Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.CO[C:16]1[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=1>C1COCC1>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: COC1=CC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(=O)CC2)cc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
A solution of 4-iodotoluene (10 g, 45 mmol) in THF (300 mL) at −78° C. was treated with a solution of n-butyllithium (2.5 M in hexanes; 20 mL, 50 mmol) such that the reaction temperature remained ≦−78° C. After 15 minutes, a solution of 3-methoxy-2-cyclopenten-1-one (5.78 g, 52 mmol) in THF (50 mL) was added such that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl and concentrated in vacuo to remove THF. A solution of 1N HCl (40 mL) was added, the solution was stirred for 30 min and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using heptane/EtOAc as the eluting solvent to afford 4.92 g of 3-p-tolyl-cyclopent-2-enone as a white powder (Yield 63.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.42 (s, 3 H) 2.59 (ddd, J=4.83, 2.64, 2.49 Hz, 2 H) 3.05 (td, J=4.98, 1.76 Hz, 2 H) 6.55 (t, J=1.66 Hz, 1 H) 7.27 (d, J=8.00 Hz, 2 H) 7.57 (dt, J=8.30, 1.90 Hz, 2 H).
Reaction SMILES: O[C:2]1[C:14]2[N:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]3=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[C:14]2[N:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]3=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccncc23)c(C)c1
Product: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccncc23)c(C)c1

Procedure:
A solution of 4-Hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2′,3′:4,5]pyrrolo[1,2-a]pyrazine (220 mg) in phosphorus oxychloride (2 mL) is heated to 100° C. for 1 hour. The resulting dark tan solution is concentrated in vacuo, diluted with water, and neutralized by adding saturated sodium bicarbonate solution. The neutralized solution is extracted 3 times with dichloromethane and the combined extracts are dried (Na2SO4), filtered, concentrated, and chromatographed on silica gel (10 to 20% ethyl acetate in hexane) to give 120 mg of the title compound as a yellow foam: 1H nmr (400 MHz, CDCl3) d 2.03 (s, 5 H), 2.38 (s, 3 H), 2.69 (s, 3 H), 7.03 (s, 2 H) 7.25 (s, 1 H), 7.66 (d, 1 H), 8.70 (s, 1 H), 9.00 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Reactant: ClCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) produced in Example 102 was suspended in dimethyl sulfoxide (8 ml). After adding potassium carbonate (204 mg), the mixture was stirred at room temperature for 30 minutes, and 3-picolylchloride (0.09 ml) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (20 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (177 mg, 72%).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C@@H:20]5[O:29][C@@H:21]53)C=C4)[CH2:12][CH2:11]2)C)OC1.C(=O)([O-])O.[Na+].ClC1C=CC=[C:40]([C:44]([O:46]O)=O)C=1>C(Cl)Cl>[O:29]1[C:20]2=[C:21]3[C@:22]([CH3:23])([CH2:17][CH2:18][C:19]2=[O:30])[C@@H:24]2[C@H:14]([C@H:13]4[C@:27]([CH3:28])([CH2:26][CH2:25]2)[C@@H:10]([CH2:8][CH3:5])[CH2:11][CH2:12]4)[C@@H:40]2[O:46][C@:44]123
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Yield: 79 %

Procedure:
To a solution of 0.43 g (1.0 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one in 10 ml of methylene chloride was added 3 ml of 0.5M-aqueous sodium hydrogen carbonate solution under stirring and cooling in an ice-water bath, followed by gradual addition of 0.34 g (2.0 mmoles) of m-chloroperbenzoic acid. The mixture was stirred at room temperature for 2 days. The reaction mixture thus obtained was subjected to phase separation and the aqueous layer was extracted twice with 10 m{portions of methylene chloride. The extract was combined with the organic layer obtained above and the mixture was washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 0.35 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn- 4-en-3-one (yield:79%). The 1H-MNR and IR spectra of this product were in agreement with those of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one obtained in Example 7.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)n1
Product: CC(=O)Nc1cccc(C)n1
Temperature: 25 °C

Procedure:
To a solution of 6-methyl-pyridin-2-ylamine (50 g, 0.462 mol) in acetic anhydride (200 mL) was heated to 90° C. for 90 minutes. The reaction mixture was cooled to room temperature and evaporated. An aqueous saturated solution of NaHCO3 was added to the residue until pH 8. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, and the solvent was evaporated. The title compound was obtained as a white solid (68 g, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][C@@H:63]([C@H:83]([OH:85])[CH3:84])[C:64]([NH:66][C:67]1([C:70]2[N:75]=[CH:74][C:73]([C:76]3[C:77]([CH3:82])=[N:78][N:79]([CH3:81])[CH:80]=3)=[CH:72][N:71]=2)[CH2:69][CH2:68]1)=[O:65]>C1COCC1>[CH3:81][N:79]1[CH:80]=[C:76]([C:73]2[CH:74]=[N:75][C:70]([C:67]3([NH:66][C:64]([C@@H:63]([NH:62][C:16]([C:13]4[N:12]5[C@@:8]([CH2:7][C:6]6[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=6)([CH3:29])[C:9](=[O:28])[N:10]([C:19]6[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=6)[C:11]5=[N:15][CH:14]=4)=[O:18])[C@H:83]([OH:85])[CH3:84])=[O:65])[CH2:68][CH2:69]3)=[N:71][CH:72]=2)[C:77]([CH3:82])=[N:78]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Reactant: Cc1nn(C)cc1-c1cnc(C2(NC(=O)[C@@H](N)[C@@H](C)O)CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1-c1cnc(C2(NC(=O)[C@@H](NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)c(F)c(Cl)c3)[C@@H](C)O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask was added (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.80 g, 2.18 mmol), TBTU (0.73 g, 2.28 mmol) and Et3N (0.91 mL, 6.54 mmol) and THF (10 mL). The mixture was allowed to stir at RT for 30 min. The mixture was transferred to a separate flask containing (2S,3R)-2-amino-N-{1-[5-(1,3-dimethyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-cyclopropyl}-3-hydroxy-butyramide hydrochloride (1.0 g, 2.18 mmol) in THF (30 mL). The mixture was stirred at RT for 24 h. The mixture was concentrated and purified by silica gel chromatography to provide 1.45 g of the title compound as a white solid following removal of the solvent, m/z=771.8 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:24])[CH:4]=1)#[CH:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:24])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 91 %

Procedure:
4-(4-Ethynyl-2-fluoroanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-(4-ethyl-2-fluoroanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (91%), m.p. (EtOAc) 231-233° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.28 (br s, 1H), 10.02 (s, 1H), 8.41 (t, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.32 (t, J=8.3 Hz, 1H), 7.19 (dd, J=11.9, 1.8 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 5.33 (s, 1H), 4.44 (t, J=5.1 Hz, 1H), 3.46 (q, J=5.2 Hz, 2H), 3.30-3.22 (m, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.66 (pentet, J=6.7 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). Anal. Calcd for C17H20FN3O3: C, 61.1; H, 6.1; N, 12.6. Found: C, 61.3; H, 5.9; N, 12.7.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:19])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[Cl:19][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:27](=[S:28])[C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=1)([C:3]#[N:4])[CH3:20])[C:14]=2[O:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCOc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CCCOc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-propoxy-2H-indazol-2-yl)-2-methylpropionitrile (104 mg, described in Example 124) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (88 mg, 46%). MS (ES): M/Z [M+H]=497. 1H NMR: (400 MHz, CHLOROFORM-d): 1.14 (t, J=7.4 Hz, 3H), 1.90 (s, 3H), 1.92-2.04 (m, 2H), 4.51 (d, J=14.2 Hz, 1H), 4.56-4.70 (m, 2H), 4.82 (d, J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.62 (dd, J=9.1, 0.5 Hz, 1H), 7.79 (dd, J=8.3 Hz, 2H), 7.91-7.99 (m, 2H) and 9.17 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17].Cl>O1CCCC1.O>[CH3:14][O:15][C:16]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
L-Valine (S) (0.213 mol) was dissolved in anhydrous tetrahydrofuran (645 mL) with NaHCO3 (0.640 mol) in water (645 mL). Methylchloroformate (0.235 mol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was acidified to pH 3 with 1N HCl. The aqueous layer was extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 1 as a white solid in 98% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.93 (d, J=7.00 Hz, 3H), 1.00 (d, J=7.00 Hz, 3H), 2.23 (m, 1H), 3.70 (s, 3H), 4.33 (m, 1H), 5.26 (brs, 1H), 8.50 (brs, 1H); and MS (ESI, EI+) m/z=176 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]12([C:23]3[CH:32]=[C:31]4[C:26]([CH:27]=[CH:28][C:29](B(O)O)=[CH:30]4)=[CH:25][C:24]=3[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][C:23]([C:13]45[CH2:14][CH:15]6[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]6)[CH2:22]4)[CH2:20]5)=[C:24]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:25]=3)[CH:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
300 mg (8.8 mmol) of tetrakis(triphenyl-phosphine)palladium(0), 50 ml of toluene and 2.46 g (8.8 mmol) of methyl 2-hydroxy-4-iodobenzoate were introduced into a three-necked flask under a stream of nitrogen and stirring was carried out at room temperature for 20 minutes. 5.52 g (13.4 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid and 8.8 ml of an aqueous potassium carbonate solution (2N) were then added and the reaction mixture was heated at reflux for 8 hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). 1.65 g (36%) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate were obtained.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:5](=[N:6][CH:7]([CH3:9])[CH3:8])[NH:4][CH:1]([CH3:3])[CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: OCc1ccccc1
Product: CC(C)N=C(NC(C)C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A neat solution of 18.6 mL (15 g, 118.8 mmol) of 1,3-diisopropylcarbodiimide and 60 mg (0.6 mmol) of cuprous chloride was placed under a blanket of argon and then cooled to 0° C. in an ice bath. To this reaction mixture was added dropwise (via syringe) 12.9 mL (13.5 g, 124.7 mmol) of benzyl alcohol. The resultant green reaction mixture was allowed to stir at 0° C. overnight, filtered through celite (rinsing with hexane) and the filtrate then Kugelrohr distilled (105° C., 2mm Hg) to give 2-benzyl-1,3-diisopropyl isourea as a clear, colorless oil. To a solution of 650 mg (4.7 mmol) of 4-hydroxybenzoic acid in 20 mL of tetrahydrofuran was added 1.1 g (4.7 mmol) of 2-benzyl-1,3-diisopropyl isourea. The reaction mixture was allowed to stir at ambient temperature overnight, filtered (rinsing with tetrahydrofuran) and then concentrated in vacuo. Purification by flash chromatography (silica, 25% ethyl acetate in hexane) gave the title compound as a white solid.
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:12]2[CH:18]=[CH:17][S:16][C:13]=2[NH:14][N:15]=1.[I:19]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[I:19][C:17]1[S:16][C:13]2[NH:14][N:15]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:12]=2[CH:18]=1
Reactant: c1ccc2cc(-c3n[nH]c4sccc34)ccc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1cc2c(-c3ccc4ccccc4c3)n[nH]c2s1
Temperature: 40 °C
Yield: 71.3 %

Procedure:
To a solution of 70 mg of 3-naphthalene-2-yl-1H-thieno[2,3-c]pyrazole obtained by Example 78 in 3.0 mL of N,N-dimethylformamide was added 63 mg of N-iodosuccinimide at room temperature, and stirred at 40° C. for a day. Then the solution was added with 1.0 mL of 10% sodium thiosulfate aqueous solution, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to afford 75 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:27][CH2:28][CH2:29][N:30]([CH2:34][C:35]([NH2:37])=[S:36])[C:31](=[O:33])[CH3:32])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:37]=[C:35]([CH2:34][N:30]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])[C:31](=[O:33])[CH3:32])[S:36][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Reactant: CC(=O)OCCN(CC(N)=S)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(CCOC(C)=O)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, by reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-[N-(2-acetoxyethyl)-N-acetylamino]thioacetamide in ethanol gave 1-ethyl-6-fluoro-1,4-dihydro-7-[2-[[N-(2-acetoxyethyl)-N-acetylamino]methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 148°-152° C., resolidified and melted 164°-165° C., which was hydrolyzed with refluxing 6 N hydrochloric acid to afford the titled compound, mp 290° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]([OH:22])[CH2:19][O:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:34])[F:35])[CH:27]=2)=[CH:37][CH:38]=1
Reactant: COCC(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: COCC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (40 mg, 0.072 mmol, example 7f) in methyl sulfoxide (4 mL) was added acetic anhydride (37 mg, 0.363 mmol) dropwise. Then the mixture was stirred at 25° C. for 16 h. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over sodium sulfate, filtered and was concentrated to give crude product. This crude material was further purified preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-methoxy-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (12 mg, 30.2%) as white solid. 1H-NMR (CD3OD) δ 7.56-7.52(t, 1H), 7.42-7.39(d, 2H), 7.36-7.31(m, 4H), 7.24-7.22(d, 1H), 5.45(s, 2H), 4.92(s, 2H), 4.24(s, 2H), 3.46(s, 3H), 3.39(s, 3H). LCMS retention time 3.210 min; LCMS MH+ 553.
Reaction SMILES: Cl.[P:2]([O-:13])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:14][C:15]([CH3:17])=[O:16]>C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-]>[CH2:4]([O:3][P:2]([C:15]([OH:16])([CH3:17])[CH3:14])(=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCOP([O-])OCCCC
Reactant: CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CCCCOP(=O)(OCCCC)C(C)(C)O
Temperature: 80 °C
Yield: 91.7 %

Procedure:
Next, into a two-liter four-necked flask provided with a stirrer, a thermometer, a dropping device, a hydrochloric-acid-recovering device and a condenser, 213.4 g (1.1 moles) of dibutyl phosphite, 5.6 g (0.06 moles) of triethylamine and 1.9 g (0.020 moles) of magnesium chloride were fed. While stirring the resulting mixed solution at 40° C., 70.2 g (1.2 moles) of acetone was added thereto in an hour. The mixed solution was further stirred for 1 hour at the same temperature (40° C.) to complete the reaction. Thereafter, the resulting reaction solution was washed with a 1% dilute hydrochloric acid aqueous solution and a saturated sodium carbonate aqueous solution successively and rinsed with water twice to remove the triethylamine and the magnesium chloride. Then, while heating the reaction mixture to 80° C., water was recovered under a reduced pressure of about 2.7 kPa. Further, nitrogen topping was carried out under the same conditions to remove the low-boiling point portions, thereby obtaining 254.6 g of dibutyl(1-hydroxy-1-methylethyl)phosphonate (raw material 2).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[N:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:27]([OH:28])[C:26]4[C:21](=[N:22][CH:23]=[CH:24][N:25]=4)[C:20]3=[O:29])=[N:16]2)=[CH:11][CH:10]=1>C(#N)C.C(Cl)Cl>[CH2:1]([NH:5][C:6]([O:28][CH:27]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[C:20](=[O:29])[N:19]1[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[N:18][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCNC(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 50.7 %

Procedure:
n-Butyl isocyanate (5 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (7.8 g.) in anhydrous acetonitrile (156 cc.) and the mixture is heated at the reflux temperature for 7 hours. The insoluble product is filtered off and washed with anhydrous acetonitrile (2 × 10 cc.). The product obtained is dissolved in methylene chloride (430 cc.) and the resulting solution is washed by successive decantations with 0.1N sodium hydroxide solution (85 cc.) and water (85 cc.). After drying, the organic phase is concentrated to dryness under reduced pressure (20 mm.Hg). Recrystallisation of the residue obtained, from acetonitrile (230 cc.), gives 5-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (5.2 g.) melting at 264° C.