Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH2:4][F:5].[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([NH:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1)=[O:12])[CH2:2][F:1]
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(CF)CF)c2)n1
Yield: 65.8 %

Procedure:
A solution 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (3.00 g, 9.31 mmol), 3-amino-1-methylpyrazole (1.83 g, 18.6 mmol), HATU (4.60 g, 12.1 mmol) and DIPEA (3.25 mL, 18.6 mmol) in DMF (12 mL) was stirred at RT overnight. Water (150 mL) was added and the solution partitioned with ethyl acetate (250 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired product (2.46 g).
Reaction SMILES: [OH-].[K+].COC([C:7]1([C:20]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O.O1CCOCC1>O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(Cl)ccc23)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 4,7-Dichloroquinazoline (800 mg, 4 mmol) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.2 g, 5.2 mmol), as prepared in Example 1a, in a sealed vial at rt was added drop-wise a 1 M solution of LiHMDS in THF (6 mL, 6 mmol). The mixture was stirred at rt overnight. It was then quenched with aqueous NaH2PO4 and the mixture was extracted with DCM. The DCM layer was drawn off, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 2.2 g (>100%) of crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a) as a yellow semi-solid which was used as such for the next step. Solid KOH (224 mg, 4 mmol) was added to a suspension of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a; 41 mg, 0. 1 mmol) in a 1:1 mixture of dioxane and water (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (3b). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine (3c) as a di-HCl salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15](Cl)[N:14]=[C:13]([S:20][CH3:21])[N:12]=1.O>CS(C)=O.CCOC(C)=O>[Cl:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=[C:13]([S:20][CH3:21])[N:12]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of aniline (550 microliter (hereinafter “μL” or “uL”), 6 millimoles (hereinafter “mmol”), 1.2 equivalents (hereinafter “eq”)) in dry DMSO (100 mL) was added NaH as a 60% suspension in mineral oil (240 milligrams (hereinafter “mg”), 6 mmol, 1.2 eq) and the reaction mixture was stirred for 1 hour (hereinafter “h”). To the red solution was then added 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1.11 grams (hereinafter “g”), 5 mmol) [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] dissolved in anhydrous DMSO (20 milliliters (hereinafter “mL”)). The reaction mixture turned yellow and was stirred 2 h at 23°, H2O (250 mL) was added followed by EtOAc (500 mL). The layers were separated; the organic layer was washed with saturated (hereinafter sat'd) aq. NaCl, dried (MgSO4) and filtered. The organic layer was evaporated and the crude residue was dissolved in isopropanol (50 mL) and heated to 60°, H2O (50 mL) was added and the solution was cooled slowly to 230. The product was isolated by filtration and dried in vacuo to afford 1.06 g (76% yield) of pure 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.59 (s, 3H), 7.21 (m, 1H), 7.44 (m, 2H), 7.68 (m, 2H), 10.37 (s, 1H), 11.38 (br s, 1H). LC MS (m/e)=280 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]#[N:14])(=[O:3])[CH3:2].[OH2:15].C([O-])([O-])=O.[Na+].[Na+].[NH2:22]O.Cl>C(O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[NH:22])[NH:14][OH:15])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)N1c2ccccc2CC1C#N
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1c2ccccc2CC1C(=N)NO
Temperature: 85 °C

Procedure:
1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (0.0132 mole) was treated with water (54 ml) and the resulting suspension was treated sequentially with Na2CO3 (0.00726 mole) and NH2OH.HCl 0.0145 mole). The mixture was treated with ethanol (26 ml) and heated to 80-90° C. Upon achieving reaction temperature, the mixture was still a suspension. Added another 26 ml of ethanol which afforded a clear solution. The reaction was heated for 2.5 hours and cooled to room temperature with stiffing. A voluminous precipitate formed which was collected by suction filtration, washed with cold distilled water, and air dried, yielding 2.23 g of 1-acetyl-2,3-dihydro-N-hydroxy-1H-indole-2-carboximidamide (intermediate 14, mp. 204-205° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:19]=[CH:18][C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[CH:6]=1)=[C:15]([OH:17])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:1]([NH:4][C:5]1[CH:19]=[CH:18][C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[CH:6]=1)=[C:15]([O:17][C:20](=[O:22])[CH3:21])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc2cnc3cccc(O)c3c2c1
Product: CC(=O)Nc1ccc2cnc3cccc(OC(C)=O)c3c2c1

Procedure:
Alternatively, the corresponding 9-acetamido-1-hydroxybenzo[c]quinoline is obtained when the residue obtained upon hydrogenation is acetylated with acetic anhydride by the procedure of Example 7. When a molar excess of acetic anhydride is employed, the corresponding 9-acetamido-1-acetoxybenzo[c]quinoline is obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[C:9]([O:12][C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[CH:10]=2)[O:5][C:3](=[O:4])[CH:2]=1.O.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:26]([O:24][C:8]1[C:9]([OH:12])=[CH:10][C:11]2[CH:1]=[CH:2][C:3](=[O:4])[O:5][C:6]=2[CH:7]=1)[CH3:27]
Reactant: O=c1ccc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc2oc(=O)ccc2cc1O
Reaction time: 5 h

Procedure:
110 g (300 mmol) esculine×1.5 H2O, 70 g (450 mmol) ethyl iodide and 82.8 g (600 mmol) of potassium carbonate are agitated in 400 ml DMF for 30 h at 85° C. This was followed by filtration, reduction of the filtrate to approximately 250 ml, the addition of approximately 200 ml ethanol and crystallization at 0° C. The crystals were boiled in 800 ml of 2N sulfuric acid for 5 h under reflux. The product was vacuum filtered, washed with water and recrystallized from water and ethanol: yield 43.2 g (70%), fusion point 145° to 146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[N:20]([CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[C:21]=S.IC>C(Cl)Cl.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:21]([NH:20][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:15][N:14]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: S=C=NCCN1CCCCC1
Solvent: CI
Solvent: CCO
Solvent: ClCCl
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnc(NCCN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (300 mg; 0.81 mmol; 1 eq) in DCM (5 mL), 1-(2-Isothiocyanato-ethyl)-piperidine (192 mg; 1.13 mmol; 1.4 eq) was added. The reaction mixture was refluxed for 4 hrs under argon. A yellow solid precipitated out and filtered to afford an intermediated that was suspended in ethanol (5 mL). Iodomethane (148 mg; 1.05 mmol; 1.3 eq) was added to the reaction mixture and stirred overnight at RT, then heated to 80° C. and stirred for another 2 hr. The mixture was filtered to give a yellow solid product 40 mg. LC/MS (Method A) [3.89 min; 509(M+1)]
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Br:22][Si](C)(C)C>ClCCl>[Br:22][CH2:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[CH:11][CH:10]=1)=[O:14]
Reactant: CC(=O)c1ccc(-c2cnco2)cc1
Reactant: C[Si](C)(C)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(1,3-Oxazol-5-yl)phenyl]-1-ethanone (2.81 g) and triethylamine (6.27 mL) were dissolved in dichloromethane mL), and bromotrimethylsilane (3.96 mL) was added dropwise to the solution under ice cooling. The mixture was stirred at room temperature overnight under argon. The reaction mixture was washed sequentially with water and saturated saline, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the formed brown oily matter was dissolved in tetrahydrofuran mL). Subsequently, N-bromosuccinimide (2.67 g) was added to the solution, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified through flash column chromatography (dichloromethane), followed by concentration under reduced pressure. The obtained solid was recovered through filtration by use of n-hexane, to thereby yield the title compound (3.35 g).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH3:23])[CH2:5][C@@H:6]([CH3:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:24]I.O>CN(C)C=O>[CH3:24][O:3][C@@H:4]([CH3:23])[CH2:5][C@@H:6]([CH3:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H](C)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
0.13 g of 55% sodium hydride was mixed with 1 ml of dimethylformamide. A solution of 0.56 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile prepared in the above Example 1 in 2 ml of dimethylformamide was added dropwise thereto under ice-cooling. The obtained mixture was then stirred at room temperature for one hour. Subsequently a solution of 0.36 g of methyl iodide in 2 ml of dimethylformamide was added thereto and the obtained mixture was stirred at room temperature for two hours. 10 ml of water was carefully added to the reaction mixture and the obtained mixture was extracted with diethyl ether. After thoroughly washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography, similar to the case of Example 1, with the use of a mixture of n-hexane and ethyl acetate (4:1) as a developing solvent. Thus 0.36 g of the title compound, namely, (R,S)-4-[4'-(3"-methoxy-1"-methylbutoxy)phenyl] benzonitrile was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CNc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 6.1 g. (0.024 mole) of N-(4,6-dichloro-2-pyrimidinyl)glycine ethyl ester, 3.4 g. (0.024 mole) of p-chlorobenzylamine and 2.6 g. (0.024 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hours. The reaction mixture was filtered and the filtrate on cooling gave a precipitate. The precipitate was collected and recrystallized twice from benzene to give 4.6 g. of product, m.p. 132°-135°C.
Reaction SMILES: BrC1C(O)=C([C:9]2([C:12](N)=[O:13])[CH2:11][CH2:10]2)C(C#N)=C(C)C=1C1C=CC=CC=1.C1(C(O[C:30]2([NH2:46])[C:35]([C:36]#[N:37])=[C:34]([CH3:38])[C:33]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:32]([Br:45])[CH2:31]2)=O)CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:45][C:32]1[C:33]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[C:34]([CH3:38])[C:35]([C:36]#[N:37])=[C:30]2[C:31]=1[O:13][C:12]([CH:9]1[CH2:11][CH2:10]1)=[N:46]2
Reactant: Cc1c(C#N)c(C2(C(N)=O)CC2)c(O)c(Br)c1-c1ccccc1
Reactant: CC1=C(C#N)C(N)(OC(=O)C2CC2)CC(Br)=C1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(Br)c2oc(C3CC3)nc2c1C#N
Yield: 85.7 %

Procedure:
Next, a mixture of (2-bromo-5-cyano-3-hydroxy-6-methylbiphenyl-4-yl)cyclopropanecarboxamide/4-amino-2-bromo-5-cyano-6-methylbiphenyl-4-yl cyclopropanecarboxylate mixture (160 mg, 0.426 mmol), p-toluenesulfonic acid monohydrate (24 mg, 0.128 mmol) and toluene (13 ml) was heated under reflux for 1.5 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (129 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:13][C:11]1[S:10][CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([F:14])=[C:2]([CH3:1])[CH:7]=2)[N:12]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(-c2csc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.4 mg) with purity >90%. MS (pos) m/z 431.1, 433.1.
Reaction SMILES: C(Cl)CCl.CC1=CCCC(C)=CC[C@:13]2(C)[C:25](=[O:26])[C:24](O)=[C:23]([C@@H:28]([CH2:30][OH:31])C)[C@H:14]2[CH2:15][CH:16]=C(C)[C@@H](O)CC1.C(C(CCCCN)C(O)=O)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:26]1[C:25]2[C:24](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:28][C:30]1=[O:31]
Reactant: CC1=CC[C@]2(C)C(=O)C(O)=C([C@H](C)CO)[C@H]2CC=C(C)[C@@H](O)CCC(C)=CCC1
Agent: C/C1=C\C[C@]2(C)C(=O)C(O)=C([C@H](C)CO)[C@H]2C/C=C(\C)[C@@H](O)CC/C(C)=C/CC1
Agent: CC(C)(C)OC(=O)C(CCCCN)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=c1ccc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
EDC (1.0 mg, 0.0052 mmol) and DMAP (0.64 mg, 0.0052 mmol) were added to a stirred solution of terpestacin (2.0 mg, 0.005 mmol) and Boc-6-aminohexanoic acid (1.2 mg, 0.0052 mmol) in DMF (2 mL) at 0° C. The reaction mixture was reacted overnight at room temperature. The reaction product was extracted with ethanol (4 mL×3), treated with 20% TFA in CH2Cl2 (1 mL) and stirred at room temperature for 2 hours. DIPEA (1.3 mg, 0.01 mmol) and 6-((7-amino-4-methylcoumarin-3-acetyl)amino)hexanoic acid succinimidyl ester (2.2 mg, 0.005 mmol, MOLECULAR PROBES®) were added thereto at 0° C. After being stirred at room temperature for 4 hours, the reaction product was extracted with ethanol (20 mL) and purified by TLC (CH2Cl2:MeOH=10:1) to obtain coumarin-conjugated terpestacin (yield: 61%). The synthesized coumarin-conjugated terpestacin is depicted in Formula 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].C1CCN2C(=NCCC2)CC1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>C(Cl)Cl>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:8]2[S:7](=[O:13])(=[O:12])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:10](=[O:11])[CH2:9]2)=[CH:35][CH:34]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CBr)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound in Example 9, 2,4-dimethoxybenzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 6.98 mmol) in CH2Cl2 (100 mL) is treated with DBU (1.06 g, 6.98 mmol). α, α′-Dibromo-p-xylene (9.2 g, 34.9 mmol) is added and the mixture is stirred at RT for 16 h. The mixture is filtered and the filtrate is concentrated to 20 mL. The mixture is chromatographed on silica gel using CH2Cl2 as the eluent. The residual α, α′-dibromo-p-xylene is removed from the product by triturating with Et2O to afford 5-(4-bromomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: [M+H]+=469.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[NH:20][CH3:21].[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[ClH:22].[Cl:22][CH2:23][C:24]([N:20]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[CH3:21])=[O:25]
Reactant: CNc1cc2c(Nc3cccc(C)c3)ncnc2cc1F
Reactant: O=C(Cl)CCl
Product: Cc1cccc(Nc2ncnc3cc(F)c(N(C)C(=O)CCl)cc23)c1
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 4, 7-fluoro-6-methylamino-4-(3'-methylanilino)quinazoline was reacted with 2-chloroacetyl chloride to give 6-(2-chloro-N-methylacetamido)-7-fluoro-4-(3'-methylanilino)quinazoline hydrochloride (0.097 g);
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:15]3[C@H:11]([CH2:12][NH:13][CH2:14]3)[C@:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[C@H:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@@H:40]([CH3:44])[C:41](O)=[O:42]>>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:15]3[C@H:11]([CH2:12][N:13]([C:41](=[O:42])[C@@H:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH3:32])[CH3:44])[CH2:14]3)[C@:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[C@H:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@@H](C)C(=O)O
Reactant: COc1ccccc1[C@@]1(O)[C@H](O)CC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Product: COc1ccccc1[C@@H](C)C(=O)N1C[C@@H]2[C@H](C1)[C@@](O)(c1ccccc1OC)[C@H](O)CC2(c1ccccc1)c1ccccc1
Yield: 43.2 %

Procedure:
By working according to the procedure of Example 1, starting from 0.2 g of (3aR,4R,5R,7aR)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol and 0.11 g of (R)-2-(2-methoxyphenyl) propionic acid, 0.12 g of (3aR,4R,5R,7aR)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(R)-2-(2-methoxyphenyl) propionyl]perhydro-4,5-isoindolediol is obtained, melting at 178°-180° C.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([OH:6])=[O:5].OO.[OH2:14].C[OH:16]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][S:2]([CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([OH:6])=[O:5])(=[O:16])=[O:14]
Reactant: CO
Reactant: O
Reactant: CSC(C(=O)O)c1ccsc1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)C(C(=O)O)c1ccsc1
Reaction time: 72 h

Procedure:
α-Methylthio(3-thienyl)acetic acid (1.487 g) was dissolved in 20 ml of methanol, and 10 mg of sodium tungstate and 2.5 ml of a 30% aqueous solution of hydrogen peroxide were added. The mixture was stirred for 3 days. To the reaction mixture was added 50 ml of water, and the mixture was extracted four times with 80 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Crystallization of the residue from methylene chloride/carbon tetrachloride afforded 950 mg of α-methylsulfonyl(3-thienyl)acetic acid as pale yellow crystals having a melting point of 123 to 123.5° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][S:11]([C:4]2[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:3]=2)(=[O:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCn1cc(Br)nc(S(=O)(=O)Cc2ccc(Cl)cc2)c1=O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1cc(-c2ccccc2)nc(S(=O)(=O)Cc2ccc(Cl)cc2)c1=O
Yield: 26.2 %

Procedure:
200 mg (0.51 mM) of 5-bromo-3-[(4-chlorobenzyl)sulfonyl]-1-ethylpyrazin-2(1H)-one and 20 mg of tetrakis Pd(PPh3) in 4 ml of toluene were stirred for 10 min at room temperature under nitrogen atmosphere. 93.4 mg (0.77 mM) of phenyl boronic acid and 1.5 ml of a 2M cesium carbonate aqueous solution were added and the reaction mixture was refluxed under stirring for 1 h30. 10 ml of water and 10 ml of toluene were added, the organic layer was separated. The aqueous layer was extracted with toluene and the combined organic layer was separated and washed with water, dried on anhydrous sodium sulfate and concentrated under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane/dimethylketone (95/5) as eluant, to give 52 mg of 3-[(4-chlorobenzyl)sulfonyl]-1-ethyl-5-phenylpyrazin-2(1H)-one as a solid. Yield: 26%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([NH:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])[CH3:16]>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:18][C:15](=[O:17])[CH3:16])[CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CC(=O)Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
A 1.5 g (7.46 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Aldrich) and 1.69 g (11.19 mmol) of 3-acetamidophenol (Aldrich) were added to a complex of TPP and TBAD, (prepared as in Example 5b above, 11.19 mmol of each) in 50 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with 100:3 chloroform:methanol to give 1.62 g of the title compound.