g, 98%). MS (EI): calcd. for C16H25FOSi, 280.5; m/z found 280.1 [M]. 1H NMR (400 MHz, CDCl3), δ 7.08-7.04 (m, 1H), 6.90-6.83 (m, 2H), 3.81 (tt, J=9.4, 7.8 Hz, 1H), 2.32 (dtd, J=10.3, 7.8, 2.4 Hz, 2H), 2.14-1.80 (m, 4H), 1.03 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:20])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(I)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(I)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of methyl 3-iodo-4-methylbenzoate (compound 5.3, 3.00 g, 10.9 mmol) in CCl4 (50 mL), NBS (2.9 g, 16.3 mmol), azobisisobutyronitrile (360 mg, 2.19 mmol) and potassium carbonate (1.65 g, 11.9 mmol). The resulting mixture was stirred overnight at 70° C., then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and the mixture was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20) as the eluent to yield 3.0 g (78%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.C(OCC)(=[O:22])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:22])[C:6]=2[CH:19]=1
Reactant: CCOC(C)=O
Reactant: CC1(C)C=C(c2ccccn2)c2cc(Br)ccc2O1
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(Br)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 6, from 6-bromo-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-(6-bromo-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 146°-148° C. (from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Yield: 25.3 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.341 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one, 98.2 mg (0.409 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, 16.4 mg (0.409 mmol, 60% dispersion in oil), and 3.5 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 39 mg of 3-(4-Methoxy-3-methyl-benzoyl)-1-(6-trifluoromethyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C25H19F3N2O3 [M+H]: 453.13 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylimidazole (1.0 g, 0.003 mol), nitric acid (70% w /w, 1 ml) and sulphuric acid (98% w /w, 1 ml) was stirred and heated at 75° C. for 4 hours then at 100° C. for 2 hours. After cooling the reaction mixture was added to a mixture of ice and water (20 ml) and the precipitated solid was filtered off. Recrystallisation from toluene gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methyl-5-nitroimidazole (0.66 g), m.p. 316.5°-317.5° C., as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[OH:24][C@H:25]([CH3:43])[CH2:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]([CH2:26][C@H:25]([OH:24])[CH3:43])[C:31]=2[CH3:32])=[O:34])=[CH:18][C:17]=1[F:23]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@@H](C)O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (5.0 g, 0.016 mol) and (R)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (6.2 g, 0.022 mol) in CH2Cl2 (100 mL) at 0° C. was added TEA (5.5 g, 0.054 mol), followed by HATU (10.3 g, 0.027 mol) in portions. The reaction mixture was stirred at 0° C. for 2 h, warmed up to rt and continued to stir overnight. The reaction mixture was washed with water (30 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was crystallized in a mixture of EtOAc/n-hexane (50 mL, v/v=5:1) to give the title compound as a pale yellow solid (7.8 g, 85.2%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([OH:25])[CH2:22][CH:23]=[CH2:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27].[H-].[Na+]>C1COCC1>[C:14]([Si:1]([O:18][CH2:19][CH2:20][CH:21]([O:25][CH2:26][CH3:27])[CH2:22][CH:23]=[CH2:24])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:16])([CH3:17])[CH3:15]
Reactant: CCI
Reactant: C=CCC(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 1-(tert-butyl-diphenylsilanyloxy)-5-hexen-3-ol (Tetrahedron, 57, 4023-4034 (2001)) (5.0 g) and ethyl iodide (2.03 mL) in THF (10 mL) was added dropwise to a suspension of sodium hydride (60%, 1.85 g) in THF (40 mL) at 50° C. over 10 minutes. The reaction solution was stirred at 50° C. for one hour. Ethyl iodide (6.0 mL) was added to the solution at 50° C., and the mixture was stirred at 60° C. for 1.5 hours. The reaction solution was returned to room temperature and poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (4.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].ClC(=O)[C:31]([O:33]C)=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](=[O:21])[C:31]([OH:33])=[O:32]
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)C(=O)O)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A from reaction of Example 1 with methyl 2-chloro-2-oxoacetate (hydrolysis of the crude upon column chromatography afforded Example 31). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (s, 3 H) 3.17 (s, 3 H) 7.28 (s, 1 H) 7.61 (m, 1 H) 7.84 (m, 1 H) [M+H] calc'd for C14H11FIN3O5, 448; found, 448.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:24])[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1cccc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c12
Yield: 85.6 %

Procedure:
2.00 g (9.19 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.26 g (8.33 mmol) of 2-amino-6-methylbenzoic acid were treated in the same way as in Example 1 to obtain 2.50 g of the above-identified compound (yield 85.6%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 2.56 (3H,s), 6.99 (2H,t), 7.49 (1H,t), 7.77 (2H,d), 8.20 (2H,d), 11.54 (1H,br).