Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 133 (t=0.93 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH3:32])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: CI
Reactant: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Product: Cc1ccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
2′-Methyl-N-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4carboxamide was prepared from 2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.88,(1H, d), 7.75,(1H, s), 7.55-7.47,(5H, m), 7.25-7.08,(4H, m), 4.65-4.49,(2H, m), 2.88,(3H, m), 2.55,(3H, s), 2.32,(6H, m). LCMS; retention time 3.60 min, MH+ 412.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][C:22](O)([CH3:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:19][C:18](=[O:20])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)-N-Boc-4-fluorophenylalanine (2.83 g, 10.0 mmol), DMAP (0.12 g, 1.0 mmol) in DCM (20 mL) and 2-methyl-2-propanol (1.05 mL, 11.0 mmol), was added DCC (2.27 g, 11.0 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered and washed several times with DCM. The filtrate was concentrated in vacuo and chromatographed on silica gel eluting with ethyl acetate:isohexane (1:4) to give the title compound. δH (CDCl3): 1.39 (9H, s), 1.41 (9H, s), 3.01 (2H, m), 4.41 (1H, m), 4.98 (1H, m), 6.95 (2H, m), 7.12 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.O.NN>CCO>[Cl:1][C:2]1[C:3]([CH2:24][NH2:25])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Yield: 64.9 %

Procedure:
To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:21][C@H:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Mg]Br)[CH:23]=1>>[CH2:14]([O:13][CH2:12][C@@H:11]([CH2:31][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)[C@@H:10]([OH:21])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(C[Mg]Br)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Product: Cc1cccc(C[C@H](COCc2ccccc2)[C@@H](O)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
325 mg of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether obtained in Example 53, was subjected to Grignard reaction in the same manner as in Example 53 by using 3-tolylmethyl magnesium bromide (0.8M diethyl ether solution). The product was purificated by silica gel column chromatography to obtain 210 mg of (2R,3R)-4-benzyloxy-1-tert-butyldimethylsiloxy-3-(3-tolylmethyl)-2-butanol as colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH:19]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:19])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)CSCc1ccc(OC)c([N+](=O)[O-])n1
Reactant: OO
Solvent: CC(=O)O
Product: COC(=O)CS(=O)Cc1ccc(OC)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
Methyl 2-((5-methoxy-6-nitropyridin-2-yl)methylthio)acetate (1.0 mmol, 0.27 g) and hydrogen peroxide 30% (1.0 mmol, 0.12 mL) were dissolved in acetic acid (10 mL). The mixture stirred at r.t. for 6 hrs and the solvent was evaporated in vacuo. The mixture was purified by column chromatography using 1:1 PE/EtOAc to give the titled compound. Yield 95%; 1H-NMR (DMSO-D6) δ: 3.74 (s, 3H, OCH3), 3.76 (d, 1H, J=14.2 Hz), 4.02 (d, 1H, J=14.2 Hz,), 4.07 (s, 3H, OCH3), 4.27 (d, 1H J=12.9 Hz, CH), 4.42 (d, 1H J=12.9 Hz, CH), 7.76 (d, 1H, J=8.6 Hz, Py-H), 7.94 (d, 1H, J=8.6 Hz, Py-H); 13C-NMR (DMSO-D6) δ: 51.90, 55.1756.52, 57.31, 124.13, 130.82, 141.18, 146.90, 166.11, 205.26. HR-MS (ESI+) m/z 289.0428 [M+H]+ C10H12N2O6S, requires 288.0416.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([NH:19][CH:2]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:29]=[CH:28][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.3 g), methyl 4-amino-2-methoxybenzoate (1.1 g), sodium carbonate (1.1 g) and sodium iodide (3.0 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (5 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.9 g, 46%) as an amorphous compound.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1)#[N:2].O.NN>C(O)C>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH2:9])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1)#[N:2]
Reactant: CCOc1cc(C#N)ccc1CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOc1cc(C#N)ccc1CON
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Into a reaction vessel was charged N-(4-cyano-2-ethoxybenzyloxy)phthalimide (17) (27.0 g, 0.084 mol) and ethanol (270 ml), and hydrazine monohydrate (4.6 g, 0.091 mol) were added, and the mixture was stirred for 2 hours at approximately 80° C. The precipitated white solid was removed by filtrated, and the resulted filtrate was subjected to reduce pressure to distill off the solvent. Next, ethyl acetate was added and the mixture was washed with a dilute sodium carbonate aqueous solution, dried over anhydrous magnesium sulfate, then, the solvent was distilled off under reduced pressure, to obtain O-(4-cyano-2-ethoxybenzyl)hydroxyamine (18) (13.4 g, yield from (17) is 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.B(Br)(Br)[Br:22]>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6]([Br:22])[N:5]=[CH:4][N:3]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(F)cc(NC(=O)c2c(N)ncnc2Cl)c1
Solvent: ClCCl
Product: Nc1ncnc(Br)c1C(=O)Nc1cc(O)cc(F)c1
Yield: 78.2 %

Procedure:
4-Amino-6-chloro-N-(3-fluoro-5-methoxyphenyl)pyrimidine-5-carboxamide (458 mg, 1.54 mmol) was treated with boron tribromide (1M in dichloromethane, 0.46 ml, 4.6 mmol) an using dichloromethane (7 ml) as a solvent according to the method described in Example 23. The solid residue (394 mg, 71% yield) was used in the next synthetic step without further purification. Purity 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 85 %

Procedure:
4-Amino-phenol (12 g, 0.11 mol, Acros and Aldrich) was dissolved under an inert atmosphere, with stirring, in dry DMF (50 ml) and cooled in an ice-bath. Triethylamine (TEA, 11 g, 0.11 mol) was added and stirring continued for 1 hour. 4-Chloro-3-nitro-benzoyl chloride (22.2 g 0.1 mol, Acros and Aldrich) was added slowly and stirred overnight. The precipitated triethylamine.hydrochloride salt was filtered off and DMF removed under reduced pressure. The residue was extracted with EtOAc (3×100 ml) and citric acid (1M, 3×100 ml). The organic phase was dried with magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The title product was recrystallised from methanol/water (1:1, 250 ml), yield 85%, and analysed by NMR and MS.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[Cl:34].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+].CCN(C(C)C)C(C)C>ClCCl>[Cl:34][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: O=C(Cl)C1CC1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Cyclopropanecarbonyl chloride (0.045 ml, 0.5 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (220 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (0.30 ml, 1.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (135 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:20])[NH:30][C:29]3[CH:31]=[CH:32][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:27][CH:28]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 59.1 %

Procedure:
A procedure similar to that described in Example 52 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (50 mg, 0.14 mmol) and p-sulfamoylaniline (25 mg, 0.15 mmol) to give 42 mg of the title compound (58%) after recrystallization from acetone-methanol-water: mp 279.5°~295° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.09 (s, 1H), 10.32 (s, 1H), 7.76 (d, 2H, J=8.9 Hz), 7.70 (d, 2H, J=8.9 Hz), 7.23 (s, 2H), 7.21 (s, 1H), 7.18 (s, 1H), 4.95~5.05 (m, 1H), 3.21 (dd, 1H, J=17.8, 5.9 Hz), 2.52~2.66 (m, 3H), 2.28~2.42 (m, 1H), 0.87 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][SH:2].Cl[C:4]1[S:5][C:6]([C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O>C(O)C>[CH3:1][S:2][C:4]1[S:5][C:6]([C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: CS
Solvent: CCO
Solvent: O
Product: CSc1sc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Liquid methylmercaptan (4 ml) was added to a solution of 0.82 g of Na in 50 ml of absolute ethanol. The resulting solution was added to a solution of 7.2 g of 2-chloro-3-nitro-5-acetylthiophene in 200 ml of absolute ethanol in 15 minutes at 5° C. After stirring at room temperature for 30 minutes, 100 ml of water was added, after which the precipitate was sucked off and washed successively with water and isopropanol. The precipitate was boiled a moment with 300 ml of carbontetrachloride, cooled down, and sucked off. After drying the title compound was obtained in a yield of 6.4 g; m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of postassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: N[C@H](C=O)CCSC.[C:9](=[O:16])([O:13][CH2:14][CH3:15])OCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=O)=[CH:20][CH:19]=1.C(OCC)C>C(O)C.C(O)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[CH2:25])[C:9]([O:13][CH2:14][CH3:15])=[O:16])=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: CSCC[C@H](N)C=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: C=C(C(=O)OCC)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
Metal sodium (1.5 g) was gradually added to ethanol (50 ml) at room temperature, followed by stirring for 5 minutes, and diethyl carbonate (8.9 ml, 73 mmol) was added thereto at room temperature. Further, a solution of ethyl 4-chlorophenylacetate (10 g) in ethanol (10 ml) was added dropwise thereto with stirring, and the stirring was continued for 2 hours. The reaction mixture was concentreated, and diethyl ether (150 ml) and 10% aqueous acetic acid (150 ml) were added to the residue for extraction. The aqueous layer was further washed with diethyl ether (50 ml). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue were added water (25 ml) and 37% aqueous formaldehyde (8 ml) at room temperature, followed by vigorous stirring at room temperature. After addition of an aqueous solution (36 ml) of potassium carbonate (6.5 g) over 5 minutes, the mixture reaction was stirred for 4 hours and extracted with diethyl ether (100 ml×2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of ethyl 4-chlorophenyl-α-methyleneacetate (yield, 10 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2ccc3ccccc3c2)c(C)n1
Yield: 56 %

Procedure:
First, to a recovery flask equipped with a reflux pipe were placed 2.25 g of 2-chloro-3,5-dimethylpyrazine, 2.71 g of 2-naphthylboronic acid, 1.67 g of sodium carbonate, 0.072 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 15 mL of water, and 15 mL of acetonitrile, and the atmosphere in the flask was replaced with argon. This reaction container was subjected to irradiation with a microwave (2.45 GHz, 100 W) for 10 minutes to be heated. Then, water was added to this solution, and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. After drying, the solution was filtrated. The solvent of this solution was distilled off and the residue obtained by distillation was purified by silica gel column chromatography using dichloromethane as a developing solvent. In this way, Hdm2npr (a light orange powder, yield: 56%), which was a target substance, was obtained. For the irradiation with a microwave, a microwave synthesis system (Discover, manufactured by CEM Corporation) was used. A synthesis scheme of Step 1 is shown in the following (B-1).
Reaction SMILES: Br[C:2]1[C:3]([C:21]#[N:22])=[CH:4][C:5]([F:20])=[C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[C:21]([C:3]1[C:2]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])=[C:5]([F:20])[CH:4]=1)#[N:22]
Reactant: N#Cc1cc(F)c(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccccc3)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-phenylpropanamide (362 mg, 1.00 mmol), 5-amino-3-methylisothiazole hydrochloride (166 mg, 1.10 mmol), BINAP (70 mg, 0.112 mmol), Pd(OAc)2 (35 mg, 0.156 mmol) and K2CO3 (430 mg, 3.11 mmol) in dioxane (5 mL) was degassed with Ar, then was stirred at 120 C for 18 h. More Pd(OAc)2 (35 mg, 0.156 mmol) was added. The mixture was stirred at 120 C for another 18 h. Water and EtOAc were added. After being filtered, the filtrate was washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-phenylpropanamide as a crude residue.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]([F:30])([F:29])[F:28])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)=O.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[OH:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=2[S:16][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][N:6]1[CH:7]=[C:3]([CH2:1][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:4]([C:27]([F:29])([F:30])[F:28])=[N:5]1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Cn1cc(CNCC(F)(F)F)c(C(F)(F)F)n1)Nc1sc2c(c1C(=O)NCCO)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
2-(2-(4-Formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (30 mg, 0.068 mmol), 2,2,2-trifluoroethylamine (19.8 mg, 0.20 mmol) and DCM (1 mL) were treated with acetic acid (5 drops) and sodium triacetoxyborohydride (58 mg, 0.272 mmol) and the mixture stirred at RT overnight. The sample was concentrated and re-dissolved in dimethylsulfoxide (1 mL), filtered and purified by preparative LCMS followed by additional purification by SCX ion exchange chromatography to yield the title compound (10 mg, 0.02 mmol, 29%).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([C:15]([O:17]C)=[O:16])[CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO.C(OC(=O)C)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)c(=O)n(C2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)O)cn(C2CCCC2)c1=O

Procedure:
A mixture of Methyl 5-cyano-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (290 mg, 1.2 mmol) and 1N sodium hydroxide (6 mL, 6.0 mmol) in methanol (12 mL) was heated to reflux for 1 h and brought to RT. The mixture was concentrated and the residue obtained was dissolved in ethylacetate (20 mL), acidified with 1N hydrochloric acid (pH ˜5). The organic phase was separated, dried over magnesium sulfate and concentrated to afford the title compound as a light yellow solid. MS m/z: 233 (M+1).