Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:13])=[N+:8]([CH2:10][CH2:11][CH3:12])[CH:9]=1)[CH3:3].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1.CCOCC>CO>[Br-:1].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:13][C:7]2[CH:6]=[CH:5][C:4]([CH2:2][CH3:3])=[CH:9][N+:8]=2[CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=1
Reactant: CCC[n+]1cc(CC)ccc1C
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCNCC1
Product: CCC[n+]1cc(CC)ccc1C=Cc1ccc(N(C)C)cc1
Yield: 62.2 %

Procedure:
5-Ethyl-2-methyl-1-propylpyridinium bromide (8.1 g, 0.033 mole) and 4-dimethylaminobenzaldehyde (6.0 g, 0.04 mole) were refluxed in methanol (50 ml) in the presence of piperidine (1.5 ml) under nitrogen for four hours. Ether was added to the cool solution and, on scratching, a red solid crystallised which was collected and washed with a little isopropanol to give 2-[4-(dimethylamino)-styryl]-5-ethyl-1-propylpyridinium bromide (7.7 g). Melting point 236°-237° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1.[CH3:17][O:18][C:19](=[O:54])[NH:20][C@H:21]([C:25]([N:27]1[CH2:31][C@@H:30]([S:32][CH3:33])[CH2:29][C@H:28]1[C:34]1[NH:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[N:38]=1)=[O:26])[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:42]2[CH:43]=[CH:44][C:39]([C:37]3[N:38]=[C:34]([C@@H:28]4[CH2:29][C@H:30]([S:32][CH3:33])[CH2:31][N:27]4[C:25](=[O:26])[C@@H:21]([NH:20][C:19]([O:18][CH3:17])=[O:54])[CH:22]([CH3:24])[CH3:23])[NH:35][CH:36]=3)=[CH:40][CH:41]=2)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[O:16]
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)OC)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (184 mg, 0.62 mmol), [(S)-2-methyl-1-((2S,4S)-4-methylsulfanyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (300 mg, 0.55 mmol) and potassium carbonate (344 mg, 2.49 mmol) at RT was added toluene (1.35 mL) followed by water (0.69 mL). The reaction mixture was purged with nitrogen, Pd(dppf)Cl2CH2Cl2 (27.4 mg, 0.034 mmol) was added under an atmosphere of nitrogen. The reaction vial was capped and heated at 100° C. overnight, cooled to RT and partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate as an orange oil. (m/z): [M+H]+ calcd for C30H33F3N4O6S 635.21. found 635.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].ClC(Cl)C.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[Cl:14][C:15]([Cl:20])([Cl:19])[C:16]([O:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:17]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)OCCOC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Hydroxyethylmethacrylate (13.0 g) was placed in a 250 ml, three-necked, round-bottomed flask, fitted with a stirrer, air condenser and two dropping funnels, as well as a thermometer. The apparatus was placed in an ice/salt freezing bath. Dichloroethane (100 ml) was added, followed by the simultaneous dropwise addition of triethylamine (10.1 g) and trichloroacetyl chloride (18.2 g). During the addition the temperature was not allowed to rise above 2° C. After the addition was complete, the mixture was stirred for a further 6 hours, during this time the temperature rose gradually to room temperature. The mixture stood overnight, and the precipitated salt was filtered off, and the residue was washed thoroughly with dichloroethane. The washings and the filtrate were combined and the solvent was removed on a rotary evaporator. The residue still contained some solid. It was dissolved in ether, the ether solution was washed with water (3 times). The solution was then dried (MgSO4), filtered, and the solvent was removed under vacuum. The residue was distilled under high vacuum, collecting the fraction, boiling between 84°-90° C./0.1 mm (16 g).
Reaction SMILES: CO.[F:3][C:4]([F:13])([F:12])[C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].CC1C=CC(C(C)C)=CC=1>C(N(CC)CC)C.C(O)=O>[F:3][C:4]([F:12])([F:13])[CH:5]([OH:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=CO
Solvent: CO
Product: COC(=O)CC(O)C(F)(F)F
Temperature: 35 °C
Reaction time: 15 h

Procedure:
To 6 mL of methanol were added 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 1.0 g of methyl 4,4,4-trifluoro-3-oxobutanoate, and 7.5 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active methyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 94.6% e.e. and 100%, respectively.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([CH2:10][OH:11])=[N:8][N:9]=1.O.[C-]#[N:20].[Na+]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([C:10]([NH2:20])=[O:11])=[N:8][N:9]=1
Reactant: [C-]#N
Reactant: Cn1c(CO)nnc1Cc1c(F)cccc1F
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O
Reaction time: 4 h

Procedure:
1.43 g (6 mmol) of 5-(2,6-difluorobenzyl)-3-hydroxymethyl-4-methyl-4H-1,2,4-triazole and 5.22 g (60 mmol) of manganese dioxide are heated under reflux in 40 ml of toluene for 3 hours using a water separator. The reaction mixture is then cooled and filtered over Hyflo, and the filtrate is concentrated by evaporation. The residue is added to 90 ml of isopropanol saturated with ammonia. At 0°, 1.47 g (30 mmol) of sodium cyanide and 10.44 g (120 mmol) of manganese dioxide are added. The reaction mixture is stirred for 4 hours at 0° and filtered over Hyflo. The filtrate is concentrated by evaporation. Recrystallisation of the residue from ethanol yields the pure 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]#[N:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:21]([CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[N:22]
Reactant: COC(=O)c1ncc(O)cc1C
Reactant: N#CCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(OCC#N)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 5-hydroxy-3-methylpicolinate (0.8063 g, 4.82 mmol, step 3 intermediate 38) and cesium carbonate (0.772 ml, 9.65 mmol, Alfa Aesar) in DMF (48.2 ml) was added bromoacetonitrile (0.336 ml, 4.82 mmol, Sigma-Aldrich Chemical Company, Inc.). The reaction mixture was stirred for 4 h at rt. The reaction mixture was diluted with aqueous, saturated sodium bicarbonate solution and extracted with EtOAc. The organic extract was washed with aqueous, saturated sodium bicarbonate solution, brine and dried over MgSO4. The filtrate was concentrated in vacuo. MS m/z=207.1 [M+H]+. Calculated for C10H10N2O3: 206.069. 1H NMR (400 MHz, CHLOROFORM-d) ppm 2.67 (s, 3H) 3.98 (s, 3H) 4.88 (s, 2H) 7.20 (d, J=2.35 Hz, 1H) 8.32 (br. s., 1H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:48]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:17])([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: O=C(C[C@H](C(=O)O)c1ccn(-c2ccc(F)cc2)c1)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C
Yield: 82 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-succinic acid 4-benzyl ester and L-t-leucine N-methylamide (see Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 as gradient eluant provided in 82% yield N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid benzyl ester as a crisp foam.
Reaction SMILES: C([O:7][CH2:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11])(=O)C(C)(C)C.[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>CO>[F:14][C:9]([F:15])([S:10]([O-:13])(=[O:12])=[O:11])[CH2:8][OH:7].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)CO
Reaction time: 8 h

Procedure:
In 760 g of methanol was dissolved 243.5 g (0.48 mole) of triphenylsulfonium 2-(pivaloyloxy)-1,1-difluoroethane-sulfonate. To this solution under ice cooling, an aqueous sodium hydroxide solution (40 g sodium hydroxide in 120 g water) was added dropwise at a temperature below 5° C. The reaction solution was allowed to mature at room temperature for 8 hours, and dilute hydrochloric acid (99.8 g 12N hydrochloric acid in 200 g water) was added thereto at a temperature below 10° C. to quench the reaction. The methanol was distilled off in vacuum. To the residue was added 1,000 g of dichloromethane. The organic layer was washed three times with 30 g of saturated saline and concentrated. Diisopropyl ether, 1 L, was added to the concentrate for crystallization. The crystals were filtered and dried, obtaining the target compound (PAG1), 187 g (purity 78%, net yield 78%). PAG1 has the following structure.
Reaction SMILES: C([Li])CCC.C[C:7]([CH3:10])([O-:9])[CH3:8].[K+].C(NC(C)C)(C)C.[O:19]([C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:42]([CH2:43][CH2:44][C@:28]12[CH3:29])[C:41]1C=[CH:39][C:38]([O:45][CH3:46])=[CH:37][C:36]=1CC3)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].B(OC)(OC)OC.OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O:19]([C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:42]([CH2:43][CH2:44][C@:28]12[CH3:29])[C:41]1[CH:36]=[CH:37][C:38]([O:45][CH3:46])=[CH:39][C:10]=1[CH:7]([OH:9])[CH2:8]3)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]12
Reactant: CC(C)(C)[O-]
Agent: COB(OC)OC
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]12
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
n-Butyllithium (2.5 M in hexane, 40 ml, 100 mmol) was added to potassium tert-butoxide (1M in tetrahydrofuran, 100 ml, 100 mmol) at −70° C. under nitrogen atmosphere, followed by addition of diisopropylamine (19.1 g, 100 mmol) at the same temperature. After the mixture was stirred for 10 minutes, 17β-(t-butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-triene (10 g, 25 mmol) synthesized by the method described in Tetrahedron Lett., 3223 (1988) and dissolved in tetrahydrofuran (40 ml) was added dropwise at −70° C. over 10 to 15 minutes, and the resulting mixture was stirred for 4 hours. Trimethyl borate (15.6 g, 150 mmol) was added to the reaction mixture, which was then warmed to ice cold temperature and stirred for 1 hour and further stirred with 30% hydrogen peroxide (35 ml) for 1 hour at room temperature. The reaction mixture was cooled again on ice and 10% aqueous sodium thiosulfate (150 ml) was added to stop the reaction. After the reaction mixture was extracted with ether, the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. After distilling off the solvent, the residue was purified by silica gel flash chromatography (eluent: hexane/ethyl acetate=5/1→3/1) to give 17β-(t-butyl-dimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-ol (8.38 g, Yield 82%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:17]3[CH:24]=CC=CC=3C=O)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[OH-].[Na+].[N:29]1C=CC=CC=1.S(Cl)(Cl)=O.[C-]#N.[Na+]>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:17][C:24]#[N:29])[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1-c1ccc(OC(F)F)c(OC2CCCC2)c1
Reactant: c1ccncc1
Agent: [BH4-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: N#CCc1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 199.5 %

Procedure:
To a solution of (3-cyclopentyloxy-4-difluoromethoxyphenyl)benzaldehyde (3.4 g, 13.4 mmol) in absolute ethanol (33 mL) under an argon atmosphere at room temperature was added sodium borohydride (1.06 g, 28 mmol). After 20 min, 10% aqueous sodium hydroxide (15 mL) was added, the ethanol was removed in vacuo and the aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, was dried (magnesium sulfate) and evaporated to a pale yellow oil (3.44 g). A solution of this alcohol (1.52 g, 5.89 mmol) and pyridine (0.48 mL, 6 mmol) in alumina-dried chloroform (15 mL) under an argon atmosphere was treated with thionyl chloride (0.52 mL, 7.08 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil, which was dissolved in dimethylformamide (10 mL) under an argon atmosphere and treated with sodium cyanide (0.58 g, 11.8 mmol). After stirring at room temperature for 72 h, the mixture was partitioned between 5% aqueous sodium carbonate and ether. The organic extract was washed four times with water, was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 15-20% ethyl acetate/hexanes, provided a pale yellow solid (3.2 g, 90%): m.p. 39°-41° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:8][CH2:9][CH2:10][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCOc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A suspension of phenol (5 g, 0.053 mol), 1,2-dibromethane (60 g, 0.319 mol) and K2CO3 (22 g, 0.16 mol) in dry acetonitrile (100 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to yield (10 g) of the sub-title compound as a solid.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][N:7]=1.[C:14]([NH:17]/[C:18](/[CH2:39][CH2:40][CH2:41][CH3:42])=[C:19](/[CH2:24][C:25]1[CH:26]=[N:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]#[N:38])=[CH:29][CH:30]=1)\[C:20](OC)=[O:21])(=O)[CH3:15].[Cl-].[NH4+]>CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl.ClCCCl>[CH2:39]([C:18]1[N:17]=[C:14]([CH3:15])[N:5]([C:6]2[N:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][N:7]=2)[C:20](=[O:21])[C:19]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]#[N:38])=[N:27][CH:26]=1)[CH2:40][CH2:41][CH3:42]
Reactant: COc1cnc(N)nc1
Reactant: CCCC/C(NC(C)=O)=C(\Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CCCCc1nc(C)n(-c2ncc(OC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Reaction time: 1.33 h
Yield: 76.5 %

Procedure:
Process 3: Under argon atmosphere, trimethylaluminum (2 mol/L hexane solution, 1.45 mL, 2.90 mmol) was added to 1,2-dichloroethane (30 mL) solution of 2-amino-5-methoxypyrimidine (220 mg, 1.74 mmol) at room temperature, and stirred at the same temperature for 80 minutes. 1,2-dichloroethane (20 mL) solution of methyl(Z)-3-acetamido-2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-2-heptenoate (227 mg, 0.58 mmol) was added dropwise thereto at room temperature followed by reflux for 17 hours under heating. An aqueous solution of ammonium chloride and chloroform were added to the reaction mixture, which was then filtered through a pad of celite. The organic layer in the filtrate was separated, and the aqueous layer was extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residues obtained were subjected to silica gel column chromatography (hexane/ethyl acetate=2:1) to obtain 2-{5-{[4-butyl-1-(5-methoxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (207 mg, 77%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N+:27]([O-:29])=[O:28])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 2-nitrobenzaldehyde to provide 32 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:11][CH:10]=3)[C:5]([F:25])=[CH:4][N:3]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OCCCN2CCOCC2)cc1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OCCCN4CCOCC4)cc3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine. LCMS: retn, time: 14.72 min.; purity: 94%; MS (m/c): 484 (MH+); 1H NMR (CDCl3): δ 7.89 (1H, d, J=3.3 Hz), 7.47 (2H, d, J=9 Hz), 7.22 (1H, d, J=2.2 Hz), 6.93-6.76 (5H, m), 6.64 (1H, d, J=2.2 Hz), 4.01 (2H, t, J=5.6 Hz), 3.86 (3H, s), 3.72 (3H, s), 3.71 (4H, m), 2.58-2.44 (6H, m), 1.97 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15](=[O:23])[N:14]([CH3:24])[C:13](=[N:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>CO.O>[C:18]([CH2:17][N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[N:25][C:26]2[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=2[CH3:32])[N:14]([CH3:24])[C:15]1=[O:23])([OH:20])=[O:19]
Reactant: CCOC(=O)Cn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethoxycarbonylmethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (4 g) in methanol (30 ml) was added a solution of sodium hydroxide (0.52 g) in water (6 ml) and stirred at room temperature for 3 hours. After removal of methanol, the residue was dissolved in water (40 ml) and adjusted to pH 5.8 and extracted with chloroform. The chloroform layer was washed with brine, dried over magnesium sulfate and evaporated to give a residue, which was triturated in n-hexane to give colorless powders (3.3 g) of 3,4-dihydro-1-carboxymethyl-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1
Reactant: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)OCC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}phenyl)carbonyl](methyl)amino}propanoate (289 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (153 mg, 56%) as a pale-yellow solid.