Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1(C#N)[CH2:14][CH2:13][CH2:12]1.C[Mg]I.IC.[Mg].CC[O:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:26](=[O:25])[CH3:27])[CH2:14][CH2:13][CH2:12]1
Reactant: N#CC1(c2ccc3ccccc3c2)CCC1
Reactant: CCOCC
Agent: C[Mg]I
Agent: [Mg]
Solvent: CI
Solvent: Cc1ccccc1
Product: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(2-naphthyl)cyclobutanecarbonitrile (48.2 g) in toluene (100 ml) was added dropwise under nitrogen to a stirred solution of methylmagnesium iodide [prepared in the usual manner from iodomethane (22 ml) and magnesium (8.16 g)] in ether (60 ml), then the mixture was stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed with ether (50 ml), and added in portions to a mixture of concentrated hydrochloric acid (125 ml) and water (200 ml). The mixture was heated at 100° C. with occasional stirring for 10 minutes, then it was cooled to ambient temperature. The product was extracted into toluene (3×200 ml), then the extracts were washed with water (200 ml), and the solvent was removed in vacua. The residue was triturated with petroleum ether (b.p. 40-60° C.) (100 ml), and the resulting solid was collected by filtration and dried in vacuo to give 1-[1-(2-naphthyl)cyclobutyl]ethanone as a yellow solid (35 g) which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([F:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>C(Cl)Cl>[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:1]([CH2:4][CH2:5][C:6]2[N:7]=[C:8]([F:30])[N:9]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)=[O:3])=[CH:49][CH:48]=1
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: Nc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)Nc1ccc(Cl)cc1
Reaction time: 0.42 h

Procedure:
A solution of 4-(2-carboxyethyl)-2-fluoro-1-triphenylmethylimidazole in CH2Cl2 was treated with triethylamine. The mixture was cooled, isobutyl chloroformate added, and stirred for 25 min. 4-Chloroaniline was then added, and stirring continued for 1 hour. Extractive work-up, followed by chromatography, gave 4-[2-(4-chlorophenylcarbamoyl)ethyl]-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 +d6DMSO: 2.4-2.75 (m, 4H); 6.25 (s, 1H); 6.9-7.65 (m, 19H); 9.9 (br s, 1H).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.CN(C)C=O.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1>O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:11]
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred and hot (50° C.) mixture of 4.1 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 31.5 parts of N,N-dimethylformamide was added dropwise a solution of 9.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 31.5 parts of N,N-dimethylformamide at 50° C. Upon completion, stirring was continued for 3 hours at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 9.8 parts (80%) of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]benzamide; mp. 171.7° C. (intermediate 157).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[C:4]([F:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])I>CS(C)=O.O.[Cu]>[F:19][C:4]1[CH:3]=[C:2]([C:22]([F:25])([F:24])[C:21]([F:27])([F:26])[F:20])[CH:18]=[CH:17][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)ccn1
Temperature: 120 °C
Yield: 22.3 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol) and copper (1.6 g, 24.61 mmol) in DMSO (15 mL), in a bomb, 1,1,1,2,2-pentafluoro-2-iodo-ethane (4.1 g, 16.47 mmol) was bubbled through. The vessel was sealed and heated at 120° C. for 16 hours. The reaction mixture was diluted with water and filtered through a plug of silica and then extracted with ethyl acetate (4×). The organics combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a crude mixture that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-40%) to give 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 22%) as an off white solid. ESI-MS m/z calc. 364.06. found 365.3 (M+1)+; Retention time: 1.39 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4 Hz, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: ClC1C=[C:4]([C:11](C)([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=CC=C(OC3C=CC=CC=3)[CH:16]=2)C=CC=1OCC.[OH-].[K+].CN1CCN(C)C1=O.Cl>O>[CH3:4][CH:11]([CH3:28])[CH2:12][O:13][CH2:14][CH:15]([CH3:20])[CH3:16]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)COCC(C)C
Temperature: 150 °C
Reaction time: 18 h

Procedure:
100 g of 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether and 25 g of 97% potassium hydroxide were added to 300 ml of 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI) and the mixture was stirred at 150° C. for 18 h. After cooling to room temperature, the mixture was poured into water and made acidic with a concentrated aqueous hydrochloric acid solution. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure and the obtained oily residue was purified according to a column chromatography (silica gel, developer: benzene) to obtain 45.6 g of 3-phenoxybenzyl 2- 3-chloro-4-hydroxyphenyl)-2-methylpropyl ether (m.p. 68° to 69° C.).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCC(CC1)CN2>C(O)C.C1C=CC=CC=1.O.[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: Cl[Rh]
Agent: C1CN2CCC1CN2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CC=CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reaction time: 24 h

Procedure:
To a solution of Compound 5 (3.2 g., 5.84 mmol) in ethanol:benzene:water (7:3:1, v/v) (250 ml.) were added diazabicyclo[2.2.2]octane (0.2 g, 1.8 mmol) and tris(triphenylphosphine) rhodium(I) chloride (0.4 g., 0.43 mmol). The mixture was stirred for 24 h. under reflux. Solvents were evaporated and coevaporated with toluene. A portion of the product, purified on a column of silica gel, afforded an amorphous solid, [α]D25 -7.4°, [α]43625 -13/3° (chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[Br:36][CH2:37][CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:36][CH2:37][CH2:38][O:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (4 g, 8.14 mmol), 1,2-dibromoethane (2.1 mL, 24.42 mmol) in acetone (20 mL) was added potassium carbonate (4.50 g, 32.6 mmol). The resulting solution was stirred for 16 h at reflux. Add another 4 eq of potassium carbonate and 3 eq of 1,2-dibromoethane. The mixture was refluxed for another 7 hs. After cooling to rt, the white solid was filtered and washed with actone. The filtrate was concentrated and purified by Biotage eluting with 20-33% ethyl acetate in hexane to give tert-butyl 4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (2.91 g, 60%) as white solid.
Reaction SMILES: FC(F)C1C([C:8](Cl)=[O:9])=CN(C)N=1.Cl.[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:16]=1[O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:16]=1[O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH:8]=[O:9]
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CN1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.243 g; 1.24 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine hydrochloride (0.35 g; 1.24 mmol), which was prepared as described in example P12, and triethylamine (0.35 ml; 2.48 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 3 hours. The reaction mixture was washed with 1M NaOH (10 ml), 2M HCl (10 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.45 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 2:8). 0.27 g (50% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil which solified after standing.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:28])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:21])[CH:15]=1.[CH3:29]N(C)P(N(C)C)(N(C)C)=O>>[CH3:29][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:28])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:21])[CH:15]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)CNC(=O)c1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Product: COC(=O)CNC(=O)c1cccc(C=CC(=O)c2c(OC)cc(C)n(C)c2=O)c1

Procedure:
According to the same manner as that of Example a-25 except that 0.25 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone was used in place of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, and 6 ml of hexamethylphosphoramide was used in place of dimethylformamide, 0.13 g of 4-methoxy-3-[3-[3-[(methoxycarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (83a)] was obtained as a pale yellow crystal.
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(NC(C)C)(C)C.C([Li])CCC.F[B-](F)(F)F.[CH3:32][N:33]([CH3:45])[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:36]=[N+](C)C.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O.ClCCl>[CH3:32][N:33]([CH3:45])[C:34](=[CH:35][CH:36]=[C:2]([C:1]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCCCCCCCCC(=O)OCC
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCC(=CC=C(C(=O)OCC)N(C)C)C(=O)OCC
Temperature: -78 °C
Yield: 55.5 %

Procedure:
Ethyl n-decanoate (10 g) is added in the course of 10 minutes at a temperature in the region of -78° C. to a stirred mixture of diisopropylamine (5.6 cc), a 1.6M solution (37.5 cc) of n-butyllithium in hexane and tetrahydrofuran (30 cc). Stirring is maintained for 30 minutes at the same temperature, N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (14.3 g) is then added and stirring is maintained for 3 hours at a temperature in the region of -78° C. After a gradual warming to approximately 20° C., ammonium chloride (4 g) dissolved in water (50 cc) is added to the reaction medium. Dichloromethane (200 cc) and water (100 cc) are added, and the organic phase is separated off after settling has taken place. The aqueous phase is washed with dichloromethane (2×50 cc). The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and evaporated at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is dissolved in a mixture (30 cc) of cyclohexane and ethyl acetate (60:40 by volume), and the solution obtained is poured onto silica (600 g) contained in a column 7 cm in diameter. Elution is performed with a mixture of cyclohexane and ethyl acetate (60:40 by volume), and the eluate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl 2-dimethylamino-5-ethoxycarbonyl-2,4-tridecadienoate (9.8 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8](NC)=[N:9][C:10]=2[N:14]([CH3:16])[CH3:15].NC1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(N(C)C)N=1.C(NC1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(N(C)C)N=1)C.FC1C=CC=C(F)C=1CN1C=NC2C1=NC(NC)=NC=2.FC1C=CC=C(F)C=1CN1C=NC2C1=NC(N(C)C)=NC=2.CN(C1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(N(C)C)N=1)C.NC1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(NC)N=1.CNC1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(NC)N=1.NC1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(N)N=1.NC1N=C(NC)N=C2C=1N=CN2CC1C(F)=CC=CC=1F.NC1N=C(N(C)C)N=C2C=1N=CN2CC1C(F)=CC=CC=1F.C(NC1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=C(N)N=1)C.[Cl:263]C1N=C2C(N=CN2CC2C(F)=CC=CC=2F)=CN=1>>[Cl:263][C:8]1[N:7]=[C:6]2[C:11]([N:12]=[CH:13][N:5]2[CH2:4][C:3]2[C:2]([F:1])=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])=[C:10]([N:14]([CH3:16])[CH3:15])[N:9]=1
Reactant: Fc1cccc(F)c1Cn1cnc2cnc(Cl)nc21
Reactant: CNc1nc(N(C)C)c2ncn(Cc3c(F)cccc3F)c2n1
Agent: CCNc1nc(N(C)C)c2ncn(Cc3c(F)cccc3F)c2n1
Agent: CCNc1nc(N)c2ncn(Cc3c(F)cccc3F)c2n1
Agent: CN(C)c1nc(N(C)C)c2ncn(Cc3c(F)cccc3F)c2n1
Product: CN(C)c1nc(Cl)nc2c1ncn2Cc1c(F)cccc1F

Procedure:
9-(2,6-difluorobenzyl)-6-(N,N-dimethylamino)-2-(N-methylamino)-9H-purine; 2-amino-9-(2,6-difluorobenzyl)-6-(N,N-dimethylamino)-9H-purine; 2-(N-ethylamino)-9-(2,6-difluorobenzyl)-6(N,N-dimethylamino)-9H-purine; 9-(2,6-difluorobenzyl)-2-(N-methylamino)-9H-purine; 9-(2,6-difluorobenzyl)-2-(N,N-dimethylamino)-9H-purine; 2,6-bis(N,N-dimethylamino)-9-(2,6-difluorobenzyl)-9H-purine; 2-amino-9-(2,6-difluorobenzyl)-6-(N-methylamino)-9H-purine; 2,6-bis(N-methylamino)-9-(2,6-difluorobenzyl)-9H-purine; 2,6-diamino-9-(2,6-difluorobenzyl)-9H-purine; 6-amino-9-(2,6-difluorobenzyl)-2-(N-methylamino)-9H-purine; 6-amino-9-(2,6-difluorobenzyl)-2-(N,N-dimethylamino)-9H-purine; 2-(N-ethylamino)-6-amino-9-(2,6-difluorobenzyl)-9H-purine and 2-chloro-9-(2,6-difluorobenzyl)-9H-purine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(CNC(CN2C3C(=CC=CC=3)C(C=O)=C2)=O)=CC=1.[N:42]([CH2:45][C@H:46]1[O:50][C:49](=[O:51])[N:48]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[C:54]([F:65])[CH:53]=2)[CH2:47]1)=[N+]=[N-].C([BH3-])#N.[Na+]>O1CCCC1>[NH2:42][CH2:45][C@@H:46]1[O:50][C:49](=[O:51])[N:48]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])=[C:54]([F:65])[CH:53]=2)[CH2:47]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: O=Cc1cn(CC(=O)NCc2ccccc2)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (7.61 g, 29.0 mmol) was added to a mixture of BAL aldehyde resin (33.3 g, 9.67 mmol) and 5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one (9.76 g, 29.0 mmol) in tetrahydrofuran (170 ml) under nitrogen at room temperature. The mixture was agitated at room temperature for 2 h and then at 75° C. for 16 h. The mixture was cooled to room temperature, and 1 M sodium cyanoborohydride in THF (58.0 ml, 58.0 mmol) was added in one portion. The reaction mixture was agitated for 8 h. The resulting amine resin was filtered, washed liberally with methanol and dichloromethane, and dried under vacuum.
Reaction SMILES: C(N)CC.[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17](C(=O)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:7])=[O:6]>C(Cl)(Cl)Cl>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:7])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCCN
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
Propan-1-amine (136 mmol) was added to a solution of ethyl 2-(2,4-dinitrophenyl)-3-oxobutanoate (135 mmol) in chloroform (500 mL). The reaction mixture was maintained for 12 h at rt and was concentrated. The residue was purified by chromatography 20/1 hexane/ethyl acetate to provide ethyl 2-(2,4-dinitrophenyl)acetate in 99% yield as a brown oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)[O:20][C:23]=2[CH:24]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1ccc(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc2cc(-c3nc4ccc(Cl)cc4o3)ccc2n1C1CCOCC1
Yield: 1.4 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-5-chlorophenol (0.15 g, 1.05 mmol), anhydrous DMF (10 mL) and WSC (0.22 g, 1.14 mmol) were stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.38 g, 2.00 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (5 mg, 1.4% yield) as an orange solid.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19](F)[CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[C:21]([CH:22]=1)[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluoronitrobenzene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(=O)oc2ccc(O)cc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4oc(=O)cc(C)c4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 14.8 %

Procedure:
6-Hydroxy-4-methyl-chromen-2-one (238 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (165 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 3.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (24 mg, yield 5%).