Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([CH:17]=O)[C:13]([CH3:19])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=1)=[O:23]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[CH:17][NH:31][NH:30][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:33][CH:32]=3)[C:13]([CH3:19])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: Cc1nn(-c2ccc(C(C)(C)C)cc2)c(O)c1C=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1
Yield: 41.9 %

Procedure:
1.0712 g (4.21 mmol) of the 1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde synthesized in 1) and 819.6 mg (4.22 mmol) of 4-methoxycarbonylbenzhydrazide were stirred in 10 ml of dimethylformamide at room temperature for 3 hours. After the solvent was removed by evaporation, the precipitated solid was washed with a small amount of methanol and dried to obtain 765.9 mg of the above-identified desired product as a yellow solid (yield 42%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22][N:23]=[N:24][N:25]=2)=[CH:13][CH:14]=1)=[O:6].[OH-].[Mg+2:34].[OH-].[OH-].[Ca+2:37].[OH-]>C(O)(C)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22][N:23]=[N:24][N:25]=2)=[CH:13][CH:14]=1)=[O:6].[Ca:37].[Mg:34]
Reactant: [Mg+2]
Reactant: [Ca+2]
Agent: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: [Ca]
Product: [Mg]

Procedure:
21.5 g of valsartan in 200 ml of isopropanol and 100 ml of water are stirred for ca. 3 hours at ca. 25° C. with 1.5 g of magnesium hydroxide and 1.9 g of calcium hydroxide. The practically clear solution is concentrated in a vacuum at ca. 50° C. A total of 240 ml of ethyl acetate is added with stirring to the still warm, semi-solid residue which contains residual water. Upon stirring over night at ca. 25° C., initially sticky constituents are transformed into a homogeneous suspension. The suspension is filtered by suction and washed with 20 ml of ethyl acetate. The moist filter cake is dried in a vacuum at 30-40° C. A colourless crystal powder is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:34]([N:24]3[CH2:25][CH2:26][N:27]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:23]3=[O:22])=[O:35])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 118.9 %

Procedure:
A 0° C. mixture of Example A5 (1 g, 4.51 mmol) and pyridine (1.1 mL, 13.6 mmol) in DCM (25 mL) was treated with a solution of Example B2 (1.680 g, 7.22 mmol) in DCM (8 mL), warmed to RT and stirred 45 min. The mixture was concentrated to dryness, the residue treated with DCM and Et2O, sonicated and the resulting solid collected via filtration. The solid was dissolved in DCM, washed with water, the aqueous layer back-extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (2.24 g, 119%) which was used without further purification. MS (ESI) m/z: 418.1 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][C:12]2([C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29].O>O1CCCC1>[C:32]([O:31][C:27](=[O:30])[CH2:28][CH2:29][N:17]1[C:18]2[C:23](=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:12]2([CH2:13][C:14](=[O:15])[N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:11]2=[O:26])[C:16]1=[O:25])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of sodium hydride (60% dispersion in oil, 7 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2 ml) was treated with 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 14 (50 mg, 0.15 mmol). After stirring at ambient temperature for 30 minutes, tert-butyl acrylate (0.03 ml, 0.19 mmol) was added and the resultant mixture stirred for 2 hours and left to stand at ambient temperature for 18 hours. Water (15 ml) was added and the mixture extracted with ethyl acetate (3×15 ml). The combined extracts were washed with brine (15 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude 3-(1′-Benzyl-5-chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)-propionic acid tert-butyl ester. This was purified by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 50%) of ethyl acetate to give a white solid (37 mg 54%). This was sufficiently pure by 1H NMR to take on to the final hydrolysis step.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>C1COCC1>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:8][CH:5]1[CH2:6][CH2:7][S:2][CH2:3][CH2:4]1)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCSCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCSCC1
Temperature: 13 °C
Reaction time: 23 h
Yield: 92.5 %

Procedure:
To a suspension of tetrahydro-2H-thiopyran-4-amine hydrochloride (80.0 g) in THF (800 mL) were added triethylamine (239 mL) and 2-nitrobenzenesulfonyl chloride (126.9 g) under ice-cooling at an inside temperature of 2-24° C., and the mixture was stirred at room temperature for 23 hr. The reaction solution was partitioned and extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to the extent crystals do not precipitate and purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)]. The obtained solid was washed with ethanol-diisopropyl ether (1:4), and dried under reduced pressure to give the title compound (145.6 g, yield 92%) as a pale-green solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([C:23]#N)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O-])[OH:31].[Na+].Cl.C[OH:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:28])[CH3:29])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([C:23]([O:31][CH3:30])=[O:37])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C([O-])O
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(C#N)nc2[nH]1
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc2nc(-c3cc(OCc4ccccc4)ccc3OC(C)C)[nH]c2n1
Yield: 61 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-5-carbonitrile (60 mg) in hydrochloric acid-methanol (5 ml) was heated under reflux for 6 hr. The reaction mixture was adjusted with aqueous sodium hydrogencarbonate solution to pH 8, and extracted with ethyl acetate. The extract was washed with water; dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with ethanol to give the title compound (40 mg, yield 61%) as colorless crystals. purity 95%. M+H: 418. 1H NMR (CDCl3) δ: 1.50 (6H, d, J=6.2 Hz), 4.06 (3H, s), 4.75-4.82 (1H, m), 5.17 (2H, s), 7.02-7.07 (1H, m), 7.10-7.15 (1H, m), 7.31-7.50 (5H, m), 8.12-8.22 (3H, m), 11.17 (1H, s).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22].[C@@H:23]12[CH2:29][C@@H:26]([CH:27]=[CH:28]1)[CH2:25][C@H:24]2[CH2:30][C:31](O)=[O:32].[H][H]>>[C@@H:23]12[CH2:29][C@@H:26]([CH2:27][CH2:28]1)[CH2:25][C@H:24]2[CH2:30][C:31]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22])=[O:32]
Reactant: [H][H]
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Reactant: Nn1nc(-c2ccc(C(F)(F)F)cc2)c2ccccc2c1=O
Product: O=C(C[C@@H]1C[C@@H]2CC[C@H]1C2)Nn1nc(-c2ccc(C(F)(F)F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 147A and 2-[(1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl]acetic acid were treated using a method similar to that described in Example 17C, followed by treatment with hydrogen similar to that described in Example 66 to give the title compound. 1H NMR (400 MHz, DMSO) δ 11.41-11.35 (m, 1H), 8.45-8.38 (m, 1H), 8.01-7.91 (m, 4H), 7.88-7.81 (m, 2H), 7.76-7.70 (m, 1H), 2.37-2.30 (m, 2H), 2.28-2.22 (m, 1H), 2.22-2.13 (m, 2H), 1.82-1.72 (m, 1H), 1.62-1.43 (m, 2H), 1.39-1.29 (m, 2H), 1.29-1.21 (m, 1H), 1.19-1.08 (m, 1H), 0.79-0.70 (m, 1H); MS (DCI+) M/Z 459 (M+NH4)+.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[O:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>>[F:30][C:28]1[CH:27]=[CH:26][C:25]2[C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@@H:12]4[N:8]5[C:9]6[C:4](=[CH:3][CH:2]=[CH:1][C:10]=6[C@@H:11]4[CH2:16]3)[CH2:5][CH2:6][CH2:7]5)=[N:22][O:23][C:24]=2[CH:29]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2c(CCCN3CC[C@H]4[C@@H](C3)c3cccc5c3N4CCC5)noc2c1
Yield: 79.2 %

Procedure:
The title compound (0.31 g, 75%) was prepared by the general method of Example 402 from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. The 1H NMR was identical to that of Example 408, (±)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.Cl.[NH2:22][C:23]1[CH:28]=[C:27]([NH2:29])[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:22][C:23]1[CH:28]=[C:27]([NH2:29])[N:26]=[CH:25][N:24]=1)=[CH:7]2
Reactant: Nc1cc(N)ncn1
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)ncn1

Procedure:
Prepared according to Procedure H using 8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.035 g, 0.11 mmol), 4,6-diaminopyrimidine hydrochloride (0.032 g, 0.22 mmol, 2 eq) and DIEA (0.55 mL, 2.2 mmol, 20 eq) in ethanol (1 mL). N4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)pyrimidine-4,6-diamine [PI3Kδ IC50=6868 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (1H, s), 8.05 (1H, dd, J=8.4, 1.0 Hz), 7.95 (1H, dd, J=7.4, 1.2 Hz), 7.84 (1H, s), 7.51-7.67 (5H, m), 7.24 (1H, s), 6.19 (2H, s), 5.32 (1H, s), 4.33 (1H, s) Mass Spectrum (ESI) m/e=396.1 and 398.0 (M+1)
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([C:11](=[C:17]=[CH:18]N(C)C)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)C.[CH2:22](O)C>CCOCC>[C:2]([N:6]1[C:18]([CH3:22])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=C=CN(C)C)C(C)=O
Reactant: CC(C)(C)NN
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)n(C(C)(C)C)n1
Yield: 45 %

Procedure:
In ethanol (5 mL) was placed the t-butylhydrazine hydrochloride (0.79 g, 6.3 mmol) and ethyl 2-acetyl-3-(dimethylaminomethylene)acrylate (1.0 g, 6.3 mmol). The mixture was refluxed for 8 hours. The mix was evaporated at reduced pressure to give an oil. The oil was dissolved in ether (25 mL) and washed successively with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL) was dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexanes) to obtain ethyl 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylate (0.60 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.54 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.44 (s, 3H), 2.42 (s, 3H), 1.57 (s, 9H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 211.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37][CH2:38]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (75 mg), potassium carbonate (30 mg), and 1,3-dibromopropane (75 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 50 mg (yield 52%) of N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (30 mg), potassium carbonate (20 mg), and N-methylpiperazine (40 μl) were dissolved in N,N-dimethylformamide (3 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 63%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]([CH2:20][O:21][CH3:22])[C:8]([CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9][C:5]=2[CH:4]=1.COC1C=CC2N=C(CN(C)C(=O)OC(C)(C)C)N(COC)C=2C=1.ClCCl.[Br:52]N1C(=O)CCC1=O>CCOC(C)=O>[Br:52][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[N:7]([CH2:20][O:21][CH3:22])[C:6]=2[CH:23]=1
Reactant: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(OC)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2ccc(OC)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(OC)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a mixture of a mixture (946 mg) of tert-butyl {[5-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and dichloromethane (10 mL) was added N-bromosuccinimide (527 mg) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with a saturated aqueous NaHCO3 solution and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=85/15-60/40) to obtain a mixture (855 mg) of tert-butyl {[6-bromo-5-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[5-bromo-6-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:19]([O:21][CH2:22][CH2:23]Cl)[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:21][CH2:22][CH2:23][O:10][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:20]
Reactant: CCOCCCl
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)cc(C)c1C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 2,3,5-trimethylphenol (3.0 g, 22.0 mmol), potassium carbonate (3.65 g, 26.4 mmol) and potassium iodide (0.55 g, 3.3 mmol) in N,N-dimethylformamide (50 mL) was added 2-chloroethyl ethyl ether (3.59 g, 33.3 mmol) under stirring at room temperature, and the mixture was stirred at 70° C. for 24 hr. To the reaction mixture were added reagents (potassium carbonate, potassium iodide and 2-chloroethyl ethyl ether) in the same amount as mentioned above, and the mixture was further stirred at 70° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1-hexane/ethyl acetate=4/1) to give the title compound (4.1 g, yield 90%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14](=[O:16])[CH3:15].[N:17]([O-])=O.[Na+]>[CH]Cl.O>[CH3:7][N:6]1[C:2]2[N:1]=[N:17][CH:15]=[C:14]([OH:16])[C:3]=2[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5]1
Reactant: O=N[O-]
Reactant: CC(=O)c1c(-c2ccccc2)nn(C)c1N
Agent: [CH]Cl
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2ccccc2)c2c(O)cnnc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
A suspension of 1-(5-amino-1-methyl-3-phenyl-pyrazol-4-yl)ethanone (241 mg, 1.12 mmol) in cHCl (6.7 mL) and water (1 mL) was cooled to −5° C. A solution of sodium nitrite (155 mg, 2.24 mmol) in water (0.6 mL) was added and the reaction mixture was stirred at −5° C. for 20 min, then at room temperature for 10 min, then at 65° C. for 30 min and finally cooled to room temperature. The reaction mixture was filtered and the solid was washed with cHCl (2 mL), suspended in MeOH/CH2Cl2 (9:1), filtered and dried, to yield the title compound as a solid (125 mg).
Reaction SMILES: C(O)(=O)C.O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:30]([F:33])([F:32])[F:31])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23]([N+:25]([O-])=O)[CH:24]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1>[Fe].C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:30]([F:32])([F:31])[F:33])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23]([CH:24]=3)[NH2:25])[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: CCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
An iron powder (4.33 g) was added to a mixture of acetic acid (0.5 ml), water (22 ml) and ethanol (34 ml) at room temperature, and thereto was added 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-ethylnitrobenzene (5.60 g) obtained by Reference Production Example 29 at 75° C., and the mixture was stirred at the same temperature for 3 hours. After cooling to room temperature, the reaction mixture was filtrated and washed with ethyl acetate. To the filtrate was added an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-ethylaniline (5.20 g).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg][Cl:7].Cl[CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O1CCCC1.Cl>CCOCC>[ClH:7].[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: CN(C)CCC[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCCC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
The Grignard solution prepared in Step A. is cooled to room temperature and stirred while a solution of 5.05 g. (0.0221 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 25 ml. of dry tetrahydrofuran is added dropwise, external cooling being applied as required to maintain the temperature close to room temperature. When the addition is complete, the mixture is heated to refluxing for 15 minutes. The bulk of the tetrahydrofuran then is distilled under reduced pressure, keeping the water-bath temperature at 50°-60°C. The syrupy mixture is dissolved in 75 ml. of benzene and water, 15 ml., is added dropwise with stirring. The benzene layer is decanted from the gelatinous precipitate which then is re-extracted with three 20 ml. portions of boiling benzene. The combined benzene extracts are washed with water and extracted with three 15 ml. portions of 3N hydrochloric acid. The acid extract is made basic with sodium hydroxide and the yellow oily base that separates is extracted into hexane. After washing the combined extracts with water, the hexane is evaporated and the product obtained as a yellow oil in a yield of 4.61 g. The base is converted to the hydrochloride by dissolving it in a mixture of 15 ml. of absolute alcohol and 15 ml. of absolute ether and adding 1.8 ml. of a 10.28 N solution of dry hydrogen chloride in absolute alcohol. The solution then is diluted to incipient crystallization by the addition of 25 ml. of absolute ether. The yield of 5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride, m.p. 186°-190°C. is 4.17 g. Recrystallization from mixtures of absolute alcohol and absolute ether gives the product, m.p. 191°-193°C.