Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>O1CCCC1.C(OCC)C>[Si:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.1 %

Procedure:
To a solution of sodium hydride (1.3 g, 55.48 mmol) in anhydrous tetrahydrofuran (150 mL) at 0° C. under argon, was added a solution of 1,4-butanediol (5 g, 55.48 mmol) in anhydrous tetrahydrofuran (50 mL). The resulting mixture was stirred at room temperature for 45 minutes over which time a large amount of a white precipitate formed. t-Butyldimethylsilyl chloride (8.3 g, 55.48 mmol) was then added and the resulting mixture was stirred vigorously for 45 minutes and then diluted with diethyl ether (200 mL) and filtered. The filtrate was washed with 10% aqueous potassium carbonate (25 mL) and brine (2×50 mL). Purification by silica gel chromatography using hexane/ethyl acetate as eluent (7:3) gave 1-t-butyldimethylsilyloxy-4-hydroxybutane as a colorless oil (9.2 g, 80%). 1-t-Butyldimethylsilyloxy-4-hydroxybutane (2.0 g, 9.85 mmol), triphenylphosphine (3.07 g, 11.74 mmol) and diethyl azodicarboxylate (1.8 mL, 11.74 mmol) were added successively to a solution of 1,8-naphthalimide (1.92 g, 9.785 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. under an atmosphere of argon. The reaction was allowed to warm to room temperature and stirred overnight. After removing the solvent under reduced pressure, the product was purified by silica gel chromatography using hexane/ethyl acetate (9:1) as the eluent to provide 4-t-butyldimethylsilyloxybutyl-1,8 naphthalimide as a colorless oil (3.68 g, 87%).
Reaction SMILES: [C:1]([C:3]1([C:10]([O:12]CC(C)C)=[O:11])[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:2].C(O)C.[OH-].[K+]>O>[C:1]([C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:2]
Reactant: CC(C)COC(=O)C1(C#N)CC2C=CC1C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1(C(=O)O)CC2C=CC1C2

Procedure:
To a solution of 250 g (1.14 moles) isobutyl 2-cyano-5-norbornene-2-carboxylate (IBC/CPD adduct) in 1000 ml. 95% ethanol is added a solution of 112 g (1.71 moles) of potassium hydroxide (86%w) in 1000 ml. water. The solution is refluxed on a steam bath for one hour, diluted with 3500 ml. water, and extracted with 2 × 400 ml. benzene to remove any unreacted ester. The aqueous phase is acidified to pH 1 with 6 N HCl and the oily product extracted into 4 × 200 ml. chloroform. The combined extracts are backwashed with 3 × 200 ml. water (which removed the orange color), dried over anhydrous sodium sulfate, and solvent stripped to give 182.3 g (98% theory) of the crude adduct, a pale orange syrupy liquid. Crystallization from benzene/hexane gives three crops of purified 2-cyano-5-norbornene-2-carboxylic acid: (1) 89.7 g, mp 87.5°-92° C, (2) 34.2 g, mp 87.5°-96.5° C, and (3) 15.9 g, mp. 85°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[F:23])[C:17](O)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.NC1C=C(C=CC=1F)C([NH:34][CH2:35][CH2:36][N:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH3:44])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:34][CH2:35][CH2:36][N:37]4[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]4[CH3:44])[CH:20]=[CH:21][C:22]=3[F:23])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A step 3) (1.150 g, 4.77 mmol) was suspended in toluene (10 ml) and treated with thionyl chloride (1.045 ml, 14.32 mmol). The mixture was at 100° C. for 2 hrs. The solvent was removed in vacuo and the solid was added to a stirred solution of 3-amino-N-(2-(2,6-cis-dimethyl piperidin-1-yl)ethyl)-4-fluorobenzamide (1.4 g, 4.77 mmol) in dry pyridine (5 ml) containing oven dried molecular sieves. The mixture was stirred at RT under nitrogen atmosphere overnight. The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:28](O)[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C(=O)O)nc3)[nH]n2)c1
Product: CCOC(=O)c1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Yield: 15 %

Procedure:
Preparation was analogous to that described for Example 67, except using 5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylic acid (55 mg, 0.15 mmol, 1 eq) in ethanol (0.5 mL) to give title compound as a white solid (9 mg, 15% yield); 1H NMR (400.13 MHz, DMSO) δ□ 1.40 (3H, t), 2.97 (4H, s), 3.79 (3H, s), 4.44 (2H, q), 6.54 (1H, s), 6.8 (1H, m), 6.87 (2H, m), 7.25 (1H, t), 8.19 (1H, d), 8.52 (1H, m), 9.25 (1H, s), 11.17 (1H, s), 12.3 (1H, s) MS m/z 395 (MH+)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1.C[C@H]1CC2C=C(C)C=CC=2O1>>[CH3:1][C@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)O[C@H](C)C2
Agent: Cc1ccc2c(c1)C[C@H](C)O2
Product: Cc1cc2c(c([N+](=O)[O-])c1)O[C@@H](C)C2

Procedure:
The title compound 5d was prepared according to the method for preparation of compound 3e of Example 3 by replacing 3d with 5c.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=C([CH:27]=[CH:28][CH:29]=4)C(O)=O)[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1.CN(C)C=O>ClCCl>[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:1]([CH:27]=[CH:28][CH:29]=4)[C:2]([Cl:4])=[O:3])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 50 °C
Yield: 95.9 %

Procedure:
Oxalyl chloride (20 ml, 0.2 mol) was added dropwise over 2 min to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (intermediate 3) (2.0 g, 6.1 mmol) in dichloromethane (10 ml) at room temperature. N,N-Dimethylformamide (50 μl) was then added and the resulting mixture heated to 50° C. for 1 h. The solution was then cooled to room temperature and then concentrated in vacuo to leave the title compound (intermediate 4) (2.0 g, 96%) as a beige solid.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccccc1F

Procedure:
The 2-trifluoroacetamido-3-(2-fluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (9.46 g, 22.2 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 6.70 g. (91.4%). EA, MS(FD).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[Br:11]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.CCOC(C)=O.O>[Br:11][C:4]1[N:3]=[C:2]([F:1])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Oc1cccnc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(Br)nc1F
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
2-Fluoropyridin-3-ol (5.96 g, 52.7 mmol) was suspended in acetic acid and cooled in an ice bath. NaOH (10.0 N, 6.0 mL, 60.0 mmol) was added and the mixture stirred for 10 min. Bromine (2.8 mL, 54.4 mmol) was added dropwise and the mixture stirred for 20 min. Sodium sulfite (1.4 g) was added and the mixture stirred for 10 min. Water (400 mL) and EtOAc (400 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 6-bromo-2-fluoropyridin-3-ol (3.67 g, 19.12 mmol, 36.3% yield) MS m/z=192.0, 194.0 [M+H]+. Calculated for C5H3BrFNO: 190.94.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]1([N:19]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[N:22][N:21]=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])=O.[Na+].[Na+].CO.O>[CH:13]1([N:19]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)=[N:22][N:21]=[N:20]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: ClCCCCc1nnnn1C1CCCCC1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Into a three-necked flask having a capacity of 300 ml were introduced 10.00 g of 6-hydroxy-3,4-dihydrocarbostyril, 16.36 g of 1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 10.16 g of potassium carbonate, 3.00 g of tetrabutylammonium chloride, 0.05 g of sodium sulfite, 30 ml of toluene and 50 ml of water. The content of the flask was heated under reflux for 8 hours with stirring. After cooling the reaction mixture to ambient temperature, the deposited crystalline product was collected by filtration and washed with 50 ml of water. Then, the crude crystal thus obtained was introduced into 70 ml of 90% methanol cooled to 5° C., and stirred at 5° C. for 10 minutes for the sake of washing. The crystal was collected by filtration and further washed on the suction filter with 20 ml of 90% methanol cooled to 5° C. The crystal was dried to obtain 21.46 g (yield 95%) of 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril as a colorless needle-like crystalline product.
Reaction SMILES: CN(C)C=O.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])=[CH2:7].[F:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[F:16][CH2:17][CH2:18][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]([CH3:8])=[CH2:7])=[CH:10][CH:11]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: FCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1ccc(OCCF)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To 30 ml of dimethylformamide were added 7.0 g of 4-isopropenylphenol, 6.1 g of 1-fluoro-2-chloroethane and 8.7 g of potassium carbonate. With stirring, they were reacted at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, and poured into water. The mixture was then extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 9.0 g of crude 4-(2-fluoroethoxy)isopropenylbenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: Nc1ncnc2onc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccc(-c2noc3ncnc(N)c23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
A 0° C. suspension of Example 29B (124 mg, 0.5 mmol) in concentrated HCl (2 mL) was treated with a solution of SnCl2 (450 mg) in concentrated HCl (1 mL), warmed to room temperature, stirred for 3 hours, and filtered. The filtrate was partitioned between ethyl acetate and saturated NaHCO3 and the organic phase was washed with brine, dried (MgSO4), filtered, and concentrated to provide 37 mg (32%) of the desired product. MS (ESI(−)) m/e 226 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:7]1([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: C1CCNC1
Solvent: CCOCC
Product: c1ccc(CN2CCCC2)cc1

Procedure:
A 25.0 ml portion of pyrrolidine was reacted with 10.9 ml of benzyl bromide in ether as described in Example 3, giving 12.3 g of 1-(phenylmethyl)pyrrolidine, which was then reacted with butyl lithium and diphenylphosphine chloride as described in Example 3, giving diphenyl]2-(1-pyrrolidinylmethyl)phenyl]phosphine.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][C:32]#[CH:33]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:34]1([CH2:30][CH2:31][C:32]#[C:33][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#CCCc1ccccc1
Reactant: Clc1nc2ccccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1nc2ccccc2o1)CCc1ccccc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 40.5 %

Procedure:
To a solution of CuI (15 mg, 81 μmol) in triethylamine (3 mL) were added 2-chlorobenzo[d]oxazole (250 mg, 1.63 mmol), (PPh3)2PdCl2 (57 mg, 81 mmol), triphenylphosphine polymer bound 3 mmol/g (98 mg, 293 μmol) and a solution of 1-(but-3-ynyl)benzene (250 mg, 1.92 mmol) in DMF (0.5 mL). The reaction mixture was stirred for 25 min at 120° C. in the microwave cavity. The reaction was quenched as described in Example 1. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 163 mg (0.66 mmol, 40%) of 2-(4-phenylbut-1-ynyl)benzo[d]oxazole as an orange oil.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:14]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(CNCc1cccc2ccccc12)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 1-naphthaldehyde (2.2 ml, 16.0 mmol) in tetrahydrofuran (6 ml) was added 2,2-diethoxyethanamine (2.9 ml, 20.0 mmol) and the mixture was stirred at room temperature 0.5 hr. And then sodium triacetoxyborohydride (10.6 g, 50 mmol) was added and the mixture was stirred for additional 4 hr. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate (5 g) and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=100:0 to 70:30) to obtain the title compound (3.0 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:4][N:3]=1.C1(C)C=CC=CC=1>ClCCl.FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 128.7 %

Procedure:
A solution of Example 221B (1.5 g, 3.4 mmol) in dichloromethane and trifluoroacetic acid (10 mL) was stirred for 2 hours at ambient temperature, treated with toluene (200 mL), and concentrated to provide 1.7 g (100%) of the desired product as the trifluoroacetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 8.42 (s, 1H), 7.95 (s, 1H), 7.76 (d, 1H), 7.54 (dd, 2H), 7.46 (dt, 2H), 7.21 (t, 1H), 7.16 (dd, 4H), 6.61 (d, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 167.0, 159.0, 158.6, 157.6, 156.0, 148.8, 137.7, 137.5, 131.0, 130.1, 128.2, 127.6, 124.0, 120.3, 119.4, 119.2, 118.7, 115.7.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[O:9]=[C:10]1[NH:14][C:13]([CH2:21][OH:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:23])[N:11]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1>CN(C=O)C>[O:9]=[C:10]1[N:14]([CH3:1])[C:13]([CH2:21][OH:22])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:23])[N:11]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(N2C(=O)NC(CO)(c3ccccc3)C2=O)ccc1C#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N2C(=O)N(C)C(CO)(c3ccccc3)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
173 mg potassium carbonate and 86 μL methyl iodide are added to a solution of 141 mg 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazolidin-1-yl]-2-methoxybenzonitrile in 2 mL DMF. The mixture is stirred overnight at room temperature, evaporated to dryness, The residue is taken in water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered, evaporated and chromatographed over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to give the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A solution of 2-(4-tert-butylphenyl)ethanol (5.35 g, 30.0 mmol) in chloroform (150 mL) was cooled in ice and Dess-Martin periodinane (16.5 g, 39.0 mmol) was added thereto. The mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was diluted with chloroform (150 mL), followed by cooling in ice. Thereafter, saturated aqueous sodium thiosulfate solution was added thereto and the mixture was stirred for 5 min. The mixture was extracted three times with chloroform and then the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then the filtrate was concentrated under reduced pressure. The resulting precipitate was filtered again, followed by washing with chloroform. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a yellow oil (4.24 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[OH:29][CH2:30][CH2:31][NH2:32].O>C1COCC1>[OH:29][CH2:30][CH2:31][NH:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Reactant: NCCO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(NCCO)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2

Procedure:
30 mg (0.08 mmol) of 2-chloro-4-(1,3-benzodioxol-5-yl)-6-benzyloxy-3,5-pyridinedicarbonitrile (example 4, step 1) and 14.1 mg (0.23 mmol) of 2-hydroxyethylamine are shaken together in 0.5 ml of THF for about 16 h. Water is added to the reaction solution and the product that crystallizes out is filtered off with suction and dried under reduced pressure. The crude product is purified by silica gel chromatography using the mobile phases dichloromethane and dichloromethane/methanol 50:1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: COc1cccc(OC)c1CN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,6-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:2].[O:13]([C:15]#[N:16])[Na]>CC(O)=O>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)[C:15]([NH2:16])=[O:13])[CH3:2]
Reactant: CCNc1ccc2c(c1)OCO2
Reactant: N#CO[Na]
Solvent: CC(=O)O
Product: CCN(C(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of N-ethyl-3,4-(methylenedioxy)aniline (8.1 g) in AcOH (100 mL) was added NaOCN (3.0 g) at 10° C. The cold bath was removed and the mixture was stirred at rt for 24 h. The solvent was removed in vacuo and the resulting residue was neutralized with 2 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic phase was washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was recrystallized from chloroform/hexane to yield the title compound (5.7 g, 56%). 1H NMR (CDCl3): 6.78-6.72 (m, 3H), 6.02 (s, 2H), 4.38 (br s, 2H), 3.66 (q, J=7.0, 2H), 1.11 (t, J=7.0, 3H).