Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][NH:11][C:10]2=[O:19]>O>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][NH:11][C:10]2=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Temperature: 120 °C
Yield: 32 %

Procedure:
Fuming nitric acid (47 ml) was added to 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (10 g, 48 mmol), in water (40 ml). The reaction mixture was heated at 120° C. for 1 hour, then allowed to cool and diluted with water. The resulting precipitate was collected by filtration, washed with water and dried to give 6,7-dimethoxy-5-nitro-3,4-dihydroquinazolin-4-one (3.9 g, 32%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:8])=[N:5][NH:6][CH:7]=1)[CH3:2].[Br:9][CH:10]([CH:13]=O)[CH:11]=O.C(O)(=O)C>C(O)C>[Br:9][C:10]1[CH:11]=[N:8][C:4]2[N:5]([N:6]=[CH:7][C:3]=2[CH2:1][CH3:2])[CH:13]=1
Reactant: O=CC(Br)C=O
Reactant: CCc1c[nH]nc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1cnn2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-ethyl-1H-pyrazol-3-amine (0.50 g, 4.50 mmol) and 2-bromo-malonaldehyde (1.47 g, 9.72 mmol) in ethanol (8.0 mL) was added acetic acid (1.21 mL, 21.2 mmol). The reaction mixture was refluxed for 4 h, then stored in a freezer overnight. The mixture was warmed to rt, the resulting precipitate was removed by filtration and the filtrate concentrated. The resulting residue was portioned between ethyl acetate and 1M sodium hydroxide and the organic layer was washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C8H9BrN3: 226.0 (M+H+); Found: 226.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][C@@H:25]([CH2:27][C:28]([O:30]CC)=[O:29])[C:24]4[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=4[CH2:22][C:21]=3[CH:37]=2)[CH:7]=1)[CH3:4].Cl>C(O)C>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][C@@H:25]([CH2:27][C:28]([OH:30])=[O:29])[C:24]4[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=4[CH2:22][C:21]=3[CH:37]=2)[CH:7]=1)[CH3:4]
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(OCC)ccn3)cc2Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2[C@H](CC(=O)O)C3)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 101.4 %

Procedure:
1.0 N NaOH (2.0 mL, 2.0 mmole) was added to a solution of ethyl (S)-10,11-dihydro-3-[3-(4-ethoxypyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (475.2 mg, 1.0 mmol) in absolute ethanol (10 mL), and the solution was warmed at 50° C. in an oil bath. After 20 hr, the reaction was concentrated and the aqueous residue was cooled to 0° C. in an ice bath. 1.0 N aqueous HCl (2.0 mL, 2.0 mmole) was slowly added with stirring. An opaque solid residue precipitated and was collected on a sintered glass funnel. Drying in a vacuum desiccator overnight gave the title compound (452.6 mg, 83%): MS (ES) m/e 447 (M+H)+. Anal. Calcd for C27H30N2O4.0.20 H2O.1.75 HCl: C, 63.10; H, 6.30; N, 5.45. Found: C, 63.10; H, 5.98; N, 5.38.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[C:49]([CH3:55])=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][CH:54]=[C:48]([F:47])[C:49]=4[CH3:55])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N)cccc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(F)c2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoro-2-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 772 [(M+H)+].
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[CH:2]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>O1CCCC1>[CH2:27]=[CH:26][C:25]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:28]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Irgasan® DP300 5-chloro-2-(2,4-dichlorophenol) (triclosan), 23.5 g (0.081 mol) was dissolved in 300 ml of dry tetrahydrofuran in a 1-I jacketed kettle with agitator, addition funnel and reflux condenser. Then 10.6 ml of triethylamine was added to the solution with agitation. To the resulting solution was added dropwise 6.68 (0.0738 mol) g of acryloyl chloride. The reaction temperature was maintained at 20° C. with a circulating cooling bath. After the addition of acryloyl chloride was completed, the agitation and temperature conditions were maintained for 5 hours. Then the reaction product was kept overnight at room temperature, filtered to remove solid triethylamine hydrochloride and the filtrate rotovapped at room temperature under 100-110 mm Hg to concentrate the product. The remaining solution was dissolved in 100 ml heptane and washed with 5% Na2CO3 solution in DI water until basic; then with DI water until neutral. The heptane solution of the product was dried with MgSO4 in a refrigerator overnight, and filtered. The filtrate contained 25.3% triclosan acrylate as determined by bromination. FTIR spectrum confirmed the presence of the unsaturated ester of a phenol (1753 cm−1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[OH:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][CH2:33]O)=[CH:30][CH:29]=1.I.N1C=CN=C1>O.ClCCl>[I:25][CH2:33][CH2:32][C:31]1[CH:35]=[CH:36][C:28]([OH:27])=[CH:29][CH:30]=1
Reactant: OCCc1ccc(O)cc1
Reactant: II
Agent: I
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triphenylphosphine (1.57 g, 0.006 mol) and imidazole (0.41 g, 0.006 mol) were added to dry dichloromethane (20 ml). When the imidazole was in solution iodine (1.52 g, 0.006 mol) was added. After precipitation of the imidazole hydroiodide (4-hydroxyphenethyl) alcohol (0.69 g, 0.005 mol) was added. The mixture was stirred at room temperature for 4 h. Then water was added and the mixture was extracted with dichloromethane. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate as a gradient eluent 9:1-6:4) gave a pure product. 1H NMR (400 MHz, DMSO-d6): 2.99 (2H, t, 3J=7.6 Hz), 3.38 (2H, t, 3J=7.6 Hz), 6.68 (2H, d, 3J=8.5 Hz), 7.03 (2H, d, 3J=8.5 Hz), 9.24 (1H, s, —OH).
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1.[ClH:38].CCOCC>O1CCOCC1>[ClH:38].[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4ccc(OC(F)F)cc4)n3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1ccn(-c2ccc(OC(F)F)cc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-(difluoromethoxy)phenyl)-1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (130 mg, 0.25 mmol) was dissolved in dioxane (0.6 ml) and a solution of HCl in dioxane (4M, 0.12 ml, 3.8 mmol) was added. The reaction mixture was stirred overnight at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo to afford (S)-1-(4-(difluoromethoxy)phenyl)-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide hydrochloride (90 mg, 79%) as an off-white solid. MS (ISP): 415.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NC1CCOCC1
Reactant: Fc1ccc2ncc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnc2ccc(NC3CCOCC3)nn12
Temperature: 40 °C
Yield: 81.6 %

Procedure:
A mixture of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.4 g, 6.6 mmol), tetrahydro-2H-pyran-4-amine (1.0 g, 9.9 mmol), cesium carbonate (4.3 g, 13 mmol), and DMF (10 mL) was maintained at 40° C. for 16 h, then cooled to RT and partitioned between ethyl acetate (100 mL) and H2O (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (4×40 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by flash chromatography (SiO2) to afford 3-bromo-N-(tetrahydro-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine (1.6 g, 80%) as a light yellow solid: 1H NMR (400 MHz, MeOD-d4) δ 7.58 (d, J=9.9 Hz, 1H), 7.42 (s, 2H), 6.71 (d, J=9.9 Hz, 1H), 3.95-4.08 (m, 3H), 3.60 (td, J=11.5, 2.3 Hz, 2H), 2.16 (d, J=11.5 Hz, 2H), 1.53-1.69 (m, 2H); LCMS (ESI) m/e 297.1 [(M+H)+, calcd for C11H13BrN4O 297.0].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[CH2:9][C@H:10]([OH:12])[CH3:11])[CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][C@@H:10]([CH2:9]/[CH:8]=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C[C@@H](O)C/C=C/c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol (6.00 g, 36.81 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (21.05 g, 110.43 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 11.67 g (84.0%) of a dark-brown, viscous oil.
Reaction SMILES: [Si](OCC[CH:11]1[N:22]2[C:23]3[C:19]([CH:20]=[CH:21]2)=[C:18]([C:24]([F:27])([F:26])[F:25])[C:17]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:16][C:15]=3[CH2:14][NH:13][CH2:12]1)(C(C)(C)C)(C)C.Cl.C1C[O:40][CH2:39][CH2:38]1>>[CH2:28]([C:17]1[C:18]([C:24]([F:26])([F:25])[F:27])=[C:19]2[C:23]3=[C:15]([CH2:14][NH:13][CH:12]([CH2:38][CH2:39][OH:40])[CH2:11][N:22]3[CH:21]=[CH:20]2)[CH:16]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CNCc2cc(CCc3ccccc3)c(C(F)(F)F)c3ccn1c23
Reactant: C1CCOC1
Agent: Cl
Product: OCCC1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-((tert-butyldimethylsilyl)oxy)ethyl-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (107 mg, 0.21 mmol) in THF was added conc. HCl (2 mL) at 0° C. and the resulting mixture stirred for 1 h. Purification by reverse-phase chromatography (25→90% CH3CN—H2O-TFA) yielded 2-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethanol (50 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:18][CH:19]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 97.5 %

Procedure:
Using aniline (1.50 ml, 16.5 mmol) and 4-nitrobenzoic acid (1.77 g, 10.5 mmol), the procedure of Reference Example 16 was repeated to obtain 2.48 g (97.5%) of the title compound in the form of colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCCCCC.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[CH3:9])=[C:4]([Sn:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1[Sn](C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-chloro N-pivaloylaniline* (2.11 g, 10 mmol) in 30 ml of dry THF was cooled in an ice bath under an atmosphere of nitrogen. Then an hexane solution of 1.6M of n-Buli (15.625 ml, 25 mmol) was added dropwise. After stirring at 0° C. for 2.5 h, trimethyltin chloride (2.19 g, 11 mmol) dissolved in dry THF (8 ml) was added within 20 min at 0° C. The reaction was then stirred for 2 h at 0° C. and for 16 h at room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (di-isopropylether: petroleum ether 40°/70°=10:23) to yield 4-chloro-2-trimethylstannyl-N-pivaloylaniline as a white solid 3.1 g; 82.9%; m.p. 169°-172° C.).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O>[OH-].[NH4+]>[Cl:17][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(-c2ccccc2)cc(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1nc(Cl)cc(-c2ccccc2)n1
Temperature: 70 °C
Yield: 86.1 %

Procedure:
A stirred suspension of 3.69 g (19.7 mmol) 2-amino-6-phenyl-3H-pyrimidin-4-one in 4.5 ml (49.2 mmol) phosphorus oxychloride was heated at reflux for 2 h. The reaction mixture was then cooled to about 70° C. and poured cautiously onto 20 ml rapidly stirred ice-water. The mixture was briefly warmed to room temperature and then was recooled to 0° C. 100 ml 25% ammonium hydroxide solution was added and the resulting crystals were collected by filtration and washed with ice-cold water and then with a little ether to afford 3.49 g (86%) 4-chloro-6-phenyl-pyrimidin-2-ylamine as a pale yellow crystalline solid. EI-MS m/e (%): 207 (M{37Cl}+, 35), 206 ([M{37Cl}—H]+, 30)., 205 (M{35Cl}+, 100), 204 ([M{35Cl}—H]+, 56), 170 ([M—Cl]+, 35), 128 (([M—C6H5]+, 85).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][C@H:25]([CH3:45])[O:26][C:27]1[CH:28]=[C:29]([OH:44])[CH:30]=[C:31]([C:33]2[NH:34][C:35]([C:38]3[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=3)=[CH:36][CH:37]=2)[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:44][C:29]3[CH:30]=[C:31]([C:33]4[NH:34][C:35]([C:38]5[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=5)=[CH:36][CH:37]=4)[CH:32]=[C:27]([O:26][C@@H:25]([CH3:45])[CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (228 mg, 0.70 mmol) synthesized in Example (121b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (293 mg, yield 71%) as a white solid.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[Br:10][C:11]1[CH:12]=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=[C:15]2[C:19]=1[NH:18][N:17]=[CH:16]2>C(OCC)(=O)C>[Br:10][C:11]1[C:19]2[C:15](=[CH:16][N:17]([CH3:6])[N:18]=2)[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2cc([N+](=O)[O-])cc(Br)c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Trimethyloxonium tetrafluoroborate (1.5 g) was added to a solution of 7-bromo-5-nitro-1H-indazole (1.21 g) in ethyl acetate (12 mL), and the reaction solution was stirred at room temperature for 6 hours. After dilution with ethyl acetate, the reaction solution was washed successively with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum, ethyl acetate and isopropyl ether were added to the resultant residue, and the deposited precipitate was filtrated to obtain 7-bromo-2-methyl-5-nitro-2H-indazole as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([OH:14])[CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:14][C:29]2[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=2)[CH:7]=[C:8]([O:10][CH:11]([CH3:12])[CH3:13])[CH:9]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(OC(C)C)c1
Temperature: 115 °C
Yield: 101.1 %

Procedure:
To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (3.20 g, 15.2 mmol) in DMF (80 mL) was added Cs2CO3 (5.45 g, 16.7 mmol) and 4-fluorophenyl methyl sulfone (2.65 g, 15.2 mmol) at rt. The resulting mixture was heated at 115° C. for 12 hr. Then the mixture was concentrated. The resulting residue was partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (2×). Combined organic layers were washed with water (1×), dried and concentrated to a residue, which was purified by silica gel flash chromatography (7.5×30 cm, hexane/EtOAc, v/v 5:1, 2:1, 1:1). Fractions containing the mono-alkylation product were pooled and concentrated to give 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester (5.60 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.90 (d, J=9 Hz, 2H), 7.41 (m, 1H). 7.26 (m, 1H), 7.10 (d, J=9 Hz, 2H), 6.79 (m, 1H), 4.56-4.63 (m, 1H), 3.90 (s, 3H), 3.06 (s, 3H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2].Cl>CO.O1CCOCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:27])([CH3:28])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)C=C(n2ccc(CO)cc2=O)c2cc(C#N)ccc2O1
Yield: 100.2 %

Procedure:
In 10.5 ml of methanol, is dissolved 1.04 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 8. Then, 2.59 ml of a 4N hydrochloric acid in dioxane is added to the solution at 0° C., and the resulting mixture is reacted at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is mixed with ethyl acetate and water and the product is extracted into the ethyl acetate. The organic layer is washed with saturated aqueou solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent to obtain 0.76 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])N)=[CH:5][CH:4]=1.[CH3:21][CH2:22][O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([O:23][CH2:22][CH3:21])=[O:25])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CC(C)c1ccccc1N(N)Cc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C(C)C)cccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-isopropylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>CN(C)C=O>[O:14]=[C:11]1[NH:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[CH2:17][C:16]([CH3:15])=[O:20])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
20 g (0.106 mole) of 3-(4-aminophenyl)-6-oxo-1,4,5,6-tetrahydropyridazine in 250 ml of dimethylformamide are stirred with 9.47 g (0.113 moles) of diketene for 12 hours at room temperature. After the mixture has been concentrated, the residue is boiled up with 100 ml of ethanol, and the product is filtered off after cooling.