Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.Cl.CCOCC>C1COCC1.CCCCCC>[CH3:1][NH:2][C:3](=[O:11])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][CH2:14][N:13]([CH3:17])[CH3:12]
Reactant: CN(C)CCCl
Reactant: CNC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)C(CCN(C)C)c1ccccc1
Yield: 83.5 %

Procedure:
To 7.46 g (0.05 mol) of N-methyl phenylacetamide (prepared by reaction of phenylacetyl chloride with monomethylamine in CH2Cl2 solvent) dissolved in 70 ml of THF and cooled in an ice-bath to 0°, was added dropwise with stirring under N2, 40 ml (0.10 mol) of a 2.5M solution of N-BuLi in n-hexane. After stirring at 0° for 30 min, the solution was treated by the rapid addition of 5.4 g (0.05 mol) of 2-(dimethylamino)ethyl chloride in 30 ml of THF and then stirred at 0° for 30 min. The reaction mixture was then poured into 250 ml of 1N HCl, ether was added and the aqueous layer was separated, basified with 2.5N NaOH and extracted with Et2O. The ether extract was dried (Na2SO4), concentrated, and kugelrohr distilled to afford 9.2 g (83.5%) of N-methyl-4-dimethylamino-2-phenylbutanamide as a viscous, colorless oil; bp 130°-135°/0.1 mm.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=3)[C:12](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:27])[N:5]=2)[CH3:3])=[N:34][CH:33]=1
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (50 mg, 0.13 mmol, 1.0 equiv) in t-BuOH (0.13 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (24 mg, 0.16 mmol, 1.2 equiv) and diisopropylethylamine (46 μL, 0.26 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 18 mg of the title compound (28% yield).
Reaction SMILES: Cl.[C:2]([CH:7]1[CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:17])[N:11]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:20]=[C:10]3[C:9]=2[CH2:8]1)([O:4][CH2:5][CH3:6])=[O:3].[CH3:28]C(O)C>>[C:2]([CH:7]1[CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:17])[N:11]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:20]=[C:10]3[C:9]=2[CH2:8]1)([O:4][CH:5]([CH3:28])[CH3:6])=[O:3]
Reactant: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 150 °C

Procedure:
To 10 mL of 2-propanol saturated with HCl gas was added 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (100 mg) and the mixture was heated in a sealed tube at 150° C. for 1 h. The reaction was cooled and the solvent was evaporated in vacuo. To the reaction mixture was added 10 mL of H2O and the mixture was then brought to pH 7 with ammonium hydroxide. The solid was collected and dried to yield 9-Carboisopropoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydroimidazo[1,2-c]-quinazolin-5(6H)-one (Compound 14), m.p. 282°-285° C.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[N:11]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][CH2:3]1)=[O:12]
Reactant: c1ccc2c(c1)NCCS2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCSc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of 3,4-dihydro-2H-1,4-benzothiazine (50.0 g, 330.8 mmol) in acetic acid (170 mL.), cooled at −10° C. in an ice/acetone bath, was added sodium nitrite (27.4 g, 397.1 mmol) in 75 mL of water over 35 min. After the addition, the mixture was warmed to room temperature and stirred for additional 1.5 hours. Cold water (150 mL) was added and the resulting mixture was extracted with dichloromethane (4×250 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 4-nitroso-3,4-dihydro-2H-1,4-benzothiazine as a semi-solid (60.26 g, 101%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ2.99-3.05 (m, 2 H), 4.16-4.24 (m, 2 H), 7.15-7.31 (m, 3 H), 7.88-7.97 (m, 1 H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([SH:23])[N:18]=1>O>[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:12]([Cl:15])([Cl:14])[Cl:13])[N:18]=1
Reactant: Oc1ccnc(S)n1
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: O
Product: O=[N+]([O-])c1ccc(SSc2nccc(O)n2)c(C(Cl)(Cl)Cl)c1
Yield: 94.1 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride are reacted with 26.6 g of 4-hydroxy-2-mercaptopyrimidine by a method similar to that described in Example 7. Water is then added and the product is filtered off. 75 g (94% of theory) of 4-hydroxypyrimidin-2-yl-dithio-(4-nitro-2-trichloromethylbenzene), of melting point 174° C., are obtained.
Reaction SMILES: C([O:3][CH:4]=[C:5](C(OCC)=O)[C:6](OCC)=O)C.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>Cl>[Br:16][C:17]1[CH:18]=[C:19]2[C:21]([C:4]([OH:3])=[CH:5][CH:6]=[N:20]2)=[CH:22][CH:23]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(Br)c1
Agent: Cl
Product: Oc1ccnc2cc(Br)ccc12
Temperature: 125 °C
Yield: 94.6 %

Procedure:
Diethyl ethoxymethylenemalonate (677 g, 3.13 moles (mol)) was added to 3-bromoaniline (491 g, 2.85 mol) over a period of one hour, the temperature rose to 60° C. during the addition. The reaction was then heated at 115° C. for 30 minutes, 125° C. for 30 minutes, and 140° C. for 15 minutes while ethanol was distilled from the reaction. The reaction temperature was adjusted to 130° C., and the reaction mixture was added over a period of 45 minutes to heated DOWTHERM A heat transfer fluid (5 liters (L), 250° C.) while maintaining the temperature of the heat transfer fluid between 242° C. and 250° C. A precipitate formed at the end of the addition. The reaction mixture was heated at about 250° C. for one hour and then cooled to 80° C. Concentrated hydrochloric acid (500 mL) was added, and the reaction mixture was heated at 110° C. for five hours, 125° C. for two hours, and 150° C. for an addition two hours, and then allowed to cool to room temperature overnight. The mixture was then heated to 200° C. over a period of two hours, further heated to 250° C., maintained at 250° C. for one hour, and allowed to cool to room temperature. A precipitate was present and was isolated by filtration, washed sequentially with heptane (2 L), ethanol (1 L), and diethyl ether (1 L) to provide 604 g of 7-bromo quinolin-4-ol as a dark red solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1[C:11]1[CH:18]=[CH:17][C:14](C#N)=[CH:13][CH:12]=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2.[F:24][C:25]([F:37])([F:36])[O:26]C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1[C:11]1[CH:18]=[CH:17][C:14]([O:26][C:25]([F:37])([F:36])[F:24])=[CH:13][CH:12]=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C#N)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Yield: 68.2 %

Procedure:
The title compound was prepared by treatment of Step 2 intermediate, Intermediate 22 (2.0 g, 5.845 mmol) with 4-trifluoromethoxyphenylboronic acid (1.684 g, 8.183 mmol) in the presence of Pd[(C6H5)3P]4 (270 mg, 0.233 mmol) and sodium carbonate (3.11 g, 35.07 mmol) in a mixture of toluene, ethanol and water to afford 1.5 g of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.02 (s, 3H), 7.41-7.59 (m, 3H), 7.53-7.56 (m, 3H), 8.03-8.07 (m, 1H), 8.84-8.87 (m, 1H); ESI-MS (m/z) 377.17 (M+H)+.
Reaction SMILES: [OH2:1].[ClH:2].[NH2:3][C@H:4]([C:12]([NH:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([CH3:26])=[CH:20][C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1)=[O:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[NH:11])[NH2:10].N[C@H](C(N[C:39]1[CH:48]=[C:47]2[C:42]([C:43](C)=[CH:44][C:45](=[O:49])O2)=[CH:41][CH:40]=1)=O)CCCNC(=N)N.Cl.C[N:53]([CH:55]=[O:56])C>O.C(O)(=O)C>[ClH:2].[C:55]([NH:53][C@H:44]([C:45]([NH:3][C@H:4]([C:12]([NH:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([CH3:26])=[CH:20][C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1)=[O:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[NH:10])[NH2:11])=[O:49])[CH2:43][C:42]1[CH:41]=[CH:40][CH:39]=[CH:48][CH:47]=1)([O:56][CH2:19][C:18]1[CH:23]=[CH:24][CH:15]=[CH:16][CH:17]=1)=[O:1]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@@H](N)CCCNC(=N)N)ccc12
Reactant: O
Reactant: CN(C)C=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc3ccccc3)NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-L-arginylamino-4-methylcoumarin hydrochloric acid salt hemihydrate (754 mg, 2 mM) was dissolved in a mixture of DMF (10 ml) and water (10 ml), and carbobenzoxy-L-phenylalanine N-hydroxysuccinimide ester (1.03 g, 2.6 mM) was added thereto. This mixture was stirred for 15 hours at room temperature and concentrated to yield a solid material. The material was purified by column chromatography (2×15 cm) using silica gel as adsorbent and a ternary mixture of chloroform, methylalcohol and acetic acid in 95:5:3 volume ratio. The main fraction was concentrated to yield solid material, dissolved in acetic acid (30 ml) and lyophilized to give 7-(Nα -carbobenzoxy-L-phenylalanyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [XV] (920 mg).
Reaction SMILES: O[C@@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[N:47]([C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(C[C@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To a suspension of 8-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 8, 500 mg, 1.13 mmol) and diphenylphosphoryl azide (643 mg, 1.36 mmol) in a mixed solvent of toluene and dichloromethane (v:v, 10:1, 11 mL) was added DBU (343 mg, 2.26 mmol). The reaction mixture was stirred at 35° C. for 20 h. The solvent was removed by evaporation and the residue was purified by flash column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 5.26 (s, 2H), 5.23 (s, 2H), 4.99 (dd, J=4.0 Hz, 9.2 Hz, 1H), 4.00 (t, J=6.8 Hz, 2H), 2.95-2.87 (m, 2H), 2.78-2.73 (m, 1H), 2.60-2.57 (m, 1H), 2.48-2.43 (m, 1H), 2.33 (s, 3H), 2.10 (t, J=6.8 Hz, 2H), 2.03-1.86 (m, 6H), 1.51-1.48 (m, 2H); MS-ESI (m/z): 466 (M+1)+.
Reaction SMILES: C[C:2]12[CH:8]3[C:9]([O:11][C:12](=O)[CH:7]3[CH:4]([CH:5]=[CH:6]1)C2)=O>CC(OOC(=O)C1C=CC=CC=1)(CCC(C)(OOC(=O)C1C=CC=CC=1)C)C>[O:11]1[C:12]([C:7]2[CH:4]=[CH:5][CH:6]=[CH:2][CH:8]=2)=[CH:9]1
Reactant: CC12C=CC(C1)C1C(=O)OC(=O)C12
Agent: CC(C)(CCC(C)(C)OOC(=O)c1ccccc1)OOC(=O)c1ccccc1
Product: C1=C(c2ccccc2)O1

Procedure:
To this inhibited epoxy diester-styrene mixture 5.49 parts of NADIC methyl anhydride, 0.048 part of 2,5-dimethyl-2,5 bis(benzoyl peroxy) hexane catalyst (sold by Wallace & Tierman Inc. under the tradename of Luperox 118), and 0.05 part of zinc ethyl hexoate catalyst were added, at 25° C., to provide the solventless epoxy-styrene varnish. The viscosity of the epoxy-styrene resin was measured to be about 200 cps at 25° C.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:13]([OH:15])=O)=O)C1C=CC=CC=1.[NH2:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26]>>[NH2:11][CH:12]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:13]([NH:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26])=[O:15]
Reactant: O=C(NC(Cc1ccco1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: NC(Cc1ccco1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of (RS)-α-(1-benzyloxyformamido)-3-(furan-2-yl)propionic acid [J. Biol. Chem. 171, 383 (1947)]and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by catalytic hydrogenation there was obtained rac-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(furan-2-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8]=O)=[CH:6][NH:5][N:4]=1)[CH3:2].[C:10]([O:19]CC)(=O)[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:22]C([O-])(C)C.[K+]>C(O)(C)(C)C>[CH2:1]([C:3]1[C:7]([CH:8]=[C:12]([CH2:11][C:10](=[O:19])[CH3:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]cc1C=O
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=Cc1c[nH]nc1CC)CC(C)=O
Temperature: 80 °C
Yield: 88.8 %

Procedure:
To a solution of 3-ethyl-1H-pyrazole-4-carbaldehyde (2.2 g, 18 mmol) and diethyl succinate (12.3 g, 71.0 mmol) in t-butanol (15 mL) was added a solution of t-BuOK (8.08 g, 53.2 mmol) in t-butanol (10 mL). The mixture was heated to 80° C. for 3 hours before the mixture was concentrated. The obtained residue was dissolved in water (30 mL), acidified (pH˜2) using 6 N HCl and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with aqueous NaHCO3 (2×50 mL). The combined aqueous layers were acidified (pH˜2) and extracted with ethyl acetate (2×75 mL). The combined ethyl acetate layers were washed with saturated aqueous NaCl (25 mL), dried over anhydrous Na2SO4 and concentrated to afford ethyl 2-[(3-ethyl-1H-pyrazol-4-yl)methylene]-4-oxopentanoate (4 g, 100%) as gum, which was taken as such into next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[CH2:37][CH3:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:39][CH2:36][CH2:37][CH3:38])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: CCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propylamine (20 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 9 mg (yield 14%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
0.24 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)-2H-pyridazin-3-one and 3 g phosphorus oxychloride were mixed. The mixture was stirred for 1 hour on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 0.25 g 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)pyridazine (hereinafter, described as compound (1) of the present invention.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O1CCOCC1>Cl[Pd]Cl.O>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]3)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(-c3ccncc3)ccc2[nH]1

Procedure:
A solution of 5-bromo-1H-indole-2-carboxylic acid (25 mg), PdCl2 HPNor2 (5 mg), K3PO4 (45 mg), 4-pyridylboronic acid (26 mg), dioxane (1 mL) and H2O (1 mL) was heated to 170° C. in a microwave for 2 h. The solution was passed thru a C18-SPE cartridge eluting with 3, 20, 60, and finally 95% CH3CN in H2O to yield the crude product. LCMS (m/z): 239.1 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.O>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
2-(2-Chloro-4-nitro-phenoxymethyl)-thiazole is prepared by adding thiazol-2-yl-methanol (2.74 g, 23.76 mmol) to a slurry of sodium hydride (1.21 g of a 60% dispersion in oil, 30.2 mmol) in DMF (10 ml) at 0° C. After several minutes, 2-chloro-1-fluoro-4-nitro-benzene (3.79 g, 21.60 mmol) is added and the reaction mixture warmed to room temperature. The reaction mixture is stirred at room temperature for 3 h, and 60° C. for 16 h. After cooling to room temperature, the reaction mixture is poured into 200 ml water. The resulting precipitate is collected by filtration, washed with water, and dried in vacuo to give 2-(2-chloro-4-nitro-phenoxymethyl)-thiazole (5.80 g, 99%) which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[N:4]([CH3:21])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:23][C:7]1[N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[N:4]([CH3:21])[C:3](=[O:22])[C:2]=1[OH:1]
Reactant: Cn1c(-c2ccc(Oc3ccccc3)cc2)ncc(O)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cn1c(-c2ccc(Oc3ccccc3)cc2)nc(Cl)c(O)c1=O
Temperature: 50 °C
Yield: 17.9 %

Procedure:
To a solution of 50 mg (0.170 mmol) 5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one in 850 μl CH2Cl2 was added 23.8 mg (0.178 mmol) N-chlorosuccinimide. The reaction mixture was heated to 50° C. for 12 h, then cooled to rt, and concentrated in vacuo. Purification by HPLC gave 10.0 mg (18% yield) of 6-chloro-5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one. 1H NMR δ (ppm) (CDCl3): 7.48-7.46 (2H, m), 7.41-7.38 (2H, m), 7.19 (1H, d, J=7.56 Hz), 7.09-7.05 (4H, m), 6.43 (1H, bs), 3.56 (3H, s). FIRMS (ESI positive) calc (M+H)+=329.0687 found 329.0693.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([OH:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[C:7]([O:13][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:18][CH3:15])=[CH:7][CH:6]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)c(O)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CBr)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c(OCc2ccc(OC)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 198.1 %

Procedure:
To a solution of 3,4-dihydroxy-6-chlorobenzoic acid ethyl ester (52.7 g: 243 mMol.) in dimethylformamide (170 ml) are added potassium carbonate (105 g; 3.1 Eq.) and p-methoxybenzyl bromide (151 g: 3.1 Eq.), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ice water and filtered to collect the resulting precipitate, which is washed with methanol and water to give 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid ethyl ester (110 g). Yield: 99%.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2.5 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (726 mg, 2.76 mmol), 4-nitrobenzoic acid (462 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 2.5 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was then carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (579 mg, yield: 90%/(S)-2-octanol).