Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.[N:10]1C=CC=C[CH:11]=1.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(Cl)Cl>[C:16]([O:9][CH2:8][CH:6]1[CH2:7][CH:3]([CH2:2][C:11]#[N:10])[CH:4]=[CH:5]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: OCC1C=CC(CO)C1
Solvent: ClCCl
Solvent: O
Product: N#CCC1C=CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 18 h
Yield: 44.6 %

Procedure:
To a stirred solution of (4-hydroxymethyl-cyclopent-2-enyl)-methanol (13.8 g, 107.81 mmol, prepared by method of Mekrami et al., Tetrahedron: Asymmetry 1992, 3, 431) in methylene chloride (100 mL) was added pyridine (25.5 g, 118.59 mmol) and trityl chloride (33.06 g, 118.59 mmol) at room temperature and the mixture was stirred for 18 h. After addition of water (50 mL), the reaction mixture was diluted with methylene chloride (100 mL) and the organic layer was separated. The aqueous layer was further extracted with methylene chloride (100 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was purified on a silica gel column using ethyl acetate in hexanes (0 to 30%), which afforded 18.25 g (45.7%) of desired product, (4-trityloxymethyl-cyclopent-2-enyl)-methanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:31])[CH:15]([NH2:30])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=4[O:28][CH3:29])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:32]([CH3:34])[CH3:33])[C:9]2=[O:35])=[CH:5][CH:4]=1.[C:38](O)(=O)[CH3:39].[CH:42](=O)[CH3:43].C([BH3-])#N.[Na+]>CO.C1COCC1>[Cl:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:31])[CH:15]([N:30]([CH2:38][CH3:39])[CH2:42][CH3:43])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=4[O:28][CH3:29])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:32]([CH3:34])[CH3:33])[C:9]2=[O:35])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CC(N)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Reactant: CC=O
Reactant: CC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C1CN(S(=O)(=O)c2cc(Cl)ccc2OC)C2CN(C(C)C)C(=O)C(Cc3ccc(Cl)cc3)N2C1=O
Reaction time: 2 h

Procedure:
50 mg of 6-(4-chlorobenzyl)-1-(2-methoxy-5-chlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrochloride (Example 1) were dissolved in 3 ml of methanol, and 100 μl of acetic acid were added. 100 μl of acetaldehyde and 1 ml of 1M sodium cyanoborohydride solution in THF were added to this solution. After 2 hours, the reaction mixture was evaporated, suspended in 5% Et3N in ethyl acetate and filtered through a small silica gel column. The eluent was evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=610.18 (calculated, monoisotopic); measured value (M+H)+: 611.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH2:17]Br)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:28]([N:37]4[CH2:40][CH2:39][CH2:38]4)[C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH3:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCN(C(=O)C=CCBr)c2cc3ccccc3o2)cc1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=CC(=O)N(CCOc1ccc(C(=O)OC)cc1)c1cc2c(N3CCC3)cccc2o1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(3-benzofuran-2-yl-4-bromobut-2-enoylamino)ethoxy]benzoic acid methyl ester (300 mg, 0.654 mmol)) in dry DMF (4 ml), potassium carbonate (180 mg, 1.31 mmol) and azetidine hydrochloride (41 mg, 0.719 mmol) were added. The reaction mixture was stirred for 4 h at 50° C. The reaction mixture was diluted with ethyl acetate and the resulting suspension was washed with water and brine. After drying the organic phase over sodium sulfate, the solvent was removed under vacuum and the residue was purified by flash chromatography, using mixture of DCM/MeOH (9.5/0.5) as eluent to give 4-[2-(4-azetidin-1-yl-3-benzofuran-2-yl-but-2-enoylamino)ethoxy]benzoic acid methyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1>CN(C)C=O>[CH:16]1([O:15][C:14]2[C:5]([N:4]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:1](=[O:3])[CH3:2])=[C:6]([CH:11]=[CH:12][C:13]=2[O:21][CH3:22])[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N(CCOC1CCCCO1)C(C)=O
Reaction time: 8 h

Procedure:
Methyl 3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoate was prepared from methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (Example 1, Step 4) and 2-(2-bromoethoxy)-tetrahydro-2H-pyran following the procedure outlined in Example 4 (with the following exceptions: the solvent used was dimethylformamide, the reaction temperature was 33° C., and the reaction was conducted overnight). MS (ESI): 458.2 (M+Na).
Reaction SMILES: N[C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si](C=[N+:16]=[N-])(C)C.O1CCCC1[CH2:23][OH:24]>>[NH2:16][C:3]1([O:24][CH3:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[C:8]=[O:10]
Reactant: OCC1CCCO1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC1(N)CCCCC1=C=O
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of 1-aminocyclohexanecarboxylic acid (600 mg) in tetrahydrofuran-methanol was stirred under ice-cooling. Thereto was added dropwise a (trimethylsilyl) diazomethane solution (4.2 mL) and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and to the residue was added diethyl ether-hexane (1/1). Thereto was added 4M HCl-ethyl acetate (1.05 mL) and the precipitates were collected by filtration and dried to give 1-amino-1-methoxy-carbonylcyclohexane (423 mg, yield: 52%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([CH3:8])[CH:7]=1.O[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].S(=O)(=O)(O)O.O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([I:9])=[CH:4][C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1=[O:22]
Reactant: Cc1cc(Br)ccc1I
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1I
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-bromo-2-iodo toluene (512 mg, 1.72 mmol) in trifluoroacetic acid (5 mL) was added N-(hydroxymethy) phthalimide (305 mg, 1.72 mmol). The mixture developed a pink color. The solution was stirred at room temperature for 22 hours then concentrated sulfuric acid (1 mL) was added. The homogeneous solution was stirred for 18 hours at room temperature. Water was added and the precipitated solid collected by filtration and dried in a current of air (0.776 gm). This material, which by proton NMR analysis contained approximately 15% of an isomeric product, was carried forward to the following procedure without further purification. 1H NMR (400 MHz, CDCl3) δ7.85 (m, 2H) 7.76(m, 2H) 7.5 (s, 1H) 7.38(s, 1H) 4.84(s, 2H) 2.31(s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1([CH:19]=CC(C)=CC1)S(C[N+]#[C-])(=O)=O)[CH2:4][CH2:5][CH3:6].[CH:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:22]=[CH2:23].[Cl-].[NH4+:29]>CCOCC.CS(C)=O>[CH2:3]([C:7]1[NH:29][CH:23]=[C:22]([CH:21]=[CH:20][C:24]([O:26][CH3:27])=[O:25])[CH:19]=1)[CH2:4][CH2:5][CH3:6]
Reactant: [NH4+]
Reactant: C=CC=CC(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)C1(CCCC)C=CC(C)=CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCCCc1cc(C=CC(=O)OC)c[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) suspension of NaH (5.4 g, 60% suspension in mineral oil) in anhydrous ether (180 ml) was added dropwise a mixture of 1-n-butyltosylmethylisocyanide (29 g) and methyl butadienecarboxylate (;2.2 ml) in anhydrous ether (180 ml) and dry dimethyl sulfoxide (90 ml) under an inert atmosphere. The reaction mixture was first stirred at 0° C. for 1 hour and then slowly brought to room temperature and the stirring continued for an additional 6 hours. The reaction mixture was then cooled to 0° C. and cautiously poured onto aqueous saturated ammonium chloride solution (200 ml). The organic layer was separated, and the aqueous layer was thoroughly extracted with ethyl acetate. The combined ether and ethyl acetate extracts were sequentially washed with saturated ammonium chloride solution in cold water, and then brine, and dried with magnesium sulfate. The solvent was removed under vacuum and the residue purified by column chromatography on silica gel, eluting with 15% ethyl acetate/hexane, to afford methyl 3-[ 2-(n-butyl)pyrrol-4-yl]acrylate as a yellow oil (15.32 g), a compound of Formula (AE), which crystallized on standing to a solid, m.p. 65°-67° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2>C(O)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]2[C:3](=[CH:14][CH:15]=1)[NH:2][CH:1]=[C:10]2[CH2:11][N:12]([CH3:4])[CH3:13]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.7 %

Procedure:
To a mixture of 40% aqueous dimethylamine (5.95 g, 52.8 mmol), 37% aqueous formaldehyde (4.21 g, 51.9 mmol) and acetic acid (7 mL) was added 5-bromo-1H-indole (9.79 g, 49.9 mmol). The reaction mixture was stirred for 21 hours at room temperature and poured into a 2.5 N sodium hydroxide/ice mixture (200 mL). This was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated to dryness. It was dried at 60° C. for 30 minutes to yield (5-bromo-1H-indol-3-ylmethyl)-dimethyl-amine (11.2 g) as a brown solid: mp 160-162° C. 1HNMR (200 MHz, DMSO-d6): δ 11.1 (br s, 1H), 7.75 (s, 1H), 7.15-7.35 (m, 3H), and 3.5 ppm (s, 2H).
Reaction SMILES: Cl[C:2]1C=C2C(C=CC(C)=N2)=C(C2C=CC(Cl)=CC=2)[C:3]=1C=C.FC(F)(F)S(O[C:28]1[C:37]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[N:35]2)=[CH:30][C:29]=1[CH3:45])(=O)=O>>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]2[C:28]([CH:2]=[CH2:3])=[C:29]([CH3:45])[CH:30]=[C:31]3[C:36]=2[N:35]=[CH:34][CH:33]=[CH:32]3)=[CH:39][CH:40]=1
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F
Product: C=Cc1c(C)cc2cccnc2c1-c1ccc(Cl)cc1

Procedure:
Compound 4E was prepared following the procedure used to prepare compound 1G of Example 1, except that 8-(4-chlorophenyl)-6-methylquinolin-7-yl trifluoromethanesulfonate (4D) was used instead of compound 1F. LCMS-ESI+ (m/z): 280.2, 282.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]([NH2:17])=[S:16])[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[I-].[Na+].[C:37](=O)([O-])[O-].[K+].[K+].[C:43](#N)[CH3:44]>>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]2[S:16][CH:37]=[C:43]([CH3:44])[N:17]=2)[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C)cs3)[C@H]2SC1

Procedure:
A mixture of 91 mg of (6R-trans)-3-[(acetyloxyl)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 33 mg of sodium iodide, 20 mg of potassium carbonate and 2 ml of acetonitrile was reacted as described in Example 2, giving the desired compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:12])=[O:11])[CH:3]=[CH:2]1.C[O:15][C:16](=O)[NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([CH3:26])[N:19]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([CH3:26])[N:19]=[C:18]([NH:17][C:16]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)(=[O:11])=[O:12])=[O:15])[N:23]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2cc[nH]c12
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cc[nH]c23)n1

Procedure:
To a solution of 1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene chloride (100 ml) was added trimethylaluminum (3.2 ml of a 2.0M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to an oil. The oil was dissolved in ether from which it quickly crystallized to give pure product (TLC) (0.56 g, m.p. 207°-209° C.).
Reaction SMILES: O.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:15]2=[O:24])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>CN(C)P(=O)(N(C)C)N(C)C>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([O:23][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:22])[C:15]2=[O:24])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(N)n1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)OCc2ccccc2)C1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising 2 g of 5-[1-(2-aminothiazol-4-yl)-1-ethoxycarbonylmethylene]rhodanine-3-acetic acid monohydrate, 3 g of benzyl bromide, 1.1 g of triethylamine and 10 ml of hexamethylphosphoric triamide was stirred at room temperature for 16 hours. The reaction mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography using as eluent a 8:2:1 by volume mixture of hexane, ethyl acetate and acetic acid, giving the desired compound as yellow crystals.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)N)([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=[CH:20][CH:19]=1)[CH:1]=[CH2:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Nc1ccccc1
Solvent: C=CCBr
Product: C=CCc1cccc([N+](=O)[O-])c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (30 ml), 3-nitroaniline (414 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 34-36° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 35° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 47:3) gave 420 mg of 3-allylnitrobenzene as a light yellow oil containing 36% of 3-bromonitrobenzene. This corresponds to 50% yield of 3-allylnitrobenzene. 1H NMR (CDCl3, 400 MHz) δ 8.10-8.08, (m, 1H), 8.08-8.05, (m, 1H), 7.56-7.51, (m, 1H), 7.50-7.44, (m, 1H), 6.02-5.91, (m, 1H), 5.20-5.10, (m, 2H), 3.50, (d, 2H, J=6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 148.8, 142.5, 136.1, 135.3, 129.7, 123.9, 121.8, 117.8, 40.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Product: N#Cc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[OH:30][C:31]1([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32]1.[H-].[Na+].Cl>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:30][C:31]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32]3)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CCOC(=O)C1(O)CC1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(OC3(C(=O)OCC)CC3)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 257.7 %

Procedure:
20 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 20 mg of ethyl 1-hydroxycyclopropanecarboxylate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 63 mg of t-butyl 4-[7-(2-butynyl)-2-(1-ethoxycarbonylcyclopropyloxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. This compound was dissolved in a solution consisting of 0.4 ml of ethanol and 0.1 ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at 50° C. overnight. 1N hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 22 mg of t-butyl 4-[7-(2-butynyl)-2-(1-carboxycyclopropyloxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. 11 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.64 mg of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:3][C:4]2[C:12]([O:13][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(O)c1O
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2cccc(OCc3ccc(OC)cc3)c2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sodium hydride (60%, 4.69 g, 0.117 mol) was added in portions to 18 (5.47 g, 35.5 mmol) in DMF (150 mL) with ice bath cooling, and the mixture was stirred at 0° C. for 45 min and at room temperature for 1 h. A solution of 4-methoxybenzyl bromide (25.0 g, 0.124 mol) in DMF (50 mL) was added to the reaction mixture over 30 min. After stirring for 20 h, quenching with H2O (30 mL) at 0° C. was performed, and solvents were removed under high vacuum. The concentrate was dissolved in EtOAc (200 mL), which was washed with H2O (100 mL) and saturated NaCl (100 mL); solvent was removed in vacuo. Flash chromatography, eluting with 5:1 hexanes/EtOAc, gave 11.33 g (62%) of 19 as a white solid, mp 108° C.: 1H NMR δ 3.77 (s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 4.95 (s, 2H), 5.03 (s, 2H), 5.25 (s, 2H), 6.76 (d, 2H, J=8.8), 6.86 (d, 2H, J=8.8), 6.89 (d, 2H, J=8.4), 7.04 (t, 2H, J=7.8), 7.11 (dd, 2H, J=8.0, 2.0), 7.18 (d, 2H, J=8.8), 7.33-7.36 (m, 4H); 13C NMR δ 55.32, 55.37, 55.40, 66.81, 71.20, 75.31, 112.97, 113.61, 114.02, 118.16, 123.93, 127.08, 128.19, 128.75, 129.51, 129.73, 130.31, 130.41, 148.43, 152.95, 159.43, 159.62, 159.70, 166.44; HRMS m/z calcd for C31H30NaO7, 537.1889 (M+Na). found, 537.1884.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1.ClC1C=CC(C(O[NH2:32])=O)=CC=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:32])[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: NOC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred, ice/water cooled mixture of 1H-pyrrole-2-carboxylic acid methyl ester (425 mg, 3.40 mmol) in NMP (10 mL) was added a solution of potassium tert-pentoxide in toluene (2.30 mL, 3.90 mmol, 25 wt % solution); then the solid of O-4-chlorobenzoyl hydroxyamine (670 mg, prepared according to the literature: Parlanti, L Discordia, R. P.; Hynes, J. Jr.; Miller, M. M.; O'Grady, H. R.; Shi, Z. Org. Lett. 2007, 9(19) 3821-3824) was added in one portion; the cold bath was removed after addition completed, and the slurry was stirred at rt for 30 min. Subsequently, the reaction was quenched by addition of saturate sodium bicarbonate solution, then extracted with EtOAc, washed with brine; organic layers was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column purified to give the desired product (309 mg). 1H NMR (CDCl3, δ in ppm): 6.94 (t, 1H, J=2.3 Hz), 6.81 (dd, 1H, J=2.0 Hz, 4.0 Hz), 6.00 (dd, J=2.7 Hz, 4.3 Hz), 5.53 (br, s, 2H), 3.82 (s, 3H).