Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:25][C@H:26]([C:33]([NH:35][C@H:36]([CH:41]=[N:42][NH:43][C:44]([NH2:46])=[O:45])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:11][CH:12]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([NH:25][C@H:26]([C:33]([NH:35][C@H:36]([CH:41]=[N:42][NH:43][C:44]([NH2:46])=[O:45])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:27][C:28]2[N:32]=[CH:31][NH:30][CH:29]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 190 mg of (±)-2-(1-naphthylmethyl)-5-phenyl-4-pentenoic acid and 400 mg of bis(P-toluenesulfonic acid) salt of L-histidyl-L-leucinal semicarbazone in 7 ml of N,N-dimethylformamide were successively added 0.16 ml of diphenylphosphoryl azide and 0.28 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted withh ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1 by volume) to obtain 151 mg of N-[(±)-2-(1-naphthylmethyl)-5-phenyl-4-pentenoyl]-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:43][CH:40]3[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[CH2:38][CH2:39]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1cc(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: COc1cc(Nc2ncnc3cc(OCC4CCN(C(=O)OC(C)(C)C)CC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Yield: 69.5 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.109 g) was reacted with 1-tert-butoxycarbonylpiperidin-4-ylmethanol (0.065 g) to give 4-(2,4-dichloro-5-methoxyanilino)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline (0.11 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([C@@:8]23[CH2:17][N:16]([S:18]([C:21]4[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=4)(=[O:20])=[O:19])[CH2:15][CH2:14][C:13]2=[CH:12][C:11]2[N:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[N:29]=[CH:30][C:10]=2[CH2:9]3)=[O:7])[CH2:3][CH2:2]1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]([C@@:8]23[CH2:17][N:16]([S:18]([C:21]4[CH:22]=[N:23][C:24]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:25][CH:26]=4)(=[O:20])=[O:19])[CH2:15][CH2:14][C:13]2=[CH:12][C:11]2[N:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[N:29]=[CH:30][C:10]=2[CH2:9]3)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(OCC1CC1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1COCCN1
Product: O=C(OCC1CC1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid cyclopropylmethyl ester and morpholine to give the title compound (0.063 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.78 (dd, 1H), 7.49-7.40 (m, 3H), 7.16 (t, 2H), 6.61 (d, 1H), 6.41 (d, 1H), 4.40 (dd, 1H), 3.95-3.85 (m, 2H), 3.81 (t, 5H), 3.66 (t, 4H), 3.31 (d, 1H), 2.95-2.87 (m, 1H), 2.58 (d, 1H), 2.49-2.41 (m, 3H), 1.20-1.10 (m, 1H), 0.57-0.48 (m, 2H), 0.33-0.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)N2CCSCC2)=C(C)C1=O
Yield: 34.3 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.070 mmol) obtained in Example 69 and thiomorpholine (0.011 ml, 0.11 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (10 mg, 0.024 mmol, yield 34%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[OH:25].Cl[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1.C(O)(C(F)(F)F)=O>C(#N)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[O:25][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1
Reactant: CN1CCCC(CCl)C1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NCc1ccc(Cl)c(OCC2CCCN(C)C2)c1)c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
A small vial was charged with 2 mL of acetonitrile, cesium carbonate (50 mg, 0.15 mmol), (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 83 (30 mg, 0.10 mmol), and 3-(chloromethyl)-1-methylpiperidine (16 mg, 0.11 mmol). The vial was placed in a reaction block and it was heated to 85° C. and stirred for 14 h. The vial was allowed to cool to room temperature and the solution was filtered through a syringe filter into a well of a 24 well plate. This plate was concentrated down in a Genevac vacuum instrument. The plate was by preparatory HPLC. The desired fractions were combined and lyophilized. The final product, (1R)—N-(4-chloro-3-((1-methylpiperidin-3-yl)methoxy)benzyl)-1-(3-chlorophenyl)ethanamine 84 (32 mg, 75% yield) was isolated as a white solid of the TFA salt. 1H NMR (400 MHz, d4-methanol) δ ppm 1.44-1.56 (m, 1H) 1.72 (m, 2H) 1.99 (m, 1H) 2.07 (m, 1H) 2.40 (m, 1H) 2.91-3.00 (m, 4H) 3.55 (m, 1H) 3.67-3.74 (m, 1H) 3.93-4.01 (m, 2H) 4.10 (dd, J=9.00, 4.11 Hz, 1H) 4.18 (d, J=13.11 Hz, 1H) 4.48 (q, J=6.85 Hz, 1H) 5.50 (s, 1H) 7.00 (d, J=8.22, 1H) 7.15 (s, 1H) 7.43-7.52 (m, 3H) 7.57 (s, 1H). Mass spectrum: calculated for C22H28C12N2O 407.4. found 408.4 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:10](=O)[CH2:11][CH3:12])=[C:5](OC)[CH2:6][CH3:7].Cl.[Br:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.CCN(CC)CC>CO>[CH3:1][O:2][C:3]([C:4]1[C:10]([CH2:11][CH3:12])=[N:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=2)[C:5]=1[CH2:6][CH3:7])=[O:14]
Reactant: CCC(=O)C(C(=O)OC)=C(CC)OC
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1nn(-c2cccc(Br)c2)c(CC)c1C(=O)OC
Temperature: -20 °C
Reaction time: 20 h

Procedure:
A solution of 7.10 g (35.5 mmol) of (E and/or Z)-3-methoxy-2-propionyl-pent-2-enoic acid methyl ester in 10 ml of MeOH was added to a solution of 8.09 g (35.5 mmol) of 3-bromophenylhydrazine hydrochloride in 150 ml of MeOH and the mixture was cooled to −20° C. To this mixture was added a solution of 3.79 g=5.22 ml (37.2 mmol) of Et3N in 40 ml of MeOH drop by drop and the reaction was then warmed up to RT. After 20 hours, it was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 7.62 g of the title compound as light red oil. MS: 337.1 (MH+, 1 Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH3:36]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH2:34][CH2:35][CH3:36])[N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: Cc1c(-c2nnn[nH]2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1nnnc1-c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Reaction time: 5 h
Yield: 36.8 %

Procedure:
5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (150 mg, 0.37 mmol) obtained in Step 1 was dissolved in dimethylformamide (1 ml), and potassium carbonate (250 mg, 1.85 mmol) and 1-iodopropane (0.07 ml, 1.1 mmol) were added thereto at room temperature. After stirring for 5 hours, the resulting solution was quenched with water (1 ml) and the mixture was three time extracted with 5 ml portion of ethyl acetate. The solvent of the extracted organic layer was evaporated under a reduced pressure and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/7 to hexane/ethyl acetate=1/5), to obtain two compounds, one of which was the title compound (61 mg, 37%) in the form of white solid.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:32][CH:33]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (25.5 mg, 0.09 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (18.1 μL, 0.09 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoro-pyridine (13.2 mg, 0.09 mmol) described in manufacturing Example 41-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (23.6 mg, 67%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][NH:18][CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[CH3:36][N:37]=[C:38]=[O:39]>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:38]([NH:37][CH3:36])=[O:39])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CNC[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 25 mg of the product of Step D (0.06 mmol) in 3 mL dry methylene chloride was added 0.01 mL pyridine (0.12 mmol) and 0.007 mL methylisocyanate (0.12 mmol). The resulting reaction mixture was stirred at RT for 1 hr, then the volatiles were removed under vacuum. The residue was purified by prep TLC eluting with methylene chloride/methanol (9/1) to give 25 mg of yellow glass. Further purification was achieved by prep HPLC on Chiralpak AD column eluting with heptanes/ethanol (95/5) to obtain a minor isomer A and the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 2.86 (2s, 3H), 3.32-3.5 (m, 3H), 3.75-3.90 (m, 3H), 4.20 (br. s, 1H), 4.53 (q, 1H, 6.5 Hz), 6.95 (t, 2H), 7.04 (m, 2H), 7.57 (s, 2H), 7.77 (s, 1H)ppm. MS: 479.1 (MH+) observed.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@@:8]3([O:21][CH3:22])[C@H:9]([CH3:20])[CH2:10][C:11](=[O:19])[CH2:12]4.[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br.[ClH:29]>C(O)C>[ClH:29].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][N:18]1[CH2:17][CH2:16][C@@:13]23[C:14]4[CH:15]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[CH2:6][C@@H:7]1[C@:8]2([O:21][CH3:22])[C@H:9]([CH3:20])[CH2:10][C:11](=[O:19])[CH2:12]3
Reactant: CC(C)=CCBr
Reactant: CO[C@@]12[C@H](C)CC(=O)C[C@@]13CCN[C@@H]2Cc1ccc(O)cc13
Agent: Cl
Solvent: CCO
Product: CO[C@@]12[C@H](C)CC(=O)C[C@@]13CCN(CC=C(C)C)[C@@H]2Cc1ccc(O)cc13

Procedure:
A mixture of 3-hydroxy-14-methoxy-8α methylmorphinan-6-one (27) (0.13 g, 0.43 mmol), dimethylallyl bromide (0.125 g, 0.84 mmol) and ethanol (10 ml) was refluxed under a nitrogen atmosphere for 16 hours (oil bath temperature 105°-110° C). The mixture was filtered and the residue washed with ethanol. The filtrate upon concentration gave a solid product which was chromatographed over silica gel using graded methanol/chroloform mixtures as the eluant. Fractions containing the desired product were collected and evaporated to give total of 0.02 g (12.6% theory) of pure product. An additional 0.026 g of less pure 28 was also obtained. The pure material was converted into the HCl salt by treatment with ethereal HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:37]O)[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccc(CO)cc1
Product: O=C1c2ccccc2C(OCc2ccc(CO)cc2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.4 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,4-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (405 mg, 78%). 1H NMR (300 MHz, CDCl3): 8.01-7.85 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.61-7.53 (m, 2H, Ar—H), 7.37-7.18 (m, 9H, Ar—H), 6.93 (d, J=7.8 Hz, 2H, Ar—H), 4.85 and 4.67 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.66 (d, J=5.7 Hz, CH2—OH), 3.90 and 3.68 (d: AB, J=11.7 Hz, 2H, OCH2), 2.12 (t, J=6.0 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 168.52, 147.63, 145.39, 144.90, 141.16, 137.34, 136.39, 135.37, 133.42, 131.73, 130.57, 130.32, 129.19, 128.38, 127.30, 127.11, 124.34, 123.69, 95.52, 65.26, 65.12, 42.89. m/z (ES): 515 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[O:26]=[CH:27][CH2:28][C:29](O)=[O:30]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[C:29]([OH:30])[CH2:28][CH:27]=[O:26]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: O=CCC(=O)O
Product: CC1=C(CCON=C(O)CC=O)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-oxopropionic acid by the method of Example 1.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([CH:21]3[C:25](=[O:26])[CH2:24][CH2:23][C:22]3=[O:27])[N:16]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[C:22](=[O:27])[CH2:23][CH2:24][C:25]=3[O:26][CH3:5])[N:16]=2)=[CH:11][CH:10]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CCC1=O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC1=C(n2nc(-c3ccc(Cl)cc3)cc2C)C(=O)CC1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
Neat dimethyl sulfate (0.12 ml, 1.3 mmol) was added at room temperature to a vigorously stirred suspension of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-cyclopentane-1,3-dione (374 mg, 1.3 mmol) and potassium carbonate (180 mg, 1.3 mmol) in acetone (10 ml). The mixture was then heated to 60° C. for 3 h with continued stirring, then cooled and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (30 ml) and 1M sodium hydroxide solution (20 ml), the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2×20 ml). The combined organics were washed with brine (20 ml), dried over magnesium sulfate and concentrated. The crude product was then purified by flash chromatography (using 20% to 100% EtOAc in DCM) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-3-methoxy-cyclopent-2-enone (253.2 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])C.CON(C)[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)=[O:27]>C1COCC1>[CH3:9][O:11][C:12](=[O:22])[CH:13]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)=[O:27]
Reactant: CCOC(=O)COc1ccccc1C
Reactant: CON(C)C(=O)c1ccnc(SC)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccccc1C)C(=O)c1ccnc(SC)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 12.9 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (31.5 mL of 1.8 M solution in THF, 56.6 mmol) in THF (180 mL) is added dropwise a solution of ethyl-(2-methylphenoxy)acetate (10.0 g, 51.5 mmol) in THF (30 mL). After stirring for 1 h at −78° C. a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (10.4 g, 48.9 mmol) in THF (30 mL) is added dropwise to the reaction mixture. After stirring 20 min at −78° C., the reaction mixture is warmed to 0° C. and stirred for an additional 30 min. The reaction is quenched by pouring into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc (×2). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by silica gel chromatography (10% EtOAc/hexanes, followed by 30% EtOAc/hexanes) to afford 2.1 g (32%) of the desired product. 1H NMR (300 MHz, CDCl3) (observed 3:1 mixture of keto:enol tautomers) keto tautomer: δ 8.80 (d, J=4.2 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 7.20-7.14 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.29 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.27 (s, 3H), 1.26 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 347.1 (100, M++H).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].O=S(Cl)[Cl:21]>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6]([Cl:21])=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O

Procedure:
4-Hydroxy-3,5-di-tert-butyl benzoic acid (12.5 g, 50 mM) was dissolved in 80 ml of chloroform. To the resulting solution was added dropwise a solution of SOCl2 (chlorination agent, 10 ml) in chloroform (20 ml), followed by heating under reflux for 3 hours. The reaction solution was then distilled off under reduced pressure to yield 4-hydroxy-3,5-di-tert-butylbenzoyl chloride.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][NH:10][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22].C(O)(=O)C>O>[Cl:17][CH2:18][C:19]1[NH:12][C:11]2[N:10]([N:9]=[C:8]([C:13]([F:15])([F:16])[F:14])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21](=[O:22])[CH:20]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1[nH]nc(C(F)(F)F)c1-c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(CCl)[nH]c2c(-c3ccccc3)c(C(F)(F)F)nn12
Yield: 11.6 %

Procedure:
Referring to the process as shown in FIG. 2 of the drawings, provide and place 0.227 g of the intermediate 4-phenyl-3-trifluoromethyl-5-amino-1H-pyrazole (1 mmol), 0.130 g of ethyl 4-chloro-3-oxobutanoate and 3 ml of acetic acid (anhydrous acetic acid) into a parallel synthesis instrument (Buchi, Switzerland), allow reflux reaction for 4 hours, stop heating, filling cold water into the low temperature module of the synthesis instrument for precipitation of solid substance, wash with acetic acid, then wash with water until the solid substance is neutral, obtain 30 mg of 5-chloromethyl-3-phenyl-2-trifluoromethylpyrazolo[1,5-a]pyrimidin-7(4H)-one, which is a white solid. The purity is greater than 98% (HPLC-UV by area normalization); ESI-Ms(m/z): 328 (M+1)+; 1HNMR (500 MHz, CD3OD): 7.56 (d, 2H), 7.42 (m, 2H), 7.33 (m, 1H), 6.12 (s, 1H), 4.57 (s, 2H).