Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>O>[CH:9]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10]
Reactant: CN1CCc2ccccc21
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Phosphorus oxychloride (1.23 g., 0.0080 mole) was slowly added dropwise to 5 ml. of DMF which was cooled in an ice bath. The solution was stirred for 5 minutes and to it there was added dropwise a solution of 1-methylindoline (1.0 g., 0.0075 mole) in 2 ml. of DMF. The resulting mixture was stirred in the ice bath for 5 minutes, then at room temperature for 1 hour and finally at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, slowly poured into water with stirring and extracted with ethyl ether. The crude oil was chromatographed on silica gel with 80/20 (v/v) CH2Cl2 /EtOAc to yield 0.745 g. (62% yield) of 5-formyl-1-methylindoline as a yellow solid, m.p. 39°-41° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][N:10]([CH:8]([C:5]2[CH:4]=[C:3]([B:28]([OH:33])[OH:29])[C:2]([F:1])=[N:7][CH:6]=2)[CH3:9])[CH2:15][CH2:14]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (8.41 g, 27.2 mmol) in tetrahydrofuran (100 mL) was chilled to −78° C. in a dry ice/acetone bath. Then n-butyllithium (1.6 M in hexanes; Aldrich; 18.69 mL, 29.9 mmol) was added via cannula into the mixture. The deep red solution was stirred at the same temperature for 1 h, then triisopropyl borate (7.50 mL, 32.6 mmol) was added into the mixture. The resulting mixture was stirred at the same temperature (−78° C.) for 30 min, then the ice bath was removed. After the reaction mixture warmed up to room temperature, the tan mixture was quenched with 1 N NaOH(aq) (50 mL) and stirred 10 min. The separated aqueous layer was collected and the round-bottomed flask was rinsed with 1 N NaOH(aq) (2×10 mL). The aqueous layer was carefully acidified with 10% HCl until acidic (about pH 5 to 6) and the resulting cloudy mixture was extracted with 3:1 dichloromethane/methanol (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave 5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (5.507 g, 15.59 mmol, 57.4% yield) as tan solid. 1H NMR (400 MHz, d6-DMSO) δ 7.79-8.70 (m, 2H) 3.66 (t, J=6.36 Hz, 1H) 3.34 (s, 4H) 2.56 (s, 3H) 2.39 (s, 4H) 1.26-1.51 (m, 12H). m/z (ESI, +ve ion) 354.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:21]1[C:22]([O:31][CH3:32])=[N:23][C:24]([CH3:30])=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:33][Mg]Br>O1CCCC1>[OH:29][C:27]([C:25]1[CH:26]=[C:21]([N:2]([CH3:1])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)[CH2:9][CH2:10]2)=[O:4])[C:22]([O:31][CH3:32])=[N:23][C:24]=1[CH3:30])([CH3:33])[CH3:28]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C(C)=O)c(C)nc3OC)CC2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C(C)(C)O)c(C)nc3OC)CC2)c1
Yield: 92 %

Procedure:
1-[N-Methyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(221 mg, 0.5 mmol) was dissolved in tetrahydrofuran(10 ml) and thereto methyl magnesium bromide(0.50 ml, 1.50 mmol). The resulting mixture was refluxed for 15 hrs, concentrated under the reduced pressure to remove used solvent, extracted with ethylacetate, filtered to dryness, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: C=O.[OH-].[K+].[CH:5]1[CH:10]=[C:9]([CH:11]=O)[C:8]2[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:7]=2[CH:6]=1>>[CH2:11]1[O:19][C:17](=[O:18])[C:13]2=[CH:14][CH:15]=[CH:16][C:7]3=[C:8]2[C:9]1=[CH:10][CH:5]=[CH:6]3
Reactant: O=Cc1cccc2cccc(C(=O)O)c12
Agent: C=O
Agent: [K+]
Agent: [OH-]
Product: O=C1OCc2cccc3cccc1c23

Procedure:
Prepared by the action of formalin and potassium hydroxide on peri-naphthaldehydic acid by the method of Fuson et. al. (J. Amer. Chem. Soc. 71, 1870).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH2:38][CH2:37][O:36][CH2:35][CH:34]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C3=CCOCC3)c2n1C
Temperature: 140 °C
Yield: 15.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (122 mg, 0.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 10 mol %) and caesium carbonate (204 mg, 0.63 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 432 as a white solid (19 mg, 15%). LCMS (Method K): RT 2.79 min [M+H]+ 394.16. 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.69 (1H, m), 7.55 (1H, dd, J=8.76, 4.82 Hz), 7.30 (2H, br s), 7.04 (1H, dd, J=10.42, 8.75 Hz), 5.87 (1H br s), 5.70 (1H, m), 4.24 (2H, s), 3.86 (2H, m), 3.73 (3H, s), 2.45-2.23 (2H, m), 1.58 (3H, d, J=6.72 Hz)
Reaction SMILES: CO.[NH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[Cl:10][C:8]1[C:7]([CH3:11])=[CH:6][C:5]([OH:12])=[C:4]([NH:3][C:13](=[O:15])[CH3:14])[CH:9]=1
Reactant: Cc1cc(O)c(N)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To 30 ml of methanol, there were added 1.0 g (6.4 mmol) of 2-amino-4-chloro-5-methylphenol and 0.71 g (7.0 mmol) of acetic anhydride and stirred at room temperature for 30 minutes. To this solution, there was added 60 ml of water. The crystals thus precipitated were filtered and recrystallized from methanol. Thus 0.89 g (4.5 mmol) of N-(5-chloro-2-hydroxy-4-methylphenyl)acetamide was obtained as pale brown crystals. The yield was 70%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC1C=CC(S(O[CH2:18][C@@H:19]([C@@H:33]2[C@:50]3([CH3:51])[C@H:36]([C@H:37]4[C@H:47]([CH2:48][CH2:49]3)[C@:45]3([CH3:46])[C:40]([CH2:41][C@@H:42]([O:59][CH:60]5[CH2:65][CH2:64][CH2:63][CH2:62][O:61]5)[CH2:43][C@@H:44]3[O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:20][CH2:21][C@H:22]([F:32])[C:23]([O:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])([CH3:25])[CH3:24])(=O)=O)=CC=1>O1CCCC1>[O:54]1[CH2:55][CH2:56][CH2:57][CH2:58][CH:53]1[O:52][C@@H:44]1[C@@:45]2([CH3:46])[C:40](=[CH:39][CH2:38][C@@H:37]3[C@@H:47]2[CH2:48][CH2:49][C@@:50]2([CH3:51])[C@H:36]3[CH2:35][CH2:34][C@@H:33]2[C@H:19]([CH3:18])[CH2:20][CH2:21][C@H:22]([F:32])[C:23]([O:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])([CH3:25])[CH3:24])[CH2:41][C@@H:42]([O:59][CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62][O:61]2)[CH2:43]1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 0.033 g. (0.00088 mole) of lithium aluminum hydride, 4 ml. of tetrahydrofuran, and 0.223 g. (0.00026 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate) was heated at reflux (60° C.) for 1 hr and cooled to 0° C. The mixture was diluted with 12 ml. of ether and quenched with the dropwise addition of 0.07 ml. of water and 0.05 ml. of 10% aqueous sodium hydroxide solution. The mixture was then stirred for 1 hr and filtered. The solids were triturated with ether and filtered. The combined filtrates were evaporated to dryness and chromatographed on 0.06-0.20 mm silica gel to yield [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].[H-].[Na+].I[CH2:41][CH3:42]>O1CCCC1>[C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([N:30]([CH2:41][CH3:42])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperidin-3-ylcarbamate (130 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added sodium hydride as a 60% dispersion in mineral oil (20 mg, 0.5 mmol) followed by iodoethane (0.06 mL, 0.75 mmol) and reaction mixture was stirred overnight at ambient temperature. The reaction was quenched with water (30 μL), diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a colorless oil, which was used in the next step without any further purification (90 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.CI>C1COCC1.C([Li])CCC.[Cl-].[NH4+]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)([CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(Cl)cc1)C1CCCC1
Temperature: -35 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.15 ml) in THF (2 ml), n-butyl lithium (1.5 M hexane solution, 0.6 ml) was added at −78° C., stirred for 10 minutes and another solution of methyl 2-(4-chlorophenyl)-2-cyclopentylacetate (200 mg) in THF (1.5 ml) was added dropwise. After 15 minutes' stirring, the system temperature was raised to −35° C., and methyl iodide (0.15 ml) was added. The reaction liquid temperature was raised to 0° C., and the liquid was stirred for 1.5 hours, diluted with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and condensed under reduced pressure. The resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate 60/1) to provide methyl 2-(4-chlorophenyl)-2-cyclopentylpropionate (180 mg) as yellow oily substance.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]#[CH:5].[ClH:7].[CH2:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[C:26]([CH3:27])=[C:25]([CH3:28])[NH:24][C:23]=12>O1CCCC1>[ClH:7].[CH:3]([N:24]1[C:23]2=[C:18]([N:9]3[CH2:10][CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:8]3)[N:19]=[CH:20][CH:21]=[C:22]2[C:26]([CH3:27])=[C:25]1[CH3:28])=[C:4]=[CH2:5]
Reactant: C#CCBr
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C=Cn1c(C)c(C)c2ccnc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.6 %

Procedure:
Sodium hydride (60%; 80 mg, 1.80 mmol) and propargyl bromide (35.6 μl, 1.40 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92.3 mg, 0.33 mol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature. Ice was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 32.5 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc2c(Cl)ncnc2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC
Temperature: 70 °C

Procedure:
According to the procedure described in Example 50, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.201 g, 0.73 mmol) from Example 1A, 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (0.195 g, 0.73 mmol) from the previous step, and Cs2CO3 (0.261 g, 0.8 mmol) in isopropanol (10 mL) was heated at 70° C. for 7 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as a solid. 1H NMR (300 MHz, CDCl3) δ 9.13 (br and s, 2H), 8.61 (s, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.31 (m, 3H), 6.97 (dd, 1H), 6.08 (s, 1H), 4.34 (t, 2H), 4.11 (s, 3H), 3.89 (t, 2H), 3.49 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH3:20][S:17]([O:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])[CH2:13]1)(=[O:18])=[O:19]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCC(=O)NC(N)=O)C1

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (3.00 g) in a mixture of methanol (30 ml) and tetrahydrofuran (60 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 5 hours in the presence of 20% palladium hydroxide on carbon (1 g). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (20 ml) and water (20 ml) was dropwise added a solution of allyl chloroformate (0.82 ml) in tetrahydrofuran (2 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (15 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (1.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[F:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][C:18]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([F:15])[CH:17]=1)[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: Cc1ccc(C[C@@H]2CCCN2)cc1F
Product: Cc1ccc(C[C@@H]2CCCN2C[C@@H](O)CO[C@H](C)c2ccccc2Br)cc1F
Yield: 92 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane described in WO 2004/106280 and (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine which had been obtained in Example 1 (1e), the reaction was carried out in the same manner as the method described in Example 1 (1f) to give the title compound as a colorless oily substance (yield 92%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]([CH:17]=[O:18])[NH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][N:23]1C2=CNC(C3C=C(C=CC=3)C#N)=C2C(=O)N(C)C1=O>>[CH:17]([C:8]1[NH:9][C:10]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][CH:12]=2)[C:22]#[N:23])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]([CH3:1])[C:7]=12)=[O:18]
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C=O)c2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]c(C=O)c2n(C)c1=O

Procedure:
The title compound was prepared in a similar manner to 1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-7-carbaldehyde (Intermediate Na), starting from 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) and omitting step 1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]2=[O:30])=[N:20][C:19]=1[CH3:31])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[CH:25][C:24]2=[O:30])=[N:20][C:19]=1[CH3:31])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: ClCc1cscn1
Product: Cc1nc(-n2ccc(OCc3cscn3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 29 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 4-(chloromethyl)thiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 29% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J=1.9 Hz, 1H), 8.79 (t, J=5.9 Hz, 1H), 8.61 (d, J=8.0 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.33-7.27 (m, 4H), 7.25-7.17 (m, 1H), 6.38-6.32 (m, 2H), 5.27 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 439.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2[CH:13]=O)=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]([O:26]CC)=[O:25])(OCC)=O)C.[H-].[Na+].Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2/[CH:13]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1
Reactant: O=Cc1snnc1-c1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1snnc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 4-(4-fluorophenyl)-1,2,3-thiadiazole-5-carbaldehyde (180 mg), ethyl diethylphosphonoacetate (450 mg), sodium hydride (60% in oil, 40 mg) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and a 6N aqueous hydrochloric acid solution (3 ml) and acetic acid (3 ml) were added to the residue. The mixture was stirred for 3 hrs. with heating under reflux. The reaction mixture was concentrated and poured into water. The precipitated solids were collected by filtration, washed with water and dried to give (2E)-3-[4-(4-fluorophenyl)-1,2,3-thiadiazol-5-yl]acrylic acid (130 mg, yield 60%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([CH3:25])[O:24][C:20]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([OH:30])C.Cl>O>[C:23]([NH:22][C:21]1[CH:26]=[CH:27][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][C:20]=1[OH:24])(=[O:30])[CH3:25]
Reactant: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(NC(C)=O)c(O)c1
Reaction time: 4 h

Procedure:
A mixture of 111 g of 6-hexadecyloxy-2-methylbenzoxazole, 1,300 ml of ethanol, 110 ml of 33% hydrochloric acid and 550 ml of water was stirred at 55°-60° C. for 4 hours. The reaction solution was cooled to precipitate crystals, and the crystals were collected by filtration. 113 g of 2-acetylamino-5-hexadecyloxyphenol was obtained.