Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[C:8]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:7]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[NH2:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:7]=3[N:6]2[CH2:5][CH2:4][CH2:3][N:2]([CH3:24])[CH3:1])=[CH:10][CH:11]=1
Reactant: CN(C)CCCn1c2c(c3ccc([N+](=O)[O-])cc31)CCCCCC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)CCCn1c2c(c3ccc(N)cc31)CCCCCC2

Procedure:
3-Amino-6,7,8,9,10,11-hexahydro-N,N-dimethyl-5H-cyclooct[b]indole-5-propanamine was prepared following the procedure of Example 1, using 6,7,8,9,10,11-hexahydro-N,N-dimethyl-3-nitro-5H-cyclooct[b]indole-5-propanamine instead of 6,7,8,9,10,11-hexahydro-N,N-dimethyl-1-nitro-5H-cyclooct[b]indole-5-propanamine and was converted to the dihydrochloride salt; m.p. 235°-238° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][CH:16]1[NH:19][C:18](=[O:20])[CH:17]1[C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])=[O:6])[CH:2]=[CH2:3].B(F)(F)F.CCOCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@@H:17]1[C@H:21]([OH:23])[CH3:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)CC1NC(=O)C1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (33.90 g) in acetonitrile (68 ml) was added boron trifluoride etherate (19.74 ml) at 5°-10° C. After stirring at 0° C. for 30 minutes, the reaction mixture was taken up into a mixture of ethyl acetate (170 ml), water (140 ml) and sodium bicarbonate (13.48 g). After stirring for 30 minutes, the organic layer was separated. The aqueous layer was extracted with ethyl acetate (70 ml). The combined organic portion was washed with brine (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]3-[(1R)-1-hydroxyethyl]-2-oxoazetidine.
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:10]3[O:11][CH2:12][C:13]4[N:14]([CH:15]=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]4[N:14]5[C:15]([Br:38])=[N:16][N:17]=[C:13]5[CH2:12][O:11][C:10]=4[N:18]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3cnnc3CO4)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(Br)nnc3CO4)cc2)CCC1
Yield: 68.5 %

Procedure:
A mixture of tert-butyl 1-(4-(8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutylcarbamate (200 mg, 0.404 mmol) and 1-bromopyrrolidine-2,5-dione (114.9275 mg, 0.646 mmol) in DCM (12 ml) and CCl4 (18 ml) was heating at 50 degree for 24 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (40 ml) and water (40 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phase was washed with water (50 ml) brine (30 ml) and concentrated to give product 159 mg. 1H NMR (500 MHz, CDCl3): 8.55 (s, 1H), 7.22-7.35 (m, 9H), 5.58 (s, 2H), 5.1 (br, 1H), 2.4-2.5 (m, 4H), 2.01-2.11 (m, 1H), 1.79-1.89 (m, 1H), 1.24-1.43 (br, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH2:14][CH3:15])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH2:14][CH3:15])[CH:12]=1
Reactant: CCNc1cc(Cl)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1cc(Cl)ncc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of ethyl 6-chloro-4-(ethylamino)nicotinate (3.9 g, 17 mmol) in anhydrous THF (50 mL) was added LiAlH4 (3.6 g, 95 mmol) at −50° C., then the resulting mixture was allowed to warm to 0° C. and stirred for 1 h. Then the mixture was quenched by the addition of 10% aq NaOH solution (3.6 mL). The mixture was filtered and the filtrate was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to provide to (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1 H), 76.55 (s, 1 H), 6.17 (m, 1 H), 5.25 (t, J=5.2 Hz, 1 H), 4.44 (q, J=7.2 Hz, 2 H), 3.23 (m, 2H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([OH:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:61][N:62](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[C:3]([CH3:18])=[C:2]([CH:7]=[CH:6][CH:5]=3)[C:61]#[N:62])[N:9]=[CH:10][C:11]=12
Reactant: CN(C)C=O
Reactant: Cc1c(Br)cccc1-n1ncc2c(O)ncnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(C#N)cccc1-n1ncc2c(O)ncnc21
Temperature: 160 °C
Yield: 81 %

Procedure:
1-(3-bromo-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate AT4) (2 g, 6.55 mmol) and Zinc cyanide (0.693 g, 5.90 mmol) were dissolved in DMF (30 mL)and sealed into a microwave tube. The tube was purged with nitrogen. 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.379 g, 0.66 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.300 g, 0.33 mmol) added. The reaction was heated to 160° C. for 10 minutes in the microwave reactor and cooled to RT. The reaction mixture was filtered and the solid washed with DMF (until the filtrate was colourless) to afford the product (1.340 g, 81%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.19 (3H, s), 7.54 (1H, t), 7.71 (1H, d), 7.94 (1H, d), 8.02 (1H, s), 8.30 (1H, s), 12.32 (1H, s)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11].Cl[CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:18][S:15]([CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11])(=[O:17])=[O:16]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1c(CO)nc2ccccc21

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)methanol (1.0 g, 6.75 mmol) and 1-chloro-2-(methylsulfonyl) ethane (1.05 g, 7.42 mmol) in DMF (3 mL) was stirred in the presence of K2CO3 (0.93 g, 6.75 mmol) at RT for overnight. The mixture was poured into water (20 mL) and extracted with DCM (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude (1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazol-2-yl)methanol which was used for next step directly.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]=[N:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8](Cl)[C:9]=1[C:10]#[N:11].[C:16]1([S:22]([O-:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>>[CH3:1][N:2]([CH3:15])[CH:3]=[N:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[C:9]=1[C:10]#[N:11]
Reactant: O=S([O-])c1ccccc1
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Agent: [Na+]
Product: CN(C)C=Nc1sc(C=O)c(S(=O)(=O)c2ccccc2)c1C#N

Procedure:
A mixture of 12.1 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)-formamidine, 8.2 parts of sodium phenylsulfinate and 70 parts of methylglycol is heated at the boil for 1 hour. The precipitated product is then filtered off under suction when the mixture is cold and is washed with methylglycol and then with water and dried. 9.7 parts of N,N-dimethyl-N'-(3-cyano-5-formyl-4-phenylsulfonylthien-2-yl)-formamidine are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=2)[N:23]=1>>[Cl:1][C:2]1[C:3]([N:8]([C:37]([C:34]2[CH:33]=[CH:32][C:31]([N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[N:22]=[N:23]3)=[CH:36][N:35]=2)=[O:38])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Reactant: O=C(O)c1ccc(-n2nnc3cccnc32)cn1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(-n3nnc4cccnc43)cn2)c2ncccc2Cl)C1
Yield: 51.7 %

Procedure:
Prepared using General Procedures A and C starting from Preparation 1 tert-butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (3.22 g, 10.3 mmol) and Preparation 7 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxylic acid (2.37 g, 9.83 mmol) to provide 2.72 g (52%) of the product isolated as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[Si:21]([O:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Si:21]([O:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:18](=[O:19])[CH2:17][C:4]2[CH:5]=[CH:6][C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]3)=[C:2]([F:1])[CH:3]=2)=[CH:34][C:33]=1[C:39]([F:40])([F:41])[F:42])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2F)OC1(C)C
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (5 g, 17.85 mmol) in DCM (100 mL) was added 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (7.10 g, 19.64 mmol), DIEA (6.24 mL, 35.7 mmol) and HATU (8.14 g, 21.42 mmol). The solution was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a white solid of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (10 g, 12.83 mmol, 72% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 6.99 (dd, J=4.8, 10.0 Hz, 2H), 3.63 (s, 2H), 3.26 (s, 2H), 2.69 (s, 2H), 1.11 (s, 12H), 0.86 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 624.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[N:10]=2)[N:7]=1>C1COCC1.[Pd]>[C:17]([C:15]1[CH:14]=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][CH:2]=[N:7][N:6]3[CH:8]=2)[CH:16]=1)#[N:18]
Reactant: CS(=O)(=O)Nc1cc(C#N)cc(-c2cn3nc(Cl)ccc3n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C#N)cc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide (0.8 mmol) and 6-chloropyridazin-3-amine (0.8 mmol) in EtOH (8 mL) was refluxed for 4 hours. After cooling, the resulting mixture was filtrated to give N-(3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-cyanophenyl)methanesulfonamide in 50% yield. 10% Pd/C (20 mg) was added to the solution of N-(3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-cyanophenyl)methanesulfonamide (0.3 mmol) in THF (25 mL. Then it was stirred at room temperature for 4 hours. After filtration, it was concentrated to give N-(3-cyano-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide in 95% yield.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:22])[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCCN(CCC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)c1ccc(Br)c2nc(Cl)n(C)c12
Yield: 99.1 %

Procedure:
A mixture of 4-bromo-7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (210 mg, 0.644 mmol) and phosphorus oxychloride (3.0, 32 mol) was refluxed for 18 h with stirring and concentrated to dryness under vacuum. The residue was diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to afford 220 mg (99%) of the title compound. The residue was used for the next reaction without further purification.
Reaction SMILES: CN(C)[CH:3]=[N:4][C:5]1[S:6][CH:7]=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].C(O)=[O:15]>O>[Cl:12][C:8]1[C:9]([C:10]#[N:11])=[C:5]([NH:4][CH:3]=[O:15])[S:6][CH:7]=1
Reactant: O=CO
Reactant: CN(C)C=Nc1scc(Cl)c1C#N
Solvent: O
Product: N#Cc1c(Cl)csc1NC=O
Temperature: 25 °C
Yield: 77 %

Procedure:
4.5 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-thien-2-yl)-formamidine in a mixture of 20 parts of formic acid and 20 parts of water are heated at the boil for 1 hour. After the mixture has cooled to room temperature, the product is filtered off under suction, washed with water and dried. 3 parts (77% of theory) of N-(4-chloro-3-cyanothien-2-yl)-formamide are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3C=CC=CC=3)=[C:15]([N+:27]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].BrCCBr>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][CH2:21][NH:27][C:15]=3[CH:14]=2)=[O:30])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
Steps 5 and 6. A solution of 4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester (26 g, 63 mmol) in DMF (2644 mL) was treated with 10% palladium on carbon (5.3 g). The reaction vessel was evacuated and filled with hydrogen. The mixture was stirred at room temperature for 4 hours, then the catalyst was filtered, washing with a small quantity of dimethylformamide. The resulting solution, containing crude 4-(3-amino-4-hydroxy-benzoylamino)-benzoic acid ethyl ester, was concentrated to a volume of 300 mL, and treated with K2CO3 (34.1 g, 247 mmol) and 1,2-dibromoethane (46.4 g, 247 mmol). The resulting mixture was warmed at 70° C. and stirred for 18 hours. The mixture was then concentrated to a volume of 100 mL and diluted with ethyl acetate and water. The organic phase was separated, washed three times with water, dried over sodium sulfate and evaporated. The residue was taken up in methanol and sonicated. The white solid was filtered, yielding pure 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (8.6 g). The filtrate was evaporated and the residue purified by flash chromatography (toluene/acetonitrile gradient) providing further 2 g of material. 4-[(3,4-Dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester was thus obtained as a white solid, 10.6 g (52%), MS (ISP): m/e=327.0 (M+H+); δH (300 MHz; d6-DMSO) 10.27 (1H, s), 7.92 (4H, s), 7.16-7.19 (2H, m), 6.75 (1H, d), 6.04 (1H, s), 4.29 (2H, q), 4.19 (2H, s), 3.32 (2H, s), 1.32 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[Se](=O)=[O:24]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Yield: 72.3 %

Procedure:
6-Methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1 g, 3.39 mmol) prepared in Preparation Example 1 was dissolved in 1,4-dioxane and selenium dioxide (5.65 g, 50.96 mmol) was added thereto. The mixture was refluxed for 24 hrs, cooled, washed with 1M sodium bicarbonate, and extracted with diethyl ether. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 756 mg of the titled compound (yield: 72%) as a red solid.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (1.1 g) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:29]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[C:36]([F:47])([F:46])[F:35])[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: CCOCC.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[OH:14].[N+:15]([O-])([OH:17])=[O:16]>O>[CH3:13][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([OH:14])[C:7]([CH3:6])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C)c(O)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C)c([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
To a stirred mixture of 130 ml of water, 130 ml of ether and 10.0 g of 2,5-dimethylphenol was added dropwise 5.2 ml of 70% nitric acid while cooling with ice. The temperature of the mixture was raised to room temperature and the reaction was continued for a day. After 500 ml of water was added, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively, and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 3.83 g of 3,6-dimethyl-2-nitrophenol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nc(C(F)(F)F)c2)cc1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(-n3cnc(I)c3)nc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from 2-chloro-6-trifluoromethyl-4-(4-trifluoromethylphenyl)-pyridine (example A.26) (2.0 g, 6.14 mmol) and commercially available 4-iodo-imidazole (1.31 g, 6.75 mmol) according to the general procedure IVa. Obtained as a white solid (1.90 g, 82%). MS (ISP) 484.1 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OC(=O)C)C>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirring solution of a mixture of (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (2.85 g, 12.43 mmol) and potassium carbonate (4.33 g, 24.87 mmol) in anhydrous N,N-dimethylformamide (60 mL) was added benzyl bromide (4.25 g, 24.87 mmol). The mixture was stirred at room temperature overnight. The resulting crude mixture was diluted with ethylacetate and the organic layer was washed with 10% sodium carbonate and brine. The organic layer was dried over sodium sulfate and volatiles were removed in-vacuo. The residue was purified on normal phase column to yield 2.82 g (71%) of desired product.