Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[C:11]([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([NH:14][C:15](=[CH:20][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:13])[CH3:12]
Reactant: Cc1cc(Br)cc(C)c1Cl
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=Cc1cc(C)c(Cl)c(C)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere 30.0 g (136.7 mmol) 5-bromo-2-chloro-1,3-dimethylbenzene, 24.0 g (164.0 mmol) methyl 2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrile were combined with 3.4 g (10.9 mmol) tri-o-tolyl-phosphane and 2.4 g (10.9 mmol) Pd(OAc)2 and stirred for 18 h at 80° C. The precipitate was suction filtered, the filtrate was evaporated down i. vac., combined with 800 mL DCM and 800 mL water, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was stirred with EtOAc, suction filtered and dried i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 28 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-5-fluorotoluene (1.495 g, 7.909 mmol, Aldrich, used as received) in conc. H2SO4 (10.0 mL) at 0° C., KNO3 (0.800 g, 7.91 mmol) was added in one lot. The resulting pale yellow solution was warmed to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil dried further under vacuum to afford 1.832 g (98%) of the title compound as an oil; 1H NMR (CDCl3): δ 2.495 (s, 3H), 7.213 (d, 1H, J1 =11.4 Hz), 8.268 (d, 1H, J1 =7.2 Hz).
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34]>C(O)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:15]1[N:16]([CH3:17])[C:12]2[C:11]3[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=3[CH:28]=[CH:27][C:13]=2[N:14]=1
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C#N
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A 25 mL round bottom flask was charged with 2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.258 g, 0.562 mmol) and a stir bar. Water (3 mL), glacial acetic acid (3 mL) and concentrated sulfuric acid (3 mL) were combined and added to the round bottom flask while still hot (60° C.). The flask was sealed with a plastic stopper and heated in an oil bath at 100° C. After 2 hours, the flask was removed from the oil bath and stirred at room temperature overnight. The clear solution was then poured onto ice and neutralized with concentrated ammonium hydroxide. The resulting precipitate was recovered by filtration, resuspended in methanol and filtered. The resulting solid was washed with methanol until the filtrate was colorless to provide 2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.106 g, 46%) as a light gray solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.47 (s, 1H), 7.78-7.68 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 4.28 (2, 3H), 2.31 (s, 3H), 2.22 (s, 3H); ESMS (m/z): found, 387.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[C:16]([CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:15]=[C:14]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)=[C:28]([O:38][CH3:39])[CH:27]=2)[N:13]=1)=C)[CH3:8].[O:40]1CCOCC1>O>[CH3:39][O:38][C:28]1[CH:27]=[C:26]([NH:25][C:14]2[N:13]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:40])[CH:17]=[C:16]([CH2:18][O:19][CH2:20][C:21]([F:23])([F:24])[F:22])[N:15]=2)[CH:31]=[CH:30][C:29]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
To a solution of sodium metaperiodate (1.200 g, 5.61 mmol) and 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine (1.3 g, 2.81 mmol) in a mixture of water (30 mL) and 1,4-dioxane (60 mL) potassium permanganate (0.066 g, 0.42 mmol) was added in portions of 10-15 mg in intervals of 5-8 min at ambient temperature. The mixture was filtered, the precipitate was washed with dioxane and ethyl acetate. Sodium bicarbonate and sodium chloride were added to the filtrate, the organic phase was separated, and the water phase was additionally extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was separated on a silica gel column using a gradient of 0-5% methanol in dichloromethane as eluent to yield the title product, 0.96 g (74%).
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:15]([OH:17])=O)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:2][C:1]([NH:5][C:6]1[O:7][C:8]([C:15]([Cl:20])=[O:17])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)([CH3:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1

Procedure:
By the procedure of Example 27, 17 g (64.5 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarboxylic acid, 67 ml thionyl chloride and 4 of drops dimethylformamide were reacted together. The product was separated and then distilled to yield 17.2 g of a yellow solid product (m.p.=52°-60° C.; b.p. 70° C. @ 0.25 mm Hg) identified in Table I.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:46](Cl)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 13.0 g (23.9 mmol) 5′-O-(4,4′-dimethoxytrityl)thymidine 16 in 50 ml DMF was added 3.0 g (44 mmol) imidazole and 3.6 g (23.9 mmol) tert-butyl-dimethylsilyl chloride. The solution was stirred at room temperature for 3 hours. DMF was then removed in vacuo and the residue was dissolved in 300 ml of ethyl acetate. The solution was washed with water and the organic layer was dried over MgSO4. After concentration of the solution and recrystallization from ethyl acetate/hexane, the solid product 5′-O-(4,4′-dimethoxy)-3′-(tert-butyldimethylsilyl)thymidine 17 was used directely for the next reaction.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.C(OC)(OC)OC.[CH2:18]([O:20][C:21](=[O:27])[CH:22]=[C:23]1[CH2:26][CH2:25][CH2:24]1)C>CO.S(=O)(=O)(O)O>[OH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([S:1][C:23]2([CH2:22][C:21]([O:20][CH3:18])=[O:27])[CH2:26][CH2:25][CH2:24]2)=[CH:3][C:4]=1[CH3:10]
Reactant: CCOC(=O)C=C1CCC1
Reactant: Cc1cc(S)cc(C)c1O
Agent: O=S(=O)(O)O
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2)CCC1
Yield: 68.2 %

Procedure:
To a solution of 4-mercapto-2,6-dimethylphenol (2.5 g) in anhydrous methanol (40 mL) containing trimethyl orthoformate (3 mL), was added cyclobutylidene-acetic acid ethyl ester (7.6 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with saturated NaHCO3 and extracted with ethyl acetate. After concentrated in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 3.1 g of methyl {1-[(4-hydroxy-3,5-dimethylphenyl)thio]cyclobutyl}acetate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][NH:19][CH3:20]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:19]([CH3:20])[CH3:18])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CNC
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CN(C)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
2.00 g (7.44 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-methylmethanamine to give after working up and purification 1.68 g (76%) of the title compound.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[CH:19]=1)[C:13]([O:15]C)=[O:14].O.[OH-].[Na+].Cl>C1COCC1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH:19]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cc(-c2nc3ccncc3s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)Nc2cc(C(=O)O)cc(-c3nc4ccncc4s3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
Methyl 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoate (80 mg, 0.167 mmol) was dissolved in 5 mL of THF and 2 mL of water containing 30 mg of sodium hydroxide. The reaction mixture was stirred at room temperature for 1 hour. It was then acidified to pH 4 with 6 N HCl and concentrated. The solids were collected by filtration and dried to afford 60 mg of 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoic acid (78% yield) (MS, M++H=466).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:19])[CH:14]=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:4][CH:3]=1.FC1C=CC(CN2C=[CH:33][N:32]3[C:35](=O)[CH:36]=[C:37](O)[C:38](O)=[C:31]3C2=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][N:10]3[C:13](=[O:19])[C:14]([CH2:33][N:32]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:31]4)=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Reactant: O=c1c2c(O)c(O)cc(=O)n2ccn1Cc1ccc(F)cc1
Product: O=c1c2c(O)c(O)c(CN3CCCCC3)c(=O)n2ccn1Cc1ccc(F)cc1

Procedure:
The title compound was prepared using a procedure similar to that described in Example 11, except that 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione was substituted with 2-(4-fluorobenzyl)-8,9-dihydroxy-2H-pyrido[1,2-a]pyrazine-1,6-dione (Example 14).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(F)ccc1N

Procedure:
A solution of 6-fluoro-3-nitropyridine-2-carboxamide (1.50 g, 8.10 mmol) in EtOAc (80 mL) is hydrogenated over 5% Pd-C (0.30 g) at 60 psi for 2 h. After removal of the catalyst by filtration, the solvent is removed under reduced pressure, to give a residue of crude 3-amino-6-fluoropyridine-2-carboxamide which is used directly in the next step. Triethyl orthoformate (60 mL) is added and the mixture is then heated under reflux with vigorous stirring for 18 h. The cooled mixture is diluted with an equal volume of petroleum ether, and the resulting precipitate collected by filtration and is washed well with petroleum ether to give 6-fluoro-3H-pyrido[3,2-d]pyrimid-4-one (1.26 g, 84%) . 1H NMR (DMSO) δ 12.72 (1H, brs), 8.31 (1H, dd, J=8.6, 7.7 Hz), 8.20 (1H, s), 7.66 (1H, dd, J=8.6, 3.0 Hz).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)C.[H][H]>[Pd]>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 1-piperazinecarboxylate (2.03 g, 9.22 mmol) was dissolved in pyridine (23.0 mL, 9.22 mmol) and cooled to 0° C. before methanesulfonyl chloride (2.85 mL, 36.9 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and warmed to RT for 2 h. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with 3 N HCl (aqueous), washed 3× with 50 mL of 3 N HCl (aqueous), and separated, before the aqueous layer was extracted 3× with chloroform/isopropanol, then dried over sodium sulfate, and concentrated in vacuo to give the title compound. Benzyl 4-(methylsulfonyl)piperazine-1-carboxylate (2.80 g, 9.4 mmol) was dissolved in ethanol (0.43 g, 9.4 mmol) before palladium, 10 wt. % on activated carbon (2.0 g) was added and a hydrogen balloon attached. The reaction mixture was stirred at RT for 2 h before it was filtered through a pad of Celite®, washed with methanol, and concentrated in vacuo to give the title compound. MS (ES+): 165 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:12][CH:11]=1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:27]1([CH2:26][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)=[CH:14][CH:15]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: BrCC1CCC1
Reactant: COC(=O)c1coc(-c2ccc(-c3nc4ccccc4[nH]3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1coc(-c2ccc(-c3nc4ccccc4n3CC3CCC3)cc2)n1
Temperature: 120 °C
Yield: 54 %

Procedure:
A mixture of methyl {2-[4-(1H-benzimidazol-2-yl)phenyl]-1,3-oxazol-4-yl}carboxylate (200 mg, 0.62 mmol), bromomethylcyclobutane (140 mg, 0.94 mmol) and K2CO3 (103 mg, 0.75 mmol) in dry acetonitrile was heated to 120° C. with microwave irradiation for 1.5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resultant residue was dissolved in CH2Cl2, washed with water, dried over Na2SO4 and evaporated to dryness under reduced pressure. This residue was purified by column chromatography (silica, CH2Cl2:MeOH 98:2) to afford the title compound in 54% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 388 (MH+).
Reaction SMILES: O[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2cnc3c(c(O)c(C)c(=O)n3C)c2=O)cc1
Product: COc1ccc(Cn2cnc3c(c(Cl)c(C)c(=O)n3C)c2=O)cc1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
5-Hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (10 g, 30.6 mmol, compound 8B) was suspended in phosphorus oxychloride (28 mL, 306 mmol) and heated at 80° C. for 5 hours. The solution was evaporated in vacuo, and the residue taken up in DCM and washed with saturated sodium bicarbonate solution until the neutral pH was observed. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica chromatography using 1% methanol in DCM as eluent to yield 9.28 g of title compound (89%). [M+H] calc'd for C17H16ClN3O3, 346; found, 346.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[CH:7][C:6]=1[NH:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([O:30]C)=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[CH:7][C:6]=1[NH:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(=O)c(C(=O)Nc3cc(O)c(C(C)(C)C)cc3C(C)(C)C)c[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3cc(O)ccc3c2=O)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-7-methoxy-4-oxo-1H-quinoline-3-carboxamide (120 mg, 0.28 mmol) in DCM (1.5 mL) was added BBr3 (1.5 mL, 15.23 mmol) dropwise at −78° C. After the addition was complete the cooling bath was removed and the resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. solution of NaHCO3. The aqueous layer was extracted with DCM and the combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified via reverse phase HPLC to give N-(2,4-ditert-butyl-5-hydroxy-phenyl)-7-hydroxy-4-oxo-1H-quinoline-3-carboxamide. LC/MS: m/z 409.5 (M+H)+ at 1.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:13]1([NH:19][C:20](=[S:23])[NH:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[N:22][NH:21][C:20](=[S:23])[NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: NNC(=S)Nc1ccccc1
Solvent: CCO
Product: S=C(NN=C(CCCCl)c1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
A mixture of 4-chlorobutyrophenone (6.7 mL, 42 mmol) and 4-phenyl-3-thiosemicarbazide (7.0 g, 42 mmol) in 500 mL of ethanol was warmed under a nitrogen atmosphere to dissolve all the solids and then the reaction stirred at room temperature for four days. The solid formed was collected by filtration and dried under reduced pressure to give 8.73 g of a white solid. Recrystallization of the solid from ethanol gave 7.99 g (57%) of the title compound as a white solid, mp 107-109° C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH2:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](OCC)=[O:27])[CH2:22][CH2:21]1)[CH3:19]>CCCCCC>[O:27]=[C:26]([C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:18][CH3:19])[CH2:21][CH2:22]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)[C@H]1CC[C@H](CC)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@H]1CC[C@H](C(=O)CP(=O)(OC)OC)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, 47 ml. of a 1.25M solution of n-butyllithium in n-hexane were added dropwise to a solution of 7.64 g. of dimethyl methylphosphonate in 120 ml. of tetrahydrofuran at -70° C. After one hour of stirring at -70° C., a solution of 5.63 g. of ethyl trans-4-ethylcyclohexanecarboxylate [c.f. N. L. Allinger and L. A. Freiberg, J. Org. Chem., 31, 894, (1966)] in 30 ml. of tetrahydrofuran was added dropwise at -70° C., and the mixture was stirred at the same temperature for one hour and further stirred at -5° C., for one hour. The reaction mixture was then acidified with acetic acid and concentration under reduced pressure. The residue was diluted with diethyl ether, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation to give 5.0 g. of the title compound having the following physical characteristics:-
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>O1CCCC1>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[OH:26]
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccccc1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2OC)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
5-Bromo-2-methoxypyridine (41.36 g) (prepared by the method of I. Kompis et al, European Journal of Medicinal Chemistry 1977, 12, 531) in dry tetrahydrofuran (50 ml) was cooled to -85° with stirring under a nitrogen atmosphere. n-Butyl lithium (137 ml of a 1.6M hexane solution) in dry tetrahydrofuran (50 ml) was added dropwise, keeping the temperature below -80°. After stirring for 5 minutes, 2-methoxybenzaldehyde (25.0 g) in dry tetrahydrofuran (150 ml) was added dropwise with stirring, keeping the temperature below -70°. The mixture was stirred whilst allowing to warm to room temperature, then quenched with saturated ammonium chloride solution (150 ml). The organic layer was separated and the aqueous was further extracted with ethyl acetate. The organic layers were combined, dried with anhydrous magnesium sulphate and evaporated to dryness to give an orange gum which was crystallised from dichloromethane/petroleum spirit (60-80°) to give 1-(2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)-methanol as a pale yellow solid (28.39 g, 63%) m.p. 83-84°.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[F:17][C:18]1[C:26]([CH3:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([N+:30]([O-:32])=[O:31])[C:19]=1[C:20](Cl)=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:20](=[O:21])[C:19]1[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([F:29])[C:25]([F:28])=[C:26]([CH3:27])[C:18]=1[F:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=CN(C)C
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
1.4 g (0.01 mol) of ethyl 3-dimethylaminoacrylate, 15 mg of ethyl acetate and 0.8 mg (0.01 mol) of pyridine were loaded and cooled below 5° C., and a liquid mixture of 3 g (0.01 mol) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride and 5 ml of ethyl acetate was added dropwise while the temperature was maintained at 0 to 5° C. The resulting mixture was stirred at 5° C. for 1 hour and then stirred at room temperature (25° C.) overnight (12 hours). The precipitated pyridine hydrochloride was filtered off, and the filtrate was concentrated under reduced pressure to give 3.62 g of ethyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate with a 87% purity (in terms of the percentage of the peak area in HPLC) as the residue.