Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[CH:12][C:11]=1[C:21]([F:24])([F:23])[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(O)C2N=NNC=2C=1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C.[F:57][C:58]([F:72])([F:71])[CH:59]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=1)[NH2:60]>ClCCl>[O:19]=[C:18]([NH:60][CH:59]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:68])([F:69])[F:70])[CH:62]=1)[C:58]([F:71])([F:72])[F:57])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C/C(=O)O)cc1C(F)(F)F
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cc(Cl)cc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
To a solution or 980 mg (1 eq. 2.84 mmol) of (2E)-3-[4-{[(tert-butoxycarbonyl)amino]methyl}-3-(trifluoromethyl)phenyl]acrylic acid in 10 ml of dichloromethane were added 481 mg (1 eq. 2.84 mmol) of 6-chlorohydroxybenzotriazole and 707 mg (1.3 eq. 3.70 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 733 mg (2 eq. 5.68 mmol, 989 μl) of Huenig's base. The reaction mixture was stirred at room temperature for 20 min. Then 1.04 g (1.5 eq, 4.26 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine as a solution in 1 ml of CH2Cl2 were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and partitioned between saturated Na2CO3 solution and ethyl acetate. After drying and concentrating the solvent, 2.108 g of tert-butyl {4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2-(trifluoromethyl)benzyl}carbamate were obtained as an oil, which was converted in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.O.CCOCC>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[C:1]#[N:2])[CH:20]1[O:22][CH2:21]1
Reactant: COc1cccc(O)c1C#N
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(OCC2CO2)c1C#N
Reaction time: 72 h
Yield: 32 %

Procedure:
2-Cyano-3-methoxyphenol (1 g, 6.7 mmol) and powdered potassium carbonate (2.78 g, 20.1 mmol) were stirred in 15 mL of acetone for 5 minutes, followed by addition of epibromohydrin (1.38 g, 10.1 mmol). The mixture was stirred for 72 hours then poured into water/ether. The ether layer was separated, washed with sodium carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude solid was triturated with ether/hexane, filtered, and dried under vacuum to give 0.44 g of 2-cyano-3-methoxyphenyl glycidyl ether.
Reaction SMILES: [Al](C)(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].C([O:16][C:17](=O)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=1[CH3:36])C.Cl>C(OCC)(=O)C.O>[CH2:30]([N:21]1[C:22]2[C:27](=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:19]([CH2:18][C:17]([NH2:13])=[O:16])=[C:20]1[CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCn1c(C)c(CC(=O)OCC)c2cc(OC)ccc21
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
A 2M solution of Al(CH3)3/toluene (15 mL, 0.03 mol) was added to 1.61 g (0.03 mol) of ammonium chloride while slowly keeping the temperature at 5-7° C. with an ice-water bath. The bath was removed, the mixture stirred for 0.5 hour and 1.01 g (3.05 mmol) of 1-hexyl-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was added. After stirring for 16 hours, 10 mL of water was added cautiously and the mixture added to 1N HCl and a large volume of ethyl acetate. The organic layer was separated, washed with water, sodium bicarbonate solution and dried (Na2SO4). After removing the solvent at reduced pressure the residue was crystallized from MeOH/water to give 0.37 g (40% yield) of 1-hexyl-5-methoxy-2-methyl-1H-indole-3-acetamide, mp, 120-121° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])[N:3]=1.[F:18][C:19]([F:27])([F:26])[C:20](=O)[CH2:21][C:22](=O)[CH3:23].O>C(O)(=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([NH:7][C:4]1[N:3]=[C:2]2[N:1]=[C:22]([CH3:23])[CH:21]=[C:20]([C:19]([F:27])([F:26])[F:18])[N:6]2[N:5]=1)(=[O:9])=[O:10]
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(F)(F)F)n2nc(NS(=O)(=O)c3ccccc3Cl)nc2n1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A mixture of 2.19 g (8.00 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide and 1.09 ml (1.38 g, 8.96 mmol) of 1,1,1-trifluoro-2,4-pentane-dione in 9 ml of glacial acetic acid was heated at reflux for 21 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ice and water. The solid which separated was collected by filtration, washed with water and dried to yield 2.90 g (93 percent) of the desired product as a white solid, mp 203°-204.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.CN(C)[CH:21]=[O:22].[C:24](OCC)(=O)C>O>[CH3:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:22][CH3:21])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1

Procedure:
A mixed solution of 4-(4′-hydroxyphenyl)benzoic acid (10.0 g, 4.67 mmol), iodomethane (19.9 g, 14.0 mmol) and N,N-dimethylformamide (80 ml) was stirred at 60° C. for 3 hours. To the obtained mixture was added ethyl acetate (200 ml) and water (150 ml), the mixture was stirred and the organic layer was separated. The organic layer was washed with 5% aqueous potassium hydrogen sulfate and water, and dried over sodium sulfate anhydride. The solvent was concentrated under reduced pressure and the object compound (10.5 g) was obtained from the residue as colorless crystals. Melting point: 177-178° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[NH2:16]C(N)=O>O>[NH2:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15]
Reactant: NC(N)=O
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Solvent: O
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
The following procedure is our modification: A mixture of 5-chloro-6-nitroisoindoline-1,3-dione (28.0 g, 0.123 mol) and urea (73.8 g, 1.23 mol) was stirred at 150° C. for 6 h. Then the temperature was reduced to 90° C., water (400 mL) was added, the mixture was stirred overnight at RT. Precipitate was collected by filtration, water (300 mL) was added and stirred for 4 h at 95° C. The solid was collected by filtration and dried under vacuum. Yellow solid, 19.6 g (94.7 mmol, 77%). LCMS [M−H]− 205.9. 1H NMR (300 MHz, DMSO): δ 11.46 (s, 1H), 8.35 (s, 2H), 8.37 (s, 1H), 7.40 (s, 1H).
Reaction SMILES: [Br-].[CH2:2]([N+:6]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][CH2:8][CH:9]([CH3:11])C)[CH2:3][CH2:4][CH3:5].[CH2:20](N(CCCC)CCCC)CCC.[Br:33]CCC(C)C>>[Br-:33].[CH2:16]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:11])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[N+](CCCC)(CCCC)CCC(C)C
Reactant: CC(C)CCBr
Reactant: CCCCN(CCCC)CCCC
Agent: [Br-]
Product: CCCCC[N+](CCCC)(CCCC)CCCC

Procedure:
Tri-n-butyl-isopentylammonium bromide can be synthesized using tri-n-butylamine and 1-bromo-3-methylbutane as starting materials, by the same method as the method for producing tri-n-butyl-n-pentylammonium bromide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22](OCC)=[O:23])[CH:14]=[N:13][C:12]1=2>C(#N)C>[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:23])[CH:14]=[N:13][C:12]1=2
Reactant: NCCN1CCCCC1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCN1CCCCC1
Temperature: 25 °C
Yield: 86 %

Procedure:
0.500 g (3.90 mmol) of 1-(2-aminoethyl)piperidine was added to a 10 ml round bottom flask equipped with a magnetic stirring bar. The amine was heated to 100°-110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was heated for one hour at which time it had solidified. The solution was allowed to cool to room temperature and 10 ml of acetonitrile was added to the solid. This mixture was stirred and the solid was collected by Buchner vacuum filtration. The white crystalline solid was washed with acetonitrile and then with ether to yield 290 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[[2-(1-piperidinyl)]ethyl]propanaide (AIT-0070). Yield: 86%.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[C:28]([O:32][CH3:33])(=[O:31])[NH:29][NH2:30]>CO.ClCCl>[CH3:33][O:32][C:28]([NH:29][N:30]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1)=[O:31]
Reactant: COC(=O)NN
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NN=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), methyl carbazate (34 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[N:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][NH2:14])=O)=[C:4]([CH3:19])[CH:3]=1.I.CS[CH:23]([NH2:25])[NH2:24].O>N1C=CC=CC=1>[NH2:25][C:23]1[NH:24][C:11]([C:10]2[CH:15]=[CH:16][N:17]=[CH:18][C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH3:19])=[N:13][N:14]=1
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)NN
Reactant: CSC(N)N
Agent: I
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(I)ccc1Nc1cnccc1-c1nnc(N)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
A reaction mixture of 3-(4-Iodo-2-methyl-phenylamino)-isonicotinic acid hydrazide (120 mg, 0.33 mmol, 1 eq) and C-Methylsulfanyl-methanediamine hydroiodide (104 mg, 0.47 mL, 1.45 eq) in pyridine (2 mL) in sealed tube was heated to 140° C. while stirring for 4 hrs. After cooling, it was poured into water, extracted with EtOAc, and the combined organic fractions, dried over anhydrous MgSO4. After filtration and solvent removal the remaining crude product was subjected to silica gel column chromatography (eluent:Hexane EtOAc=1:1) to afford the desired product (35 mg). [4.26 min; 393(M+1)]
Reaction SMILES: C([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH:15]=[N:14][C:13]=2[CH:24]=1)C1C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH:15]=[N:14][C:13]=2[CH:24]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N=C[C@H]1CCCCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1O)N=C[C@H]1CCCCN1C2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To (R,Z)-3-(benzyloxy)-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one (241) (215 mg, 0.614 mmol) in 25 ml of CH2Cl2 at 0° C. was added 25 ml of CH2SO3H. The mixture was stirred at 0° C. for 10 min and then at RT for 2 h, diluted with CH2Cl2, neutralized with cold 1.0 M NaHCO3, extracted with CH2Cl2, dried over Na2SO4, filtered, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2 (1:15) to afford 122 mg (70%) of the title product. 1H NMR (CDCl3), 7.75 (d, 1H, J=5.7 Hz), 7.28 (s, 1H), 6.70 (s, 1H), 4.08 (m, 1H), 3.83 (d, 3H), 3.61 (m, 1H), 3.08 (m, 1H), 1.91 (m, 1H), 1.81 (m, 1H), 1.71˜1.55 (m, 4H); 13C NMR 167.81, 163.46, 148.53, 145.71, 140.84, 121.23, 111.89, 111.39, 56.45, 49.83, 39.96, 24.71, 23.22, 18.60; MS m/z+283.7 (M+Na).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8]([OH:21])=[C:7]([CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]=O>C1COCC1>[C:24]([N:23]1[CH2:22][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)[C:8]=2[O:21][CH2:28]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Reactant: C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(c(-c3ccc(C(F)(F)F)nc3)c1)OCN(C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol (2.00 g, 5.26 mmol) was added to a 37% aqueous solution of formaldehyde (0.47 mL, 5.78 mmol) in THF (6 mL) and the reaction mixture stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the solid was recrystallized by heating 1.1 g of product in methanol (10 mL) then cooling to room temperature to yield a first crop of 3,6-di-tert-butyl-8-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (588 mg, 29%) as a white crystalline solid.
Reaction SMILES: [BH4-].[Na+].C1COCC1.C(O)(C(F)(F)F)=O.[BH4-].[Na+].C(O)(C(F)(F)F)=O.[C:24]1([C@@H:30]([NH:32][C:33]2[CH2:34][N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36][CH2:37][C:38]=2[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[C:24]1([C@@H:30]([NH:32][C@@H:33]2[CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:34]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C[C@@H]1N[C@@H](C)c1ccccc1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a 100 L reactor charged with NaBH4 (1.16 kg, 30.5 mol, 2.0 equiv) and anhydrous THF (60 L) under nitrogen was added TFA (10.5 kg, 92 mol, 6.0 equiv) slowly over 30 min while maintaining temperature at 0˜5° C. The mixture was then cooled to −45° C. In a separation reactor, crude product 3-3 was dissolved in anhydrous acetonitrile (30 L), which was added slowly to the above solution of NaBH4/TFA while maintaining the internal temperature between −45˜−30° C. The mixture was stirred at −45° C. for 1 h, after which time, HPLC indicated complete consumption of compound 3-3. The mixture was slowly diluted with ice water (50 kg) and the mixture was then warmed to 10° C. The product was extracted with EtOAc (2×40 L) and the combined organic layers were washed with saturated NaHCO3 solution (20 L). pH of the aqueous was ˜8. The organic layers were dried (Na2SO4) and concentrated in vacuo to nearly dryness to afford a residue which was further azeotroped with MeOH (10 L×3) to remove excess EtOAc. In the end, a 10 L solution of crude 3-4 in MeOH was obtained, which was used directly in the subsequent step without further purification. ESI-MS (M+H-1)+: 377.2. 1H NMR (400 MHz, CD3OD) δ: 7.31-7.22 (m, 5H), 4.20 (q, 2H), 4.11-3.86 (m, 3H), 3.15 (s, 1H), 3.00-2.90 (m, 2H), 2.64 (d, 2H), 1.87-1.85 (m, 1H), 1.68 (s, 1H), 1.50-1.25 (m, 15H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
In a flask were placed 2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (40 mg, 0.13 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (31 mg, 0.26 mmol), pyridine (21 μL, 0.26 mmol) and N,N-dimethylformamide (2 mL), followed by stirring at room temperature for 24 hour. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (16 mg). MS m/e (ESI) 389 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCC(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCC(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(=O)OCC
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g, 4.10 mmol) and 4-nitro phenyl boronic acid (0.81 g, 4.9 mmol), dissolved in toluene (37 mL) and dioxane (10 mL), followed by addition of saturated aqueous sodium carbonate (11 mL). A thin-gauge needle was inserted into the bi-phasic mixture and the mixture was degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.17 g, 0.20 mmol) was added, followed by 15 minutes of degassing. The mixture was heated to 85° C. for 16 h. The very darkly colored reaction mixture was allowed to cool, and diluted with ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated, the aqueous layer extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. The filtrate was concentrated under reduced pressure, leaving a dark red-brown oil, that was purified by flash chromatography (10:1 hexane:ethyl acetate, then 7:1 hexane:ethyl acetate, then 4:1 hexane:ethyl acetate) to afford ethyl 2-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate (0.71 g, 48%). LC-MS ret. time 3.88 min, m/z 369.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 0.95 (t, 3H), 1.30 (t, 3H), 1.35-1.50 (m, 2H), 1.60-1.83 (m, 2H), 3.0-3.18 (m, 2H), 3.5 (dd, 1H), 4.20 (q, 2H), 7.65-7.88 (overlapping d, 4H), 8.10 (d, 2H), 8.35 (d, 2H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(NC)C1C=CC=CC=1>[CH2:3]([N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: CN(C)C=Nc1ccncc1O
Agent: CNCc1ccccc1
Product: CN(C=Nc1ccncc1O)Cc1ccccc1

Procedure:
4-[[(Dimethylamino)methylene]amino]-3-pyridinol (3.0 g) was refluxed in N-benzyl-N-methylamine (6.12 ml) and dry toluene (60 ml) overnight. The reaction mixture was concentrated, adhered to silica (MeOH), flash chromatographed (10% MeOH/EtOAc) and concentrated to give 4.4 g of 4-[[(N-benzyl-N-methylamino) methylene]amino]-3-pyridinol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:3]=1
Reactant: Brc1ccsc1
Reactant: Clc1ccnc2ccccc12
Product: Clc1cc(-c2ccsc2)nc2ccccc12

Procedure:
The title compound, MS: m/e=245 (M+), was prepared from 4-chloro-quinoline and 3-bromothiophene.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C=O)C>[CH3:15][C:6]1[C:7]([O:14][CH2:30][CH:29]=[CH2:28])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([C:2]([F:20])([F:1])[F:21])=[N:4][C:5]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(C)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 10 g (0.03 mol) of product of Example 35 with 9.7 g (0.07 mol) of K2CO3 in 100 ml of DMF was charged 8 g (0.07 mol) of allyl bromide. The resulting mixture was stirred at 25° C. for 4 days. The reaction mixture was poured into H2O, and extracted with duethyl ether. The ether phase was dried (MgSO4), and concentrated in vacuo to 10.2 g (95%) of product as a yellow oil: nD25 1.4334
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][CH:3]=1.Br[CH2:12][CH:13](OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:8][CH:12]=[CH:13][N:7]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: COC(CBr)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Oc1ccc(-c2nccs2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-hydroxybenzothioamide (30.64 g, 0.20 mol) and 2-bromo-1,1-dimethoxyethane (31.00 g, 0.20 mol) in EtOH (600 mL) was added 4-methylbenzenesulfonic acid (34.44 g, 0.20 mol) with stirring at rt. The reaction mixture was heated at 90° C. for 24 h, then cooled to rt and concentrated in vacuo. The mixture was diluted with H2O (200 mL), adjusted to pH 10 with saturated NaHCO3 aqueous solution and extracted with DCM (200 mL×3). The combined organic phases were concentrated in vacuo to give the title compound as s yellow solid (21.3 g, 60%).