Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(Cl)nn2)cn1
Temperature: 70 °C
Yield: 46.3 %

Procedure:
A mixture of 3,6-dichloro-pyridazine (1.06 g, 6.98 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.47 g, 5.0 mmol) in 2.0 M potassium carbonate (10 mL, 20 mmol) and 1,4-dioxane (40 mL) was degassed by house vacuum for 15 min followed by bubbling with argon for ˜10 min, Peppsi-ipr (340 mg, 0.5 mmol) was then added. After flushing with argon for another ˜10 min, the mixture was heated at 70° C. for 4 h and allowed to cool to room temperature. The solid was removed by filtration through Celite, and the filtrate was separated. The aqueous solution was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, concentrated, and purified by column to provide 0.65 g desired product (46%). 1H NMR (DMSO) δ 9.08 (s, 1H), 8.47 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 1.59 (s, 3H); MS (ES) m/z 280.8(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:40]=[C:39]([CH2:41][N:42]3[CH:46]=[CH:45][CH:44]=[N:43]3)[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:40]=[C:39]([CH2:41][N:42]6[CH:46]=[CH:45][CH:44]=[N:43]6)[C:33]6[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(Cn3cccn3)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(Cn5cccn5)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
140 mg (0.508 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 210 mg (0.284 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-4-pyrazol-1-ylmethyl-3H-benzoxazol-2-one and 0.100 mL (0.581 mmol) DIPEA were combined in 1.0 mL DMF and stirred for 48 h at RT. Then the reaction mixture was purified several times by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=[CH:32][CH:33]=1)CBr.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:40][N:41](C=O)[CH3:42]>O>[CH3:40][N:41]([CH3:42])[CH2:32][CH2:33][O:24][CH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reactant: CN(C)C=O
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CN(C)CCOCc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(1-naphthylsulfonyl)-1H-indazole-5-carbaldehyde (0.17 g, 0.5 mmoles), 3-chlorobenzyl bromide (0.07 mL, 0.6 mmoles), and cesium carbonate (0.19 g, 0.6 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by normal phase HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.18 g, 0.4 mmoles).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[C:15]3[CH2:20][CH2:19][CH2:18][N:17]=[C:16]3[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:28]>ClCCl>[BrH:28].[BrH:28].[N:17]1[CH2:18][CH2:19][CH2:20][C:15](=[CH:14][C:12]2[S:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[C:16]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)s2)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Oc1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)s2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a −70° C. solution of 3-[5-(4-methoxyphenyl)thiophen-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl (20 mg, 0.05 mmol) in anhydrous dichloromethane (5 mL) was added 1.0 M BBr3 in dichloromethane (0.5 mL). The reaction mixture was maintained under an atmosphere of N2 at rt. for 6 h and an additional 0.5 ml BBr3 solution was added. The reaction mixture was maintained over night and was quenched with anhydrous methanol (1 mL) at −40° C., and was concentrated to 1 ml. This procedure was repeated twice and the residue was dried under high vacuum. The solid obtained was washed with ethyl acetate and was isolated, thus providing 15 mg of an orange solid.: 1H NMR (DMSO-d6) δ 8.89 (m, 2H), 8.08 (m, 1H), 7.70 (m, 6H), 6.85 (m, 2H), 3.76 (m, 2H), 2.97 (m, 2H), 2.13 (m, 2H); MS (EI) m/z 347 (M++1).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:27]([O:26][C:22](=[O:25])/[CH:23]=[CH:24]/[N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:13]1=[O:21])[CH3:28]
Reactant: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Reactant: C#CC(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a solution of 1-Naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (0.5 g, 1.8 mmol) in DMF (4 mL) were added ethyl propiolate (0.28 mL, 2.7 mmol) and DMAP (0.22 mL), 1.8 mmol). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture turned dark brown in color. The reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated to afford 0.68 g of the desired product as a dark brown foam. This crude product was used for the next reaction without further purification. LCMS (ESMS): m/z 373.33 (M+H+).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.Cl.[NH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[OH:12][N:11]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C=NO)cc1
Yield: 74 %

Procedure:
To a solution of 4-tolualdehyde (600 mg, 5 mmol) in tetrahydrofuran (3 ml) was added hydroxylamine hydrochloride (700 mg, 10 mmol) and triethylamine (1.4 ml, 10 mmol). The reaction was subjected to microwave; absorbance normal; temp: 150° C.; time; 600 (s). The solid material was filtered off, and solvent removed from the filtrate under reduced pressure. The residue was purified using column chromatography (2:1 Hexanes:Ethyl Acetate) to provide (hydroxyimino)(4-methylphenyl)methane (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.Cl[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32]>>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:31]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)=[O:32]
Reactant: COCCOC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: COCCOC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and 2-methoxyethyl chloroformate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl.[NH2:12][OH:13].[C-:14]#[N:15].[Na+]>>[OH2:1].[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]([OH:6])[C:14](=[N:12][OH:13])[NH2:15]
Reactant: [C-]#N
Reactant: NO
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Product: NC(=NO)C(O)c1ccc(O)c(O)c1
Product: O
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Seven and eight-tenths grams of 3,4-dihydroxybenzaldehyde were added to 100 ml. of an aqueous solution held at -15° C. containing 7.8 g. of hydroxylamine hydrochloride and 5.5 g. of sodium cyanide. The reaction mixture was stirred overnight at about 0° C. and then filtered. Four g. of 3,4-dihydroxymandelamidoxime monohydrate formed in the above reaction were obtained melting at 151° C. with decomposition (after loss of water of crystallization at about 120° C.) yield=36%
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH:24]([CH3:26])[NH:23][C:22]2=[O:27])[CH2:3]1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][S:35]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH:24]([CH3:26])[NH:23][C:22]2=[O:27])[CH2:3]1)(=[O:37])=[O:36]
Reactant: CC1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (4.30 g) in dichloromethane (50 ml) were added successively pyridine (1.1 ml), 4-(N,N-dimethylamino)pyridine (1.39 g) and methanesulfonyl chloride (0.97 ml) under ice-cooling and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.76 g).
Reaction SMILES: N(O[CH2:4][CH2:5][CH:6](C)C)=O.[C:9]([OH:18])(=O)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)N.O1C=CC=C1.[OH-].[Na+]>C(COC)OC>[CH:15]1[CH:16]=[C:10]2[C:11]([CH:6]3[O:18][CH:9]2[CH:4]=[CH:5]3)=[CH:13][CH:14]=1
Reactant: CC(C)CCON=O
Reactant: Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccoc1
Solvent: COCCOC
Product: C1=CC2OC1c1ccccc12
Yield: 51 %

Procedure:
Solutions of 20 ml of isoamyl nitrite in glyme (20 ml) and of 13.7 g of anthranilic acid in glyme (45 ml) were added simultaneously by drops to a refluxing mixture of glyme (50 ml) and furan (50 ml). Refluxing was continued for ten minutes and the brown solution was cooled, made basic with aqueous sodium hydroxide (1 N), and extracted with petroleum ether. The extract was washed thoroughly with water, clarified with Norit®, dried, and evaporated to give an oil. The oil solidified on cooling to give 7 g (51% yield) of light yellow solid. Recrystalization of the yellow solid from petroleum ether gave colorless crystalline solid of 1,4-dihydronaphthalene-1,4-endo-oxide (IIIa), m.p. 53°-54° C. (lit. m. p. 56° C.).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCCN1CCCC1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCN3CCCC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(2-aminoethyl)pyrrolidine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (CDCl3) δ 12.80 (1H, br), 10.44 (1H, t, J=6 Hz), 8.60 (1H, d, J=1 Hz), 7.81 (2H, d, J=8.2 Hz), 7.30 (3H, m), 7.19 (2H, d, J=8.2 Hz), 7.06 (1H, s), 7.01 (2H, m), 5.41 (2H, br), 4.05 (2H, s), 4.02 (2H, q, J=6.6 Hz), 3.87 (2H, br), 3.36 (2H, t, J=7 Hz), 3.02 (3H, s), 2.89 (2H, m), 2.24 (2H, br), 2.10 (2H, br); HRMS calcd for C30H32N4O5S+H+: 561.2172. Found: 561.2166.
Reaction SMILES: [C:1]1([C:11]([O-:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+].[CH2:16]1[CH2:20]OC[CH2:17]1>O>[CH:16]([O:14][C:3]1[CH:2]=[C:1]([C:11]([OH:13])=[O:12])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:20])[CH3:17]
Reactant: O=C([O-])c1cccc2ccccc12
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(C(=O)O)c2ccccc2c1
Yield: 94 %

Procedure:
A solution of methyl 3-isopropoxy)-naphthalenecarboxylate (0.60 g, 2.46 mmol) in THF (30 mL), water (12 mL) and 1N NaOH (5.16 mL, 5.16 mmol) was stirred for 21 h at room temperature. The THF was removed in vacuo and the aqueous solution acidified to pH 1 with 1N HCl. The resulting precipitate was extracted with EtOAc, dried (MgSO4), filtered and concentrated to yield title acid as a white solid (0.53 g, 94% yield). 1H NMR (DMSO-d6) δ 13.22 (s, 1H), 8.71 (d, 1H), 7.90 (d, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7.47 (m, 2H), 4.81 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H). MS rm/z 229 (M−H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44]O)=[N:41][CH:42]=1)[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:44][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:35][CH3:36])=[CH:42][N:41]=3)=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1ccc(CCO)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2ncc(OCCc3ccc(CC)cn3)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (50 mg, 0.111 mmol), 2-(5-ethylpyridin-2-yl)ethanol (16.8 mg, 0.111 mmol) and triphenylphosphine (44 mg, 0.167 mmol) were dried for 3 hrs in vacuo, purged with argon, added tetrahydrofuran (1 mL) and diethyl azodicarboxylic acid (2.2 mol/L toluene solution, 76 μL, 0.167 mmol), and stirred at room temperature for 2 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 4′-{[4-butyl-1-{5-[2-(5-ethylpyridin-2-yl)ethoxy]pyrimidin-2-yl}-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl]biphenyl-2-carbonitrile (49 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N12CCCN=C1CCCC[CH2:13]2.IC>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (75 g, 0.48 mol) in acetone (700 mL) was cooled in an ice-water bath. 1,8-Diazabicyclo[5,4,0]undec-7-ene (145 g, 0.96 mol) was then added over ca. 5 min. Finally, iodomethane (135 g, 0.96 mol) was added over 10 min. The mixture was stirred at room temperature for 16 hr. Additional 1,8-diazabicyclo[5,4,0]undec-7-ene (73 g, 0.48 mol) and iodomethane (68 g, 0.48 mol) were added, and the mixture was warmed to 50° C. for 1 hr. After a solid was removed by filtration, the concentrated filtrate was mixed with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with additional hydrochloric acid and aqueous sodium bicarbonate, concentrated, and stirred in 1% ethyl acetate in hexanes. The resulting solid was collected and dried to give 72 g (88%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[N:10]=2)[N:3]=1.[CH3:25][O-:26].[Na+].CO.[Na]>C(Cl)(Cl)Cl.O>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[N:10]=[C:9]([C:4]3[N:3]=[C:2]([O:26][CH3:25])[CH:7]=[C:6]([CH3:8])[N:5]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:17][CH:18]=1)[CH3:24]
Reactant: C[O-]
Reactant: CCOc1ccc(Oc2cccc(-c3nc(C)cc(Cl)n3)n2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOc1ccc(Oc2cccc(-c3nc(C)cc(OC)n3)n2)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To 4-chloro-2-(6-p-ethoxyphenyloxy-2-pyridinyl)-6-methylpyrimidine (3 g) was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.22 g). After the mixture was left to stand at room temperature for 30 minutes, water (30 ml) and chloroform (100 ml) were added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 2-(6-p-ethoxyphenyloxy-2-pyridinyl)-4-methoxy-6-methylpyrimidine (2.7 g, yield 91%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a suspension of 7-hydroxy-1-tetralone (1.0 g, 0.0061 mol) and K2CO3 (5.5 g) in DMF (20 mL) under an argon atmosphere was added benzyl bromide (0.725 mL, 0.0061 mol) at room temperature. The reaction mixture was then stirred at room temperature for 18 h before being poured onto ice. The aqueous solution was extracted with ethyl acetate, washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate-hexane (15%) as eluent to give compound 7-benzyloxy-1-tetralone (1.395 g, 90%): thick oil, 1H NMR (500 MHz, CDCl3): δ 2.09-2.14 (m, 2H), 2.63 (d, J=6.5 Hz, 2H), 2.90 (d, J=6.0 Hz, 2H), 5.75 (s, 2H), 7.11-7.13 (dd, J=3.0 and 8.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.31-7.45 (m, 5H), 7.62 (d, J=3.0 Hz, 1H). HFABMS m/z 253.1231 (calc for C17H16O2, MH+, 253.1229).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([CH2:25][OH:26])[C:16]1=[O:27])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:11]([N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([CH:25]=[O:26])[C:16]1=[O:27])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1c2c(cc(CO)c1=O)CCCC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1c2c(cc(C=O)c1=O)CCCC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
DMSO (0.54 mL, 7.64 mmol) was dissolved in methylene chloride (27 mL) and the solvent was cooled at −78° C. To the solvent were added dropwise oxalyl chloride (0.4 mL, 4.58 mL), a solution of 1-butyl-3-hydroxymethyl-5,6,7,8-tetrahydro-1H-quinoline-2-one (1-015-03) (0.9 g, 3.82 mmol) in methylene chloride (20 mL) and triethylamine (1.33 mL, 9.55 mmol), and then the reaction mixture was stirred at −78° C. for 5 min. The reaction mixture was gradually warmed to room temperature, and stirred at room temperature for 20 min. To the reaction mixture was added 1 mol/L diluted hydrochloric acid (50 mL), and the reaction mixture was extracted with ethyl acetate (200 mL), washed with aqueous saturated sodium hydrogen carbonate solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboaldehyde (1-015-04) (0.5 g, 56%) as a pale yellow bubbly substance.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH:25]([F:42])[O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1>>[F:24][CH:25]([F:42])[O:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(OC(F)F)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC(F)F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 183.1.1) to give the title compound as a white foam. (HPLC: tR 2.48 min (Method A); M+H=437 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.61-8.59 (m, 1H), 8.52-8.50 (m, 1H), 8.17-8.13 (m, 2H), 8.02-7.98 (m, 1H), 7.74-7.71 (m, 1H), 7.61-7.59 (m, 1H), 7.39 (t, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 1.95 (s, 3H))