Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=N[C:3](OC(C)(C)C)=O.[Cl:17][C:18]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](OC)=[CH:28][C:29]=2[OH:31])[N:24]=[CH:23][N:22]=1.O[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:3])=[CH:34][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[O:31][CH2:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:24]=[CH:23][N:22]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC)cc(O)c23)c1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccc(Cl)c(Nc2ncnc3cccc(OCCCN4CCOCC4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Di-tert-butyl azodicarboxylate (0.208 g) was added dropwise to a stirred mixture of 4-(2-chloro-5-methoxyanilino)-5-hydroxy-7-methoxyquinazoline (0.2 g), 4-(3-hydroxypropyl)morpholine (Bull. Soc. Chim. Fr., 1962, 1117; 0.131 g), triphenylphosphine (0.237 g) and methylene chloride (3 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum to give the title compound (0.12 g); NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 3.1 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.68 (t, 2), 3.8 (s, 3H), 4.0 (d, 2H), 4.02 (s, 3H), 4.6 (t, 2H), 6.93 (s, 1H), 7.05–7.15 (m, 2H), 7.5 (s, 1H), 7.57 (d, 1H), 8.87 (s, 1); Mass Spectrum: M+H+ 459 and 461; Elemental Analysis: Found C, 60.0; H, 6.0; N, 12.1; C23H27ClN4O4 requires C, 60.19; H, 5.93; N, 12.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccc(Cl)cc1
Product: Clc1ccc(-c2nc3ccccc3s2)cc1

Procedure:
2-Aminothiophenol (12.5 g, 0.1 mole) and 14.1 g (0.1 mole) p-chlorobenzaldehyde were combined in an Erlenmeyer flask at room temperature. The aldehyde dissolved in the mixture which became cloudy after a few minutes. Heat was evolved and the mixture gradually solidified. The product was recrystallized from ethanol yielding 18.0 g (73%) pale yellow crystals, mp. 85°-87°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]C(O)=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:19])=O.[N:22]([Si](C)(C)C)=[N+]=[N-].Cl>ClCCCl.CN(C=O)C>[ClH:19].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(CCCCC(=O)O)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCCCN)cc1
Temperature: 25 °C

Procedure:
The product of step B (20.3 g, 0.10 mol) was dissolved in 1,2-dichloroethane (100 mL) and oxalyl chloride (62.5 g, 0.49 mol) was added, followed by DMF (50 μL). The solution was stirred at room temperature until gas evolution ceased (c.a. 30 min). The solvent and excess oxalyl chloride was removed under reduced pressure, redissolved in 200 mL of 1,2-dichloroethane and evaporated under reduced pressure again. The residue was dissolved in dry THF (150 mL) under nitrogen and azidotrimethylsilane (12.7 g, 0.11 mol) was added. After stirring at room temperature for 5 min., the stirred solution was heated in a 70° C. oil bath until gas evolution ceased (c.a. 1 hour). The solution was cooled in an ice bath and concentrated aq. HCl (20 mL) was added all at once and the ice bath was removed. After gas evolution ceased (c.a. 15 min) the solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was made basic (250 mL of 1N NaOH) and extracted with ethyl acetate. The organic layer was washed successively with water and sat'd. NaCl, dried (MgSO4), filtered and evaporated under pressure. The residue was redissolved in 150 mL of ethyl acetate and 20 mL of dry 6.9N HCl/dioxone was added with stirring and icebath cooling. The white precipitate was filtered and washed with ethyl acetate then diethyl ether affording 16.9 g (80%) of product: m.p. 155°-160° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][NH:13][C:12]1=[S:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(O)C.CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1=[S:16]
Reactant: C=CC(=O)OCC
Reactant: S=c1[nH]ccn1C1CCc2ccccc2C1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCn1ccn(C2CCc3ccccc3C2)c1=S
Temperature: 80 °C
Yield: 66.1 %

Procedure:
A mixture of 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.3 g, 5.6 mmol), prepared as in Example 9, and ethyl acrylate (3.1 mL, 28.2 mmol) in 14 mL of ethanol and 1.28 mL of N-benzyltrimethylammonium hydroxide (2.8 mmol) in methanol was heated at 80° C. under nitrogen for 2 hours. The mixture was allowed to cool and concentrated by rotoevaporation. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (3:1) to give ethyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl]propionate (1.2 g, 3.7 mmol), m.p. 71°-73° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([OH:8])=[CH:7][C:2]=3[F:1])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(-c3cc(F)c(O)cc3F)ccc2c1
Solvent: C1CCOC1
Product: Oc1cc(F)c(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.84 mmol) and NCS. (295 mg, 2.21 mmol) in THF (37 mL) according to method Cto yield 370 mg (66%) of yellowish solid: mp:203–204° C.; 1H NMR (DMSO-d6): δ 6.90 (1H, dd, J=11.90 Hz, J=7.50 Hz), 7.32 (1H, d, J=8.88 Hz), 7.49 (1H, dd, J=11.87 Hz, J=7.60 Hz), 7.72–7.76 (1H, m), 7.84 (1H, d, J=8.97 Hz), 8.03 (1H, s), 8.06 (1H, d, 8.87 Hz), 10.58 (2H, s); MS (ESI) m/z 305/307 (M−H)−; HRMS calcd for C16H9ClF2O2 306.02591, observed 305.01863 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1I)[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH:35]=[CH:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1.64 g (2.98 mmol) of benzyl (4S)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate was dissolved in 30 ml of N,N-dimethylformamide (dehydrated). 0.65 ml (5.96 mmol) of ethyl acrylate, 2.1 ml (14.9 mmol) of triethylamine and 14 mg (0.06 mmol) of palladium acetate were added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:29])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-4-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c11) the title compound is obtained as pale yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1([CH:20]=[CH:19][CH:18]=[CH:17][CH2:16]1)[CH2:14][OH:15].O>N1C=CC=CC=1>[C:1]([O:15][CH2:14][C:13]1([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH2:20]1)(=[O:3])[CH3:2]
Reactant: OCC1(c2cccs2)C=CC=CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2cccs2)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (5 ml) was added to a solution of 1-(2-thienyl)benzyl alcohol in pyridine. The resultant solution was stirred at 70° C. for 3 h. Water (50 ml) was added and the reaction mixture was stirred at room temperature for 2 h. This was extracted with ethyl acetate (2×50 ml) and the combined organic layers dried over anhydrous MgSO4. Removal of the solvent gave crude product, which was purified by passing through silica gel using 3:1 hexane/ethyl acetate mixture to give 1-(2-thienyl)benzyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17]O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CO)cc2C1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccc(CN3CCCC3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.25 g 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (5.01 mmol) in 14 ml dichloromethane was slowly added 0.781 ml methanesulfonyl chloride (10.03 mmol) at room temperature. Subsequently the mixture was heated for 4 hours at reflux. LCMS control indicted a near complete formation of the corresponding mesylate, which was not isolated. After cooling to room temperature, 1.244 ml pyrrolidine (15.04 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was complete according to LCMS. Water was added to the reaction mixture, the acidic aqueous phase was extracted two times with dichloromethane, and the water phase was basified and extracted three times with ethyl acetate. The combined ethyl acetate solutions were extracted with brine, dried over Na2SO4, filtered, and the organic solvent was removed under reduced pressure to provide the title compound. The dichloromethane phase was extracted two times with diluted NaOH, once with brine and then dried over Na2SO4. Filtration and removal of the organic solvent under reduced pressure provided additional title compound. Both fractions were combined and used in the next step without further purification. LCMS: m/z 303.2 (M+H).
Reaction SMILES: [N:1]1[C:9]2[C:8]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:3][CH:2]=1.[H-].[Na+].Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([CH3:33])[N:24]=1>CN(C=O)C.O>[CH3:33][C:25]1[N:24]=[C:23]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8]3[C:9]4[N:1]=[CH:2][S:3][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:14][CH:15]=2)[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=1
Reactant: Oc1ccc(CCNc2ncnc3scnc23)cc1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(F)F)cc(Oc2ccc(CCNc3ncnc4scnc34)cc2)n1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
4-[2-(Thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]-phenol (0.1 g, 0.37 mmol) was dissolved with magnetic stirring in DMF (1 mL) in a microwave reactor tube, and then treated with NaH (60% dispersion in oil; 13 mg, 0.55 mmol). After bubbling had subsided, 2-chloro-6-methyl-4-trifluoromethylpyridine (86 mg, 0.44 mmol) was added and the reaction mixture was sealed and placed in a CEM Discover® microwave reactor and irradiated for 30 min, with heating to 150° C. After cooling, the reaction mixture was diluted with H2O (5 mL) and partitioned into Et2O (3×10 mL). The pooled organic fractions were diluted with an equal volume of pentane, washed with H2O, dried (Na2SO4) and filtered through a SiO2/Celite plug. The filtrate was concentrated in vacuo to provide a brown wax (126 mg). Prep RP-HPLC purification (CH3CN/H2O eluent; C18 column) afforded {2-[4-(6-methyl-4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-thiazolo[5,4-d]pyrimidin-7-ylamine (Compound 62; 36 mg) as an off white powder: mp 111-112° C.; 1H NMR (CDCl3) δ 8.76 (s, 1H), 8.55 (s, 1H), 7.31-7.29 (d, J=8.6 Hz, 2H), 7.11-7.07 (m, 3H), 6.83 (s, 1H), 6.22 (br s, 1H), 3.96-3.95 (br m, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.51 (s, 3H); ESIMS m/z 432.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.FC1C=C(F)C=CC=1[C@]1([C@H](N2C3C(=NC=NC=3OC)N=C2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:21]2[CH:20]=[N:19][C:18]3[C:22]2=[N:23][CH:24]=[N:25][C:17]=3[O:16][CH3:15])[CH3:13])[CH2:11][O:10]1
Reactant: COc1ncnc2nc[nH]c12
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: COc1ncnc2ncn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c12
Product: COc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 21.1 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (523 mg) and 6-methoxypurine 1/2 hydrate (415 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-7(7H)purinyl]ethyl]oxirane (205 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-9(9H)-purinyl]ethyl]oxirane (183 mg) were obtained as a white powder respectively by the same way as in Reference Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[C:2]1([NH:1][CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(NC2CCC3(CC2)OCCO3)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of aniline (0.58 mL, 6.4 mmol) and acetic acid (0.73 mL, 12.8 mmol) in MeOH (6 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (1.0 g, 6.4 mmol). The mixture was stirred at 50° C. for 2 h. Then, NaCNBH3 (402 mg, 6.4 mmol) was added at 0° C. The mixture was stirred at room temperature for 2 h. Then, 2 M aqueous NaOH was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to 70:30 hexane/EtOAc) to give the crude title compound (1.39 g, 93%) as a pale yellow solid:
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)(=O)=O.[NH3:27].CO>C1COCC1>[NH2:27][CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2
Reactant: N
Reactant: Cc1cc2c(-c3ccccc3)c(COS(C)(=O)=O)n(C)c(=O)c2cc1C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(-c3ccccc3)c(CN)n(C)c(=O)c2cc1C
Temperature: 140 °C

Procedure:
A mixture of the compound (0.68 g) obtained in Step 1, THF (20 ml) and 15% ammonia/methanol (20 ml) was heated for 20 hours at 140° C. in a sealed tube. The solvent was distilled off. To the residue was added ethyl acetate, and the mixture was washed with an aqueous solution of potassium carbonate and water, successively, then dried (MgSO4). The solvent was distilled off to leave the title compound as colorless crystals (0.37 g),
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.O=[CH:19][C:20]([OH:22])=[O:21]>C(Cl)Cl>[N:10]1([CH:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:20]([OH:22])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=CC(=O)O
Reactant: OB(O)c1ccccc1
Reactant: C1CCCNCC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(c1ccccc1)N1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of phenylboronic acid (400 mg, 3.28 mmol), azepane (0.37 ml, 3.28 mmol) and 2-oxoacetic acid hydrate (302 mg, 3.28 mmol) dissolved in DCM (30 ml) was stirred at room temperature overnight. DCM was removed under vacuum and the crude was purified by flash chromatography (DCM/MeOH=8/2) to obtain the title compound (476 mg, 62.2% yield) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([OH:19])[C:15]1=[O:20])=[O:13])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([OH:19])[C:15]1=[O:20])=[O:13]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N2CC[C@@H](O)C2=O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CC[C@@H](O)C2=O)cc1O

Procedure:
2.20 g of (R)-1-(3-benzyloxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone are hydrogenated in 60 ml of tetrahydrofuran over 1.80 g of 5% palladium/carbon with hydrogen at atmospheric pressure. After removal of the catalyst by filtration, concentration of the filtrate and recrystallization of the residue from ethyl acetate/n-hexane, there is obtained (R)-1-(3-hydroxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 129°-131°; [α]D20 =+175°; [α]54620 =+216°; [α]43620 =+451° (chloroform, c=1.0).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=O)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=[S:48])[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=O)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=S)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of compound 11-4 (560 mg, 1 mmole), anhydrous toluene (10 mL) and Lawesson's reagent (820 mg, 2 mmole) was refluxed for 4 hrs. Toluene was removed by evaporation. To the residue methanol (20 mL) was added, stirred for few minutes at room temperature and the product was collected by filtration and dried to give 500 mg of the title compound. MS 576 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:11]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (207 mg, 0.40 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture stirred for 2 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a white foam (131 mg, 80%). LCMS (method H): RT 1.81 min [M+H]+ 419.4
Reaction SMILES: [N:1]1([C:4]2[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=2[N+:14]([O-:16])=[O:15])[CH2:3][CH2:2]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.[OH2:28]>CN(C)C=O>[CH3:10][N:9]1[C:4]([NH:1][CH2:3][CH2:2][N:1]([CH2:4][CH2:5][CH2:27][C:17]2[CH:22]=[CH:21][C:20]([N+:14]([O-:16])=[O:15])=[CH:19][CH:18]=2)[CH2:2][CH2:3][OH:28])=[C:5]([N+:14]([O-:16])=[O:15])[C:6](=[O:13])[N:7]([CH3:12])[C:8]1=[O:11]
Reactant: Cn1c(N2CC2)c([N+](=O)[O-])c(=O)n(C)c1=O
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Cn1c(NCCN(CCO)CCCc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
An oily substance obtained by dissolving 1.0 g of 6-(aziridin-1-yl)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione, 0.99 g of N-(2-hydroxethyl)-3-(4-nitrophenyl)propylamine and 50 mg of p-toluenesulfonic acid in 1.0 ml of dimethylformamide was allowed to react at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, added with 10 ml of water and then vigorously stirred. Crystals formed were collected by filtration, dissolved in chloroform and then subjected to silica gel chromatograph (chloroform/methanol=40:1 (v/v)) for purification. Thus, 0.44 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-5-nitro-2,4(1H,3H)-pyrimidinedione (a free form of compound 180) was obtained.