Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]2=[N:18]1.[CH3:26][O-:27].[Na+].CO>C1(C)C(C)=CC=CC=1>[N:18]1[N:17]([C:3]2[C:2]([OH:1])=[C:7]([CH2:2][C:7]3[CH:6]=[C:5]([CH3:8])[CH:4]=[C:3]([N:17]4[N:18]=[C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]5=[N:21]4)[C:26]=3[OH:27])[CH:6]=[C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH:4]=2)[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=12
Reactant: C[O-]
Reactant: C=C(C)C(=O)OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)OCCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3′-N,N-diethylaminomethyl-2′-hydroxy-5′-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 10.5 g (31.1 mmols) of 2-(2′-hydroxy-5′-methacryloyloxypropylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate•methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this point were separated through filtration, and recrystallized from chloroform to obtain 12.8 g of 6-(2H-benzotriazol-2-yl)-4-methacryloyloxypropyl-2-[3′-(2H-benzotriazol-2-yl)-2′-hydroxy-5′-methylphenyl]methylphenol (hereinafter abbreviated as “RUVA-3”) as white crystals (yield 71.0%, purity 98.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[OH:6].[H-].[Na+].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH2:18]Br.Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([O:6][CH2:18][C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])=[C:4]([OH:12])[CH:3]=1
Reactant: COc1ccc(F)c(F)c1CBr
Reactant: O=[N+]([O-])c1cc(O)c(O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
To a solution of 4-chloro-5-nitrocatechol (10.4 g) in N,N-dimethylformamide (55 mL) was added sodium hydride (55%, 5.04 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (11 mL), followed by adding a solution of 2,3-difluoro-6-methoxy-benzyl bromide (14.3 g) in N,N-dimethylformamide (22 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−1/1) to give the title compound (18.5 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1)(=O)=O.[OH-].[NH4+:43]>O1CCOCC1>[CH3:24][CH:22]([CH3:23])[CH2:21][S:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([NH:11][C:9]2[C:8]([C:25]3[N:26]=[C:27]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:28]4=[N:29][CH:30]=3)=[CH:7][N:6]=[C:5]([NH2:43])[N:10]=2)[CH2:13]1)(=[O:20])=[O:19]
Reactant: [NH4+]
Reactant: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(N)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
In a 10 mL sealed tube {2-methanesulfonyl-5-[5-(2-trimethysilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine (38 mg, 609 μmol) and ammonium hydroxide (450 mg, 0.5 ml, 12.8 mmol) were combined with 1,4-dioxane (2 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 6 h. It was concentrated and diluted with water, extracted with ethyl acetate (2×20 ml). The organic layers were dried (MgSO4) and concentrated to give N*4*-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidine-2,4-diamine as a yellow foaming solid. MS (ES+): 561.
Reaction SMILES: CS[C:3]1[CH:13]=[CH:12][C:11](CCCC2C=CC=CC=2)=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl>[C:7]([Cl:31])(=[O:8])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:3]=1
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To dry methylene chloride (32 ml) there is added 2-methylthio-5-(3-phenylpropyl)cinnamic acid (1.0 g, 3.2 mmol). To this mixture is added DMF (0.25 ml, 3.2 mmol) and the reaction mixture cooled in an ice bath. Oxalyl chloride (.61 ml, 7.04 mmol) is slowly added dropwise and the resulting mixture stirred at room temperature for 2 hours to afford 2-methylthio-5-3-phenylpropyl)cinnamic acid chloride in solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O.[ClH:25].C(OCC)C>C(Cl)Cl.O1CCOCC1>[ClH:25].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-bromo-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (55 mg, 0.14 mmol, 1.0 equiv) in methylene chloride (5 mL) at 0° C. was added 0.2 mL of 4M HCl in dioxane. The reaction was stirred at ambient temperature for 1 h. Then 10 mL of diethyl ether was added to the reaction and the reaction concentrated. To this residue was added 10 mL diethyl ether and the solid was filtered off and washed with diethyl ether several times and air dried for 15 min to provide the title compound (32 mg); MS, electrospray, 298 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(-c3c(F)cccc3F)oc(=O)c12

Procedure:
2-Amino-6-methylbenzoic acid (0.498 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (20 mL) were reacted as described under (10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].C([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])C.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([OH:28])=[O:26])=[CH:30][CH:31]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)N2CCCC2C#Cc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 8 h

Procedure:
A mixture of 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (255 mg, 0.8 mmol), 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (195 mg, 0.8 mmol), EDC (230 mg, 1.2 mmol), DMAP (98 mg, 0.8 mmol) in DMF (20 mL) was stirred overnight. The reaction mixture was poured into 1 N HCl and the resulting precipitate was collected with suction and dissolve in CHCl3. The solution was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3—MeOH (100:1, v/v) as eluent to give the desired compound, which was dissolved in THF (8 mL). 0.25 N NaOH (8 mL) was added to this solution and the resulting mixture was stirred overnight. The mixture was poured into 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was recrystallized from CHCl3-n-hexane to give 144 mg (37%) 33 as a pale yellow crystalline powder. mp 152-155 (d); 1H-NMR (DMSO-d6) δ1.92-2.27 (4 H, m), 2.50 (2 H, s), 3.33-3.78 (2 H, m), 3.80 and 3.82 (total 3 H, s, each), 4.88-5.12 (1 H, m), 6.77-7.24 and 7.99-8.20 (total 7 H, m,) 7.48 and 7.52 (2 H, d, J=8.3 Hz, each), 7.91 (2H, d, J=8.3 Hz), 8.72 (1H, s), 9.18 (1H, s), 13.11 (1H, br-s); MS (FAB) m/z 516 (M++1); Anal. Calcd. for C29H26N3O5F.2H2O: C, 63.15; H, 5.48; N, 7.63. Found: C, 63.58; H, 5.15; N, 7.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5](Cl)=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cc(Br)cnc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.4 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (0.500 g, 2.89 mmol) in pyridine (1.45 ml) was dropwise added 2,4-difluorobenzene-1-sulfonyl chloride (0.614 ml, 2.89 mmol) at 0° C. The mixture was stirred for 40 min at room temperature and acidified with 1 N HCl. The residue was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70 g, 70% yield) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 6.92-7.04 (2H, m), 7.76-7.84 (1H, m), 7.86-7.95 (1H, m), 8.27 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz); NH peak was not observed.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[CH2:28][C:29](Cl)=[O:30])[CH3:18]>C(#N)C>[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[CH2:28][C:29]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:30])[CH3:18]
Reactant: CCc1cc(C)cc(CC)c1CC(=O)Cl
Reactant: CCOC(=O)C(C)=NNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.4 %

Procedure:
To a mixture of 2.0 g of ethyl 2-(methylhydrazono)propanoate and 35 mL of acetonitrile, 1.5 g of potassium carbonate was added. To the mixture, a solution of 2.6 g of 2,6-diethyl-4-methylphenylacetyl chloride in 10 mL of acetonitrile was added dropwise over about 20 minutes under ice cooling. This mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue, 20 mL of ice water was added, followed by extraction with ethyl acetate (20 mL×3). The organic layer was washed with an aqueous saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to basic alumina column chromatography (ethyl acetate:hexane=1:3) to obtain 1.9 g of ethyl 2-[2-(2,6-diethyl-4-methylphenylacetyl)-2-methylhydrazono]propanoate [compound (VI-2)] as a white crystal.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[CH3:36]>>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([O:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=3[CH:13]=2)=[C:29]([CH3:36])[CH:30]=1)#[N:33]
Reactant: Cc1cc(C#N)ccc1F
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: Cc1cc(C#N)ccc1Oc1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-3-methyl-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.14 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])=[C:7]([CH3:19])[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:25])=[C:7]([CH3:19])[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)O)c3)c3ccc(Cl)c(F)c32)cn1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)NS(C)(=O)=O)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[6-Chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl]-benzoic acid (0.107 g, 0.245 mmol) in THF (2 mL) at room temperature was added CDI (0.10 g, 0.61 mmol) and DMAP (0.005 g). The resulting mixture was stirred for 18 hrs, after which time DBU (0.15 mL, 0.98 mmol) and methane sulfonamide (0.07 g, 0.74 mmol) were added. The resulting mixture was stirred for and additional 18 hrs at room temperature, then subjected to standard aqueous workup. The crude residue was purified on silica gel (0-10% MeOH in DCM) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([N+:11]([O-])=O)[C:3]=1[CH3:14].O.O.Cl[Sn]Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([NH2:11])[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Br)ccc(N)c1N
Temperature: 80 °C
Yield: 90.4 %

Procedure:
A mixture of 154 (40 g, 154 mmol), SnCl2.2H2O (208 g, 920 mmol), EtOAc (300 mL) and EtOH (150 mL) was heated to 80° C. for 12 h, cooled to RT, poured into crushed ice (2 Kg) and the pH adjusted to pH 7-8 with solid NaHCO3. The solid was filtered and washed with EtOAc. The filtrate was thrice extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 28 g (91%) of 4-bromo-3-methyl-1,2-benzenediamine (156) as a brown oil: MS (ESI) m/z=202 [M+1]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1)=O>O1CCCC1>[C:7]([CH:9]=[CH:18][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CC#N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (1.0 mL, 1.0 mmol) was added diethyl cyanomethylphosphonate (0.15 mL, 0.92 mmol) dropwise at 0° C. and the resulting mixture was stirred at 0° C. for 1 h. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (0.15 g, 0.66 mmol) (Example 5, Step 1) in tetrahydrofuran (4.6 mL) was added dropwise, then cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was diluted with EtOAc, washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product as a mixture of E- and Z-isomers (0.14 g, 70%). LCMS calculated for C14H22N2O2Na (M+Na)+: m/z=273.2. Found: 273.0.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Nc1ccc(Cl)cc1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)cc1Br
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a stirred mixture of 2-bromo-4-chloroaniline (5 g, 24 mmol) and catalytic DMAP in CH2Cl2 (15 mL) was add acetic anhydride (2.3 mL, 24 mmol) at room temperature. The reaction mixture was stirred overnight then washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated in vacuo. The crude material was triturated with Hexane/Et2O and the solid filtered and dried in vacuo to give N-(2-bromo-4-chloro-phenyl)-acetamide (5.2 g, 86%). HPLC: Rt=2.26 min. m/z=248 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[Cl:10].[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:11]=[CH:9]2
Reactant: O=N[O-]
Reactant: Cc1c(N)ccc(Br)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1c(Br)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) in acetic acid (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=3)[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:41]([NH:43][NH2:44])=[O:42]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=3)[C:18]2=[O:28])[CH2:13][C:14]2[O:15][CH:41]=[N:43][N:44]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:41](=[N:43][NH:44][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=2)[C:18]1=[O:28])=[O:42]
Reactant: NNC=O
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)NN=C=O)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Yield: 93.2 %

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-5-methylisoindoline-1,3-dione was prepared by the procedure of Example 1. Reaction of 3-(3-ethoxy-4-methoxyphenyl)-3-(5-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (1.81 g, 4.72 mmol), carbonyldiimidazole (0.92 g, 5.7 mmol) and formic hydrazide (375 mg, 6.2 mmol) in ethyl acetate (20 mL) gave crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(5-methyl-1,3-dioxoisoindolin-2-yl)propanamide (0.93 g, 2.2 mmol), which was then treated with phosphorus oxychloride (0.4 mL, 4.3 mmol) in acetonitrile (12 mL). The product was obtained as a white solid (371 mg, 19% overall yield): mp, 122.0-124.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J=6.9 Hz, 3H, CH3), 2.48 (s, 3H, CH3), 3.80 (dd, J=6.0, 15.6 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=6.9 Hz, 2H, CH2), 4.35 (dd, J=10.3, 15.6 Hz, 1H, CHH), 5.79 (dd, J=6.0, 10.2 Hz, 1H, NCH), 6.82 (d, J=8.1 Hz, 1H, Ar), 7.12-7.17 (m, 2H, Ar), 7.47 (d, J=7.5 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 7.68 (d, J=7.6 Hz, 1H, Ar), 8.28 (s, 1H, Ar); 13C NMR (CDCl3) δ 14.61, 21.86, 27.67, 51.71, 55.83, 64.36, 111.29, 112.49, 120.22, 123.27, 123.88, 128.97, 130.23, 131.95, 134.58, 145.39, 148.33, 149.34, 152.93, 163.97, 167.91, 168.04; Anal Calcd for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.77; H, 5.07; N, 10.30.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:6]([O:25][CH3:26])=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:24][NH:23][CH2:22][CH2:21][N:11]3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[C:6]([O:25][CH3:26])=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:24][N:23]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:22][CH2:21][N:11]3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:14]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCN(Cc3ccccc3)CC1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline dihydrochloride (the compound obtained in Example 1-(6)) (2 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added potassium carbonate (2.8 g) and benzyl bromide (0.7 ml), and the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitates (1.2 g) are dissolved in chloroform, and thereto is added a 4M hydrochloric acid in ethyl acetate, and the solvent is removed by evaporation under reduced pressure. The resultant is recrystallized from ethanol to give 8,9-dimethoxy-2-benzyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline dihydrochloride (1.2 g).