Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Agent: Cl
Product: COC(=O)[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)O)=[CH:11][C:5]=2[CH2:4][O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc(C(O)c3c[nH]cn3)ccc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCc2cc(Cc3c[nH]cn3)ccc2O1
Yield: 94.5 %

Procedure:
3.4 g (0.013 mole) of alpha-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1H-imidazole-4-methanol (prepared in Example 3.4.) are hydrogenolyzed in methanol at 80° C. for 5 hours in the presence of 10% palladium on carbon and under a hydrogen pressure of 2.8 bars. The catalyst is then filtered off and the solvent is removed under reduced pressure. The residue obtained is chromatographed on silica (eluent: 90:10 v/v dichloromethane-methanol). There are obtained 3 g of 4-[(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)methyl]-1H-imidazole. Yield: 97% of theory; M.P.: 150°-170° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.[Mg].[CH:12](=[O:15])[CH2:13][CH3:14].O>O1CCCC1>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: ClCCCCC1C=CCC1
Reactant: CCC=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)CCCCC1C=CCC1
Temperature: 0 °C

Procedure:
All reactions are carried out under an inert atmosphere. 3-(4-Chlorobut-1-yl)cyclopentene {3-(4-chlorobutyl)cyclopentene} (43 g, 0.27 moles) is diluted in tetrahydrofuran (50 ml) and added dropwise to a stirred, refluxing solution of tetrahydrofuran (200 ml) containing granular magnesium (30 g, 1.25 moles). After the addition is complete and the resulting Grignard salt has formed the reaction is refluxed an additional 2 hours. The reaction vessel is then cooled in a 0° C. ice bath and propionaldehyde (15.6 g, 0.27 moles) diluted in tetrahydrofuran (20 ml) is added dropwise over 30 minutes. Then water (500 ml) is added over a period of 30 minutes and the reaction warmed to room temperature. The reaction is partitioned between ether (500 ml) and water. The aqueous layer is extracted with ether (2×500 ml) and the organic extracts are combined. The product is washed with brine (500 ml) and the solvent volume reduced under vacuum. The residue is dried over anhydrous magnesium sulfate and the solid filtered out. The remaining solvent is removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving the desired product as a clear, colorless oil (52 g, 0.29 moles), BP 76° C./0.25 mm.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl:30]C1C=C(I)C=CC=1.IC1C=CC=CC=1>>[Cl:30][C:26]1[CH:25]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:29]=[CH:28][CH:27]=1
Reactant: Clc1cccc(I)c1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cccc(Cl)c3)c(=O)c2)cc1

Procedure:
4-{3-[1-(3-Chloro-phenyl)-2-oxo-1,2-dihydropyridin-4-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 3-chloroiodobenzene for the iodobenzene in Step 3.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:7]([C:5]1[S:6][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])=[CH:3][CH:4]=1)#[N:8]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ccc(C#N)s1
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol) in 50 ml of dioxane is degassed with argon, tetrakis-(triphenylphosphine)-palladium(0) (768 mg, 0.665 mmol) is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid (2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) are successively added and the mixture is stirred for 16 hours at 85° C. Extractive work-up (2×50 ml dichloromethane and 2×30 ml water). The organic phase is dried over sodium sulfate, filtrated and evaporated. The residue (4.05 g) is purified via flash column on silica (eluent: 100% hexane>hexane/ethyl acetate 96:4 gradient to give 1.37 g of 2-(5-cyanothien-2-yl)anisole (96%). M+=215.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: O=C1Nc2ccccc2SC1CCO
Reactant: O=S(Cl)Cl
Product: O=C1Nc2ccccc2SC1CCCl
Yield: 72.7 %

Procedure:
By a process similar to that in Reference Example 13, 2-(2-hydroxyethyl)-2H-1,4-benzothiazin-3(4H)-one was allowed to react with thionyl chloride to give 2-(2-chloroethyl)-2H-1,4-benzothiazin-3(4H)-one. The yield was 72.7%. Recrystallization from methanol gave prisms, m.p. 133°-133.5° C.
Reaction SMILES: C[Al](C)C.CO[C:7](=[O:25])[CH2:8][C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH:14]=1.[NH2:26][C:27]1[C:32]([Br:33])=[CH:31][CH:30]=[CH:29][N:28]=1>ClCCCl>[Br:33][C:32]1[C:27]([NH:26][C:7](=[O:25])[CH2:8][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:13][CH:14]=2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ncccc1Br
Reactant: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 189 %

Procedure:
Trimethylaluminum (2.0 M, 2.05 mL, 4.10 mol) was added slowly to a 0° C. solution of benzyl 4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.73 mol) and 2-amino-3-bromopyridine (0.520 g, 3.00 mmol) in 1,2-dichloroethane (15 mL). After 30 min, the reaction was heated to 55° C. for 48 h. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and the mixture extracted with dichlormethane (4×). The combined organic layers were washed with 1N sodium potassium tartrate, brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 50 to 100% ethyl acetate:hexanes to give the title compound (2.44 g). MS: m/z=430.0 (M+1).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([O:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[S:32][C:28]=2[CH:27]=1)[CH3:24]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:36][S:33]([C:31]2[S:32][C:28]3[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[CH:38]=[CH:37][C:29]=3[N:30]=2)(=[O:34])=[O:35])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Product: CCOc1ccc2nc(S(=O)(=O)NC(=O)C(O)=CC(=O)N(Cc3ccc(F)cc3)OC)sc2c1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 6-ethoxy-benzothiazole-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 1.47 (t, 3, J=7), 3.62 (s, 3), 4.10 (q, 2, J=7), 4.75 (s, 2), 6.45 (s, 1), 7.02 (m, 2), 7.33-7.18 (overlapping m, 4), 8.05 (m, 1). 13C NMR (125 MHz, CDCl3) δ: 14.69, 48.31, 63.18, 64.48, 92.87, 103.88, 115.69, 115.86, 118.94, 126.40, 130.24, 130.30, 131.00, 139.50, 146.56, 158.71, 159.16, 159.36, 159.59, 161.69, 163.65, 170.75.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH2:15][O:16][CH:17]=[C:18]2[CH2:25][CH2:24][CH:23]3[CH2:26][CH:19]2[CH:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]3[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:13][CH:14]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:9]1[CH:10]=[C:11]([CH2:15][O:16][CH:17]=[C:18]2[CH2:25][CH2:24][CH:23]3[CH2:26][CH:19]2[CH:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:21]=[C:22]3[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(COC=C2CCC3CC2C(c2ccccc2)C=C3c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc(COC=C2CCC3CC2C(c2ccccc2)C=C3c2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 9.6 parts of (3-tert-Butyldimethylsiloxyphenyl) methoxy methylene-2,4-diphenyl bicyclo(3.3.1]non-2-ene (78) in 100 mL of THF was added 9 parts of 70% tetra-n-butylammonium fluoride in 30 mL of THF over a period of 10 minutes and stirring was continued for two hours. TLC on silica gel plate showed the formation of new product. Solvent was evaporated under reduced pressure and the oily material was dissolved in 300 mL of methylene chloride and washed with 2×100 mL of water. After drying over anhydrous sodium sulfate, the solvent was evaporated and the oily product was purified on silica gel column. TLC on silica gel plate of the fractions were checked and the combined organic solvent was evaporated, yield 6.24 parts. The structure of the product was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.CC1C=C[C:29]([C:32](C2N(C)C(CC(OC)=O)=CC=2)=[O:33])=CC=1.C(OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:32](=[O:33])[CH3:29])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl} amine (0.3 g, 0.88 mmol) [prepared by the method described in Example 5, but substituting zomepirac methyl ester for tolmetin methyl ester in Step (a)] and acetic anhydride (0.375 ml, 3.96 mmol) in THF was stirred at 60° C. for 4 h. The solvents were removed under reduced pressure and the residue was crystallized from hexane-chloroform to give N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-acetamide (295 mg, 88%) as a solid, mp 194-195° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([O-])=O.[Na+].[Br:14]Br.[OH-].[Na+]>CC(O)=O>[Br:14][C:4]1[N:3]=[C:2]([F:1])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: Oc1cccnc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc(Br)nc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.7 %

Procedure:
A stirred solution of 2-fluoro-3-pyridinol (1.10 g, 9.73 mmol) and NaOAc (0.80 g, 9.73 mmol) in HOAc (10 mL) was treated with Br2 (1.56 g, 9.73 mmol) at 5° C., and the reaction mixture was allowed to warm to ambient temperature, and stirred at ambient temperature for 4 h. The mixture was poured onto ice and neutralized with 2N NaOH to pH about 7, and then extracted with EtOAc. The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a yellow oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:20 EtOAc/CH2Cl2 to give a colorless oil, which solidified after standing. The solid was recrystallized from hexanes to give 0.2 g (11%) of 6-bromo-2-fluoro-3-pyridinol as a white solid. The filtrate was concentrated to a solid, which was recrystallized from 2:1 hexanes/benzene to give additional 0.57 g (31%) of 6-bromo-2-fluoro-3-pyridinol as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 7.40-7.30 (m, 2H); LRMS (ESI), m/z 192/194 (M+H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]([C:13]2[CH:21]=[CH:20][C:19]3[C:15](=[C:16]([CH3:23])[N:17]([CH3:22])[N:18]=3)[CH:14]=2)[C:9](=[O:24])[CH:8]=1)(=O)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[C:16]([CH3:23])[N:17]([CH3:22])[N:18]=4)[CH:14]=3)[C:9](=[O:24])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1c2cc(-n3ccc(COS(C)(=O)=O)cc3=O)ccc2nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(COc4ccc(Cl)cc4)cc3=O)ccc2nn1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
To a solution of [1-(2,3-dimethyl-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-4-yl]methyl methanesulfonate (140 mg) and 4-chlorophenol (77 mg) in N,N-dimethylformamide (5 ml) was added potassium carbonate (120 mg) at room temperature, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol). The obtained residue was purified by HPLC to give the title compound (20 mg).
Reaction SMILES: C([N:4]1[C:8]([NH:9][CH3:10])=[N:7][C:6]([S:11](Cl)(=[O:13])=[O:12])=[N:5]1)(=O)C.[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:17]=1[NH2:18]>N1C=CC=CC=1>[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:17]=1[NH:18][S:11]([C:6]1[N:7]=[C:8]([NH:9][CH3:10])[NH:4][N:5]=1)(=[O:12])=[O:13]
Reactant: CNc1nc(S(=O)(=O)Cl)nn1C(C)=O
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: CNc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
The product of stage (b) (4.34 g) was added with stirring to 2,6-dichloroaniline (3.24 g) in pyridine (30 ml), and the mixture was stirred at 50° C. for 18 hours. After removal of the pyridine, the residue was dissolved in sodium hydroxide solution (50 ml) and was extracted with ethyl acetate (50 ml). The aqueous phase was acidified to pH=4-5 with 2N hydrochloric acid, cooled, and the product was filtered off, washed with a little water, and dried to give 3.49 g of the desired product, mp 285°-287° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:10]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]2=[O:21])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])c(Cl)c2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
A mixture of 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (100 mg, 0.34 mmol), 2-chloro-4-fluoro-1-nitrobenzene (72 mg, 0.41 mmol), and potassium carbonate (110 mg, 0.69 mmol) in N,N-dimethylformamide (2 ml) is heated to 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-[5-(3-chloro-4-nitrophenoxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [N:1]1([CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[NH2:30]OS(O)(=O)=O>O>[NH2:30][N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]1=[O:17]
Reactant: NOS(=O)(=O)O
Reactant: O=c1ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of compound 3 (7.3 g) and NaOH (4.12 g) in water (20 ml) was stirred at room temperature for 15 minutes. Hydroxylamine-O-sulfonic acid (6.3 g) was added portionwise and the mixture was stirred for 12 hours. The precipitate was filtered off and crystallyzed from 2-propanol, yielding 2.3 g (±)-(1-amino-6-[1H-1,2,4-triazol-1-yl-[3-(trifluoromethyl)phenyl]methyl]-2(1H)-quinolinone (compound 20; mp. 222.3° C.).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
Diethylazodicarboxylate (3.73 g) was added dropwise to a mixture of tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (4.29 g), 4-chloro-6-methoxyquinazolin-7-ol (3.00 g) and triphenylphosphine (5.61 g) in methylene chloride (75 ml). The solution was then heated to 0° C. and stirred for 3 hours. After cooling the mixture was filtered and then purified by flash column chromatography eluting with isohexane/acetone/triethylamine (80/20/1) to give tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate as a colourless oil (3.29 g) which was used directly; Mass Spectrum: (M+H)+ 394.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC([O-])(C)C.[K+].[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:42]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][CH:36]=1)=O.Cl>C1COCC1.CC(=O)OCC>[C:2]1(=[CH:33][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[C:42]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][CH:36]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccccc1-c1ccc(C=O)cc1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1-c1ccc(C=C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
5.5 g of cyclohexyltriphenylphosphonium bromide and 2.6 g of KOtBu were stirred at RT for 4 h in 200 ml of anhydrous THF. 3.0 g of 4'-formylbiphenyl-2-sulfonamide were added and the mixture was stirred at RT for 18 h. It was then diluted with 200 ml of EA, adjusted to pH=6-7 using aqueous HCl solution and washed 2 times with 100 ml of a saturated aqueous NaCl solution each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using DIP yielded 1.5 g of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCC1CC1
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCC1CC1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 2-bromo-3-pyridinol (500 mg, 2.83 mmol;) in dimethylformamide (3 mL) is added at 0° C. 60% sodium hydride in mineral oil (169.81 mg, 4.25 mmol). The mixture is stirred at that temperature for 15 min and bromomethylcyclopropane (329.66 μL, 3.40 mmol) is added. Then the reaction is stirred at room temperature for 1 h and quenched with water and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over magnesium sulfate and the solvent evaporated in vacuo. The crude is passed through a short silica gel plug and the compound was eluted with dichloromethane to yield 23% of the title compound. MS (m/z): 228 (M+1), 230 (M+3).