Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[OH:2][C:3]1[C:4]([CH2:15][NH:16][C:17]([CH2:19][N+:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:5][C:6]([CH3:14])=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.C(O)(=O)C.[H][H].Cl>CO.[Pt]=O>[ClH:1].[ClH:1].[NH2:12][CH:10]1[C:11]2[C:7](=[C:6]([CH3:14])[CH:5]=[C:4]([CH2:15][NH:16][C:17](=[O:18])[CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:3]=2[OH:2])[CH2:8][CH2:9]1
Reactant: [Cl-]
Reactant: [H][H]
Reactant: Cc1cc(CNC(=O)C[n+]2ccccc2)c(O)c2c1CCC2=NO
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(CNC(=O)CN2CCCCC2)c(O)c2c1CCC2N

Procedure:
10 Grams of (2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-indene-6-yl)methylaminocarbonylmethylpyridinium chloride, 200 ml of acetic acid and 1.0 g of platinum oxide were subjected to catalytic hydrogenation under 3 atmospheric hydrogen gas pressure at room temperature for 8 hours. After the hydrogenation was completed, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under a reduced pressure. The residue thus obtained was dissolved in 100 ml of methanol and under ice-cooled condition, a methanol solution saturated with hydrogen chloride gas was added thereto so as to adjust the pH of the solution to about pH 1, then the said solution was concentrated to dryness under a reduced pressure. The residue thus obtained was recrystallized from ethanol-diethyl ether to obtain 4.8 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-piperidinylacetylaminomethyl-1H-indene dihydrochloride. Colorless powdery crystals. Melting point: 146° C. (decomposed).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([O:23]C)=[O:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[F:25][C:26]([F:35])([F:36])[O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:2]2[C:3]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=3)=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:32][CH:33]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cc(NC(=O)c2nc3ccccc3nc2Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1cc(NC(=O)c2nc3ccccc3nc2Oc2ccc(OC(F)(F)F)cc2)ccn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
A solution of methyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.6 g, 7.59 mmol), 4-(trifluoromethoxy)phenol (982.5 μL, 7.59 mmol) and K2CO3 (3.14 g, 22.76 mmol) in NMP (52.00 mL) was stirred at 70° C. for two hours and at room temperature for 12 hours. 120 ml of water were added and the reaction mixture was heated to 80° C. for 60 minutes. The reaction mixture was cooled to 45° C., aqueous HCl (1.0 N) was added until a precipitate formed. This mixture was stirred for 10 minutes, and then it was filtered. The filter cake was washed with an excess of water until the pH paper showed neutral and then it was washed with an excess of hexanes. The residue was dispersed in 120 ml of ethyl acetate, stirred for 15 minutes then it was filtered. The filter cake was washed with 10 ml ethyl acetate, 10 ml dichloromethane and dried overnight to give 44344-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid (33) (2.2 g, 61%) as a light tan-colored solid. ESI-MS m/z calc. 470.08, found 471.3 (M+1)+; Retention time: 1.51 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.67 (d, J=5.5 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 7.99 (dd, J=5.5, 2.2 Hz, 1H), 7.93-7.77 (m, 3H), 7.52 (s, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Br)c1
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCOCc1ccnc(Br)c1
Yield: 50 %

Procedure:
70 ml of 2-bromo-4-pyridinemethanol, 70 ml of dimethoxymethane and 2.15 g of p-toluenesulfonic acid monohydrate were suspended in 300 ml of benzene. The suspension was passed through a Soxhlet extractor containing 25 g of 3 Å molecular sieves, and refluxed for 20 hours. After cooling, the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried, and concentrated under reduced pressure. The residue was distilled to give 13.2 g (yield 50%) of 2-bromo-4-(methoxymethoxymethyl)pyridine.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([Cl:18])[N:10]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1>C(#N)C>[Cl:18][C:11]1[N:10]=[C:9]([NH:28][C:22]2[C:23]([O:26][CH3:27])=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: COc1ncc(Cl)cc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ncc(Cl)cc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Triethylamine (2.7 mL) and a catalytic amount of 4-diaminopyrimidine were added to a solution of 2,6-dichloro-3-nitropyridine (639 mg, 3.31 mmol) and 5-chloro-2-methoxy pyridin-3-amine (Preparation 23, 501 mg, 3.16 mmol) in acetonitrile (20 mL) and the resulting mixture was stirred overnight at 90° C. Solvent was then removed under reduced pressure until a solid precipitated. The solid was filtered, washed with acetonitrile and dried. The solid was then treated with dichloromethane, filtered, washed with more dichloromethane and the combined filtrate and washings were concentrated to dryness under reduced pressure to yield the title compound (390 mg 30%) as an orange solid.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:18]=[C:11]2[C:12]([O:14]C(=O)[NH:16][C:10]2=[CH:9][CH:8]=1)=[O:13])(=[O:6])=[O:5])[CH3:2].[Cl:19]C1C=CC(S(Cl)(=O)=O)=CC=1C(O)=O>>[CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([Cl:19])=[C:11]([CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:6])=[O:5])[CH3:2].[CH2:1]([NH:3][S:4]([C:7]1[CH:18]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([NH2:16])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CCNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Product: CCNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CCNS(=O)(=O)c1ccc(N)c(C(=O)O)c1

Procedure:
5-(N-Ethylsulfamoyl)-isatoic anhydride, which is to be used as the starting material, can be obtained, for example, in a manner analogous to that described in Example 1, using 2-chloro-5-chlorosulfonyl-benzoic acid as the starting material, the product being obtained via 5-(N-ethylsulfamoyl)-2-chloro-benzoic acid with a melting point of 186°-190° and 5-(N-ethylsulfamoyl)-anthranilic acid with a melting point of 190°-192°; the product melts at 253°-255°.
Reaction SMILES: C(O[NH:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])C>C(O)=O.ClCCl>[CH2:24]([O:23][C:20]([NH:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])=[O:22])[C:25]1[CH:17]=[CH:16][CH:15]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: O=CO
Product: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold solution of (R)-3-Benzyloxyamino-2-pentylpropionic acid (1.03 g, 3.89 mmol) in HCO2H (19 mL) and dichloromethane (19 mL) at 0° C. was added acetic anhydride (3.9 mL, 41.2 mmol). The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (50 mL) was added to it. It was washed with brine (50 mL×2), and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound. 1H NMR (400 MHz, CHCl3) δ 8.07 (br s, 1H), 7.29 (m, 5H), 4.91-4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H), 1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+294.
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:11]=[C:2]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:3]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: OB(O)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(Br)cc4ccccc43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)cc4ccccc43)ccc21
Temperature: 25 °C
Yield: 68.4 %

Procedure:
7-[3-(3-Bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), phenylboronic acid (0.12 g), tetrakis(triphenyl phosphine)palladium (0) (0.11 g), and potassium carbonate (0.39 g) were added to dioxane (5 ml). The mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→3:1). The purified product was condensed to dryness under reduced pressure, thereby obtaining the title compound (0.34 g) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[N:13]=[N:14][C:15](Cl)=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)C#N)=[C:4]([Cl:22])[CH:3]=1.[OH2:23].Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:23])[NH:14][N:13]=2)=[C:4]([Cl:22])[CH:3]=1
Reactant: CC(C)c1cc(C(C#N)c2c(Cl)cc(N)cc2Cl)nnc1Cl
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A mixture of (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl)-acetonitrile (45) (6.98 g, 19.63 mmol), water (30 mL), concentrated hydrochloric acid (120 mL) and glacial acetic acid (30 mL) was heated to 120° C. for 24 h. At this time, the reaction was cooled to room temperature and the mixture was poured onto water (250 mL). The pH was made neutral (pH=7) by the addition of a 4N aqueous sodium hydroxide solution. The suspension was placed in the freezer for 15 min. The resulting solids were filtered and washed with water and petroleum ether. The solids were collected and dissolved in hot ethyl acetate. Silica gel 60 (70-230 mesh) was added and the solvent was concentrated under vacuum. The resulting mixture was purified by flash chromatography (Biotage 75S) using silica gel eluted with 40% ethyl acetate in hexanes to 50% ethyl acetate in hexanes containing 0.5% glacial acetic acid. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (46) (4.65 g, 76%) as an off-white solid; LRMS for C14H15Cl2N3O (M+H) m/z=312. Molecular Weight=312.2012; Exact Mass=311.0592
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>CO>[CH3:1][O:2][C:3]([CH:4]([CH3:14])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])=[O:15]
Reactant: C=CC(=O)OCC
Reactant: COC(=O)C(C)CNCc1ccccc1
Solvent: CO
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C)C(=O)OC
Yield: 94.2 %

Procedure:
3-Phenylmethylamino-2-methyl-propanoic acid methyl ester (79 g, 0.38 mole) from Example and ethyl acrylate (54.2 ml, 50.06 g, 0.5 mole) were dissolved in 200 ml of methanol and then heated to reflux overnight. After being cooled, the solution was concentrated under vacuum to remove the excess of solvent and ethyl acrylate to yield the crude N-[2-(methoxycarbonyl)propyl]-N-[2-(ethoxycarbonyl)ethyl]phenylmethylamine (110 g, 95%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:14]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1)(=[O:16])[CH3:15]
Reactant: OCCOc1ccc(CCBr)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCOc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[4-(2-bromoethyl)phenoxy]ethanol (900 mg), acetic anhydride (0.5 mL), triethylamine (1.0 mL) and DMAP (13 mg) in DCM (5 mL) was stirred at room temperature for 0.5 h. The reaction was quenched by pouring into aq. NaHCO3 and the organic layer was washed with 2M HCl, dried (MgSO4) and concentrated in vacuo to give the title compound (1.03 g). LCMS RT=3.32 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[CH:21]=O)([O-:3])=[O:2].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].[S]>CN(C)C=O>[NH:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:30]=[C:21]1[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccccc1N
Agent: [S]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc([N+](=O)[O-])ccc21
Yield: 19.6 %

Procedure:
3-(1H-Benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a suspension of 720 mg of 5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-3-carboxaldehyde, of 216 mg of 1,2-phenylenediamine and of 77 mg of sulfur (0) in 70 ml of anhydrous dimethylformamide is heated at 95° C. for 16 hours. After returning to a temperature in the region of 20° C., the reaction medium is concentrated to dryness under reduced pressure and the evaporation residue is taken up with 20 ml of distilled water and 20 ml of ethyl acetate. The insoluble material floating at the surface is isolated by filtration, washed and dried and makes it possible to obtain a first crop of 160 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in the form of a yellow solid (Rf=0.22, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (75/25 by volume)). The filtrate is concentrated to dryness under reduced pressure and the solid residue is resuspended in a cyclohexane/ethyl acetate (80/20 by volume) mixture, isolated by filtration, washed and dried. A second crop of 200 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of an orangey solid with the same Rf as the first crop (mass analysis: Cl: m/z 410 (M+H)+)+ (base peak)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[N:13]=1
Reactant: CN1CCC(N)CC1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NC3CCN(C)CC3)nc21

Procedure:
The product of Example 44, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=440 (MH+). Rt=1.67 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([C:18]([Cl:23])=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(-c2ccc(F)cc2)nc2ccccc12

Procedure:
A mixture of 16.5 g of 2-(4-fluorophenyl-4-quinolinecarboxylic acid, 100 ml of thionyl chloride, and 50 ml of toluene was stirred and heated under reflux for 4 hr. The reaction mixture was the concentrated in vacuo, the residue was treated with more toluene, and the mixture again concentrated n vacuo. The residue was washed with ether to give 16 g of the above-named compound as a yellow solid.
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=O.N([O-])=O.[Na+].[CH3:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1.[N+:26]([O-:29])([OH:28])=[O:27]>O>[N+:26]([O-:29])([O-:28])=[O:27].[CH2:17]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:4])=[CH:21][CH:20]=1)[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc([N+]#N)cc1
Product: O=[N+]([O-])[O-]

Procedure:
A carbon black with a surface area of 58 m2 /g and a DBPA of 46 ml/100 g was used. A suspension of 50 g of this carbon black was prepared by stirring it into 450 g of water. A solution of 5.12 g of NaNO2 in 15 g of cold water was slowly added to a solution of 1.40 g of p-phenetidine and 1.98 g of concentrated nitric acid in 5 g of water that was cooled in an ice bath. 4-Ethoxybenzenediazonium nitrate was formed. After 15 minutes of stirring, the mixture was added to the stirring carbon black suspension. Bubbles were released. After 30 minutes, the product was collected by filtration, washed twice with water and dried in an oven at 125° C. The carbon black product had attached p-C6H4 OC2H5 groups.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][O:6][C:7]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[OH-].[Na+].Cl>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1OCc1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl

Procedure:
Ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate (3.0 g, 8.15 mmol) and sodium hydroxide (652 mg, 16.3 mmol) were dissolved in 10 mL of water and 50 mL of THF, reacted at room temperature for 5 h. The diluted hydrochloric acid was added to adjust to pH=6, extraction was performed with dichloromethane (30 mL×3), the extract was dried and concentrated to obtain a white solid, and this product was directly used in the next reaction without purification.
Reaction SMILES: CO[C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][NH2:21].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>CO.O>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][N:21]1[C:22](=[O:27])[CH:23]=[C:24]([CH3:26])[N:11]=[C:3]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]
Reactant: COC(=O)CC(C)=O
Reactant: COC(=N)c1ccccc1O
Reactant: NCCc1ccccc1F
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n(CCc2ccccc2F)c(-c2ccccc2O)n1
Yield: 10 %

Procedure:
Utilizing the methods described in Example 1 the title compound was prepared from 2-hydroxy-benzimidic acid methyl ester (750 mg, 4.0 mmol), 2-(2-fluoro-phenyl)-ethylamine (520 □l, 4.0 mmol) and methyl acetoacetate (4.0 mL) to provide 140 mg (10%) of 3-[2-(2-fluoro-phenyl)ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one as a white solid after flash chromatography on ODS silica gel eluting with methanol-water (4:7) followed by recrystallization from a large volume of toluene (100 mL).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:21][CH:20]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A suspension of the product of Example 1B (55 mg, 0.19 mmol), trans-2-(4-chlorophenyl)vinylboronic acid (41 mg, 0.23 mmol; Aldrich), dichlorobis(triphenylphosphine)palladium (II) (6.6 mg, 9.4 μmmol; Aldrich) and 1.0 M sodium carbonate (0.47 mL) in 2-propanol (1.5 mL) was purged with nitrogen and then stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was cooled and partitioned between CHCl3/2-propanol (4:1, 2×20 mL) and 1.0 M sodium carbonate (30 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4 ) δ ppm 2.03-2.16 (m, 4 H), 3.04-3.12 (m, 2 H), 3.12-3.18 (m, 1 H), 3.20-3.29 (m, 2 H), 4.24 (s, 2 H), 7.01 (t, J=7.6 Hz, 1 H), 7.19-7.26 (m, 2 H), 7.31-7.41 (m, 3 H), 7.55-7.67 (m, 3 H); MS (APCI) m/z 349 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>COCCOC>[O:19]=[C:13]1[C:12]2[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=2[C:10]2[C:15](=[N:16][CH:17]=[CH:18][C:9]=2[NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])=[CH:7][CH:6]=2)[NH:14]1
Reactant: Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2nccc(Nc3ccc(NS(=O)(=O)c4ccccc4)cc3)c2c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
340 (40 mg, 0.13 mmol), DIEA (34 mg, 0.26 mmol), and benzenesulfonyl chloride (47 mg, 0.26 mmol) were suspended in DME (2 mL), and stirred for 4 h at room temperature. The precipitate formed during the reaction was filtered, washed with EtOAc, and dried under vacuum to provide 341 (20 mg, 34% yield) as a solid. LC-MS (M+H=443, obsd.=443).