Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])([O:5][CH3:6])=[O:4].[CH2:31]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]O)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][NH:41][C:39]([O:38][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:40])=[O:16])=[O:11])([O:5][CH3:6])=[O:4]
Reactant: O=C(NCCCCCO)OCc1ccccc1
Reactant: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCCCCCNC(=O)OCc1ccccc1)OC
Reaction time: 20 h

Procedure:
The compound of example 12(g) is prepared as follows: N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (700 mg; 1.61 mmol) in dimethyl formamide (DMF) (10 ml) is treated sequentially with N-benzyloxycarbonyl-5-aminopentanol (400 mg; 1.98 mmol) in DMF (2 ml), 1-hydroxybenzotriazole (HOBT) (265 mg; 1.96 mmol), 4-N,N-dimethylaminopyridine (DMAP) (239 mg; 1.96 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (553 mg; 3.22 mmol). The mixture is stirred for 20 hours, then partitioned between ethyl acetate (50 ml) and 1N HCl(30 ml). The organic layer is washed with a saturated solution of sodium bicarbonate (30 ml), then with brine (30 ml) before being dried over anhydrous sodium sulfate. After concentration under reduced pressure, the oily residue is purified by column chromatography on silica gel, eluting first with ethyl acetate, then with 5% methanol in methylene chloride to yield N-benzyloxycarbonyl-5-aminopentyl N-[2-(dimethylphosphonomethyl amino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate as an oil; Rf(SiO2 ; MeOH/CH2Cl2):0.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][S:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N)(=O)C1C=CC=CC=1>CS(C)=O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][S:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCNCC1
Reactant: CSCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Agent: NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CSCCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 100 °C
Yield: 117.4 %

Procedure:
In a 4 mL screw-cap vial were dissolved 5-fluoro-2-[4-fluoro-2-(2-methylthioethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (131 mg, 274 μmol) and 1-methylhexahydro-1,4-diazepine (157 mg, 1.37 mmol, 5 eq) in 250 μL DMSO to give a light yellow solution. The solution was heated to 100° C. for 36 hours in a heatblock, then allowed to cool to room temperature. The resulting brown solution was diluted with 1 mL dichloromethane, washed four times with water, once with brine, then dried over sodium sulfate and concentrated. The residue was combined with that from a separate, smaller scale run (100 μmol of starting benzamide) and purified via radial chromatography with 95:5, then 9:1 dichloromethane:methanol to produce 184 mg (86%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[C:35]([CH3:36])=[CH:34][S:33][CH:32]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[C:35]([CH3:36])=[CH:34][S:33][CH:32]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Cc1cscc1N
Product: CCOC(=O)c1cnn2c(Nc3cscc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 42.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.20 g, 0.48 mmol) obtained in Example 19, step 4 and 3-amino-4-methylthiophene (0.110 g, 0.97 mmol), the title compound (0.099 g, 42%) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17].[NH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC(O)C>[CH2:14]([C:13]1[N:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: NOCCCCNC(=O)OCc1ccccc1
Reactant: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCCc1nc2cnc3ccccc3c2n1OCCCCNC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 76.5 %

Procedure:
N-(4-chloroquinolin-3-yl)valeramide (1.97 g), benzyl (4-aminooxybutyl)carbamate (2.99 g), triethylamine (0.89 g) and 2-propanol (40.69 g) were combined and heated at 80° C. for 3.5 hours. The reaction was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. Dichloromethane (20 mL) was added to the resulting solid and the mixture was stirred for twenty minutes. Undissolved solid was removed by filtration and the filtrate was washed with two 10 mL portions of water that had been made slightly acidic by the addition of 20 drops of hydrochloric acid (1.2 M). The organic fraction was dried and concentrated under reduced pressure. The crude solid was recrystallized from tetrahydrofuran to provide 2.56 g of benzyl 4-{[2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butylcarbamate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2C=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1.[NH2:22][NH2:23]>>[NH:22]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([Cl:20])[CH:18]=2)[N:3]=1)[NH2:23]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1Cl
Product: CCOC(=O)c1cnc(-c2ccc(Cl)c(Cl)c2)nc1NN
Yield: 99 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'-dichlorophenylacetamidine (5.5 g, 27 mmol) to afford 37% of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with POCl3 (14 g, 92 mmol) to afford 62% of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (1 g, 2.8 mmol) with hydrazine (0.27 g, 8.3 mmol) to afford 99% of ethyl 4-hydrazino-2-(3',4'-dichlorophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (0.9 g, 2.7 mmol) with citraconic anhydride (0.49 g, 4.4 mmol) in analogy to Example 21 to afford 47% (0.3 g) of the title compound; m.p. 119-121° C.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[N:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=[O:32]>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:31]([C:16]2[CH:15]=[C:14]([Cl:13])[N:19]=[C:18]([F:20])[C:17]=2[O:21][CH2:22][O:23][CH3:24])[OH:32])[CH:33]=1
Reactant: COCOc1ccc(Cl)nc1F
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCOc1c(C(O)c2cc(Br)ccc2F)cc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
A solution of i-Pr2NH (1100 mL, 7.72 mol) in anhydrous THF (3.5 L) was cooled to −10° C. n-BuLi (2.5 M in hexanes, 3087 mL, 7.72 mol) was added drop wise and the solution was stirred for 10 min at 0° C. The reaction mixture was cooled to −78° C. and a solution of 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1344 g, 7.02 mol) in anhydrous THF (2 L) was added slowly, keeping the internal temperature below −60° C. The resulting solution was stirred at −75° C. for 1 hr. A solution of 5-bromo-2-fluorobenzaldehyde (1430 g, 7.02 mol) in THF (1.7 L) was added drowise. After the addition was complete, the reaction mixture was stirred at −75° C. for 30 min. The reaction mixture was warmed to RT and quenched with saturated aqueous NH4Cl solution (3 L). EtOAc (5 L) was added and the mixture was stirred vigorously. After phase separation, the aqueous layer was extracted with EtOAc (3 L×2). The combined organics were washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc/hexanes) to provide 2128 g of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanol as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>CC(C)=O>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C=NCCCl
Solvent: CC(C)=O
Product: O=C(NCCCl)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2 g of 5-aminoindole in 125 mL of anhydrous acetone is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution was stirred for 16 h at room temperature, cooled at -20° C., and filtered. The solvent is evaporated and the residue was crystallized from methanol and washed with ether to give a brownish solid, yield 30%, mp 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[NH:14][C:13]2=[O:20])=[C:4]([F:21])[CH:3]=1.[H-].[Na+].Cl[CH:25]([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:25]([F:27])[F:26])[C:13]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: FC(F)Cl
Reactant: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Reaction time: 0.5 h

Procedure:
A solution of 2.00 g of 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -methyl-2,4(1H,3H)-pyrimidinedione in 20 ml dimethylformamide is added dropwise at room temperature while stirring within 30 minutes to a suspension of 0.28 g of a 55% sodium hydride dispersion in 10 ml of dimethylformamide. The mixture is subsequently stirred for 30 minutes and thereafter 5.26 g of chlorodifluoromethane are introduced at 55° C. while stirring during 18 hours. The reaction mixture is cooled, poured into a solution of 20 ml of 2N hydrochloric acid in 300 ml of water and extracted with 150 ml of ethyl acetate. The organic phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of diethyl ether and the solution is treated with active carbon and filtered. The filtrate is evaporated to dryness and the residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-difluoromethyl-6 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 97°-99° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[CH3:21][C@@H:22]([NH2:25])[CH2:23][CH3:24]>>[C@H:22]([NH:25][C:16](=[O:18])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([C:1]#[N:2])[N:8]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19])([CH2:23][CH3:24])[CH3:21]
Reactant: CC[C@@H](C)N
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Product: CC[C@@H](C)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 43 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and (R)-butan-2-amine. Yield 43%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:19])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Reactant: NCCN1CCOCC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCC(C(=O)NCCN2CCOCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 12.9 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-l-yl]-2-phenylbutanoic acid (3.544 g, 10 mmole), triethylamine (2.024 g, 20 mmole), and N,N-bis(2-oxo-3oxazolidinyl)phosphoramidic chloride (2.545 g. 10 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 4-(2-aminoethyl)morpholine (1.302 g, 10 mmole) was added. The reaction mixture was stirred at room temperature for 14 hours, washed with water (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by crystallization from ethanol/diethyl ether with addition of ethanolic HCl gave 0.6 g of the title compound as the dihydrochloride, 2.5 hydrate, 0.2 CHCl3 solvate, m.p. 60°-5° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH2:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])CCC.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.[OH-].[Na+]>O1CCCC1>[CH3:10][CH:9]([CH3:11])[CH2:8][O:7][CH2:6][B:25]([OH:30])[OH:26]
Reactant: CCCC[Sn](CCCC)(CCCC)COCC(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)COCB(O)O
Reaction time: 0.58 h
Yield: 28.9 %

Procedure:
To a solution of tributyl-(2-methylpropoxy)methyl-tin (1.00 g, 2.65 mmol) in tetrahydrofuran (20 ml) was added dropwise n-butyllithium (1.54M n-hexane solution, 1.72 ml, 2.65 mmol) at −78° C. (external temperature) under the nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 35 minutes. Then, to the reaction mixture was added triisopropyl borate (1.10 ml, 4.74 mmol) at −78° C. (external temperature) under the nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added a 1N aqueous sodium hydroxide solution at room temperature. The resultant was extracted three times, and the resulting aqueous layer was washed with diethyl ether. Then, to the resulting aqueous layer was added 5N aqueous hydrochloric acid solution to make the solution acidic, followed by extraction with diethyl ether three times. The resulting organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off from the filtrate to obtain the title compound (101 mg, 0.765 mmol, 29%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24](O)=O>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Product: Clc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c(Cl)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(2,4-dichlorophenyl)propionic acid (220 mg; 1 mmol) as described in method 2;
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1/[CH:14]=[N:15]/[OH:16]>CN(C)C=O.O>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1/[C:14](=[N:15]/[OH:16])/[Cl:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccc1OC(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O/N=C(\Cl)c1ccccc1OC(F)(F)F

Procedure:
NCS (22 g, 166.04 mmol, 1.12 equiv) was slowly added to a stirred solution of (E)-2-(trifluoromethoxy)benzaldehyde oxime (30 g, 146.27 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL) keeping the internal temperature below 25°C. The reaction mixture was stirred fo(1 h at room temperature. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed with brine (5×300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give (Z)-2-(trifluoromethoxy)benzoyl chloride oxime as a light yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[Li]CCCC.[I:32]I>C(OCC)C.C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][C:13]=1[I:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A solution of (6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester (0.90 g, 3.43 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.29 mL, 8.55 mmol) in 25 mL of anhydrous diethyl ether was cooled to −78° C. under an argon atmosphere. The resulting mixture was treated dropwise with n-BuLi (2.5 M in hexanes, 3.42 mL, 8.55 mmol) over 5 minutes, and the mixture was allowed to warm to −10° C. After 30 minutes, the mixture was cooled to −78° C. and a solution of I2 (1.14 g, 4.5 mmol) in 5 mL of anhydrous THF was added rapidly. The resulting mixture was warmed to room temperature, stirred for 1 hour, and quenched with 50 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified on SiO2 (10% ethyl acetate in dichloromethane) to afford the title compound (150 mg, 11.3% yield).
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3N)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]C1N=CN=C2C=1NC=N2.C(C1C=CC(CCl)=CC=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[Cl:26])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1ncnc2c1ncn2Cc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C(c1ccccc1)c1ccc(CCl)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Cn2cnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
The synthesis of 9'-(4-benzoylbenzyl)-9H-adenine (20) was achieved by the following procedure (Scheme 9). A mixture of 6-chloropurine (3.09 g, 20 mmol), 4-benzoyl-benzyl chloride (6.05 g, 22 mmol) and K2CO3 (3.04 g, 22 mmol) in DMF (50 ml) was stirred overnight at rt, diluted with water (400 ml), and extracted with EtOAc (3×100 ml) (Scheme 9)52. The combined organic layers were washed with water and brine, dried over MgSO4, concentrated in vacuo, and subjected to flash-chromatography on silica gel eluting with CH2Cl2 -acetone (80:20). The fractions containing the higher Rf, the major component, were combined and concentrated in vacuo to give 2.86 g (41%) of 9-(4-benzoylbenzyl)-6-chloro-9H-purine. To a solution of this iminochloride (1.05 g, 3 mmol) in EtOH (20 ml) was added a 2M solution of NH3 in MeOH. This medium was warmed overnight at 90° C. under pressure (constant volume). It was then cooled and concentrated in vacuo. The residue was washed successively with a 1M solution of NaHCO3, water, iPrOH, and hot CH2Cl2, and then was recrystallized from butanol to give 0.53 g (54%) of 9-(4-benzoylbenzyl)-9H-adenine (20). 1H NMR (DMSO) δ 5.49 (s, 2H, CH2), 7.27-7.71 (m, 9H, H--Ar), 8.15 (s, 1H, H-2), 8.30 (s, 1H, H-8). ##STR10## Synthesis of 9-[(4-bis-phenyl)buten-4-yl]-9H-adenine (21)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>C(=O)(O)[O-].[Na+].C(OCC)C.C(Cl)Cl>[OH:12][C:13]1[CH:22]=[C:21]([O:23][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chlorobenzenesulfonyl chloride (2.49 g, 0.018 mol) was added dropwise to a rapidly stirred mixture of methyl 3,5-dihydroxybenzoate in saturated sodium bicarbonate (20 mL) and diethyl ether (20 mL) and allowed to stir at ambient temperature. After 2 days, 1.25 g of 2-chlorobenzenesulfonyl chloride was added and stirred for an additional 1 day. The reaction mixture was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride. The combined methylene chloride extracts were washed with brine and water, dried, and evaporated to an oil. The oil was triturated with hexanes (4 times) before placing the residual oil on a silica gel column and eluted first with methylene chloride, then 10% ethyl acetate/methylene chloride. The appropriate fractions were evaporated to give 1.35 g of solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:24][CH2:23][CH2:22][O:21][CH3:20])[N:11]=1
Reactant: COCCN
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: COCCNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 257 mg (3.43 mmol) of 2-methoxyethylamine to give 61 mg (56% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1cnc(Cl)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=400.1 [M+H]+.