Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=3[CH3:26])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(O)=O.CO.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([NH:16][C:14]2[CH:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[N:11]=[CH:12][N:13]=2)[CH:22]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.NC1C=CC2N(C)C(=O)CCCC=2C=1>>[NH2:15][C:6]1[C:7]2[NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][C:13]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCCC(=O)N2
Agent: CN1C(=O)CCCc2cc(N)ccc21
Product: COc1ccc(N)c2c1CCCC(=O)N2

Procedure:
9-Amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was prepared from 6-methoxy-9-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one via reduction of the nitro group as described for the preparation of 7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one. The crude product was purified by flash chromatography (EtOAc) and the product was obtained as a solid (36%); (400 MHz, DMSO-d6) δ6.62 (d, J=8.84 Hz, 1H), 6.56 (d, J 8.84 Hz, 1H), 4.52 (br s, 1H), 3.66 (s, 3H), 3.16 (d, J=3.31 Hz, 2H), 2.64 (m, 2H), 2.04 (m, 2H), 1.97 (m, 2H); MS (m/e) 207 (M+H).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].[OH-:21].[K+].Cl>>[F:12][C:11]1[C:2]([OH:21])=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH3:20])[CH2:5][CH2:4]2)[CH:10]=1
Reactant: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CN1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
2.78 g of the compound (8) obtained in Example 3 was added to 10 ml of aqueous 30% potassium hydroxide solution, and the solution was heated at reflux for 6 hours. After air-cooling, the solution was acidified with 6N hydrochloric acid, and the deposited solids were filtered off and washed with water, ethanol and isopropyl ether in this order to obtain 2.60 g of the subject compound (166).
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[C:30]3[O:29][CH:28]=[CH:27][C:26]=3[CH:25]=[C:24]([NH:31][S:32]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[O:42][CH3:43])(=[O:34])=[O:33])[CH:23]=2)=[O:21])[CH2:16][CH2:15]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH3:43][O:42][C:36]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:35]=1[S:32]([NH:31][C:24]1[CH:23]=[C:22]([C:20]([N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)=[O:21])[C:30]2[O:29][CH:28]=[CH:27][C:26]=2[CH:25]=1)(=[O:33])=[O:34]
Reactant: COc1ccc(C)cc1S(=O)(=O)Nc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2occc2c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(C(=O)N2CCNCC2)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Deprotection of the N-t-BOC group in 4-[5-(2-methoxy-5-methyl-benzenesulfonylamino)-benzofuran-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (Step 3) was performed by adding HCl/ether to a solution of the said substrate in ethyl acetate and allowed to stir overnight at ambient temperature. Concentration of the solution gave the title product as a white solid. Yield: 31 mg. HPLC 96% RT=2.73 min (System A; 30-80% MeCN over 3 min), 1.05 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 Mz, methanol-d4) δ ppm 2.17 (s, 3H), 3.19 (m, 2H), 3.34 (m, 2H), 3.49 (m, 2H), 3.91 (s, 3H), 4.01 (m, 2H), 6.80 (d, J=2.2 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H). 13C NMR (400 Mz, MeOH-d4) δ ppm 19.15, 55.60, 94.55, 106.86, 112.31, 116.62, 118.32, 118.44, 125.90, 129.07, 129.89, 130.51, 133.47, 135.37, 140.33, 147.22, 147.92, 154.75, 166.24 (C═O). MS (ESI) for C21H23N3O5S m/z 430 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[S:12]([OH:15])(=[O:14])=[O:13].CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([OH:36])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3O)cc2)OC1(C)C
Reactant: O=S(=O)(O)c1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 130 °C
Yield: 1.8 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indole (300 mg, 1.30 mmol) and sulfur trioxide pyridine complex (622 mg, 3.91 mmol) in pyridine (2 mL) was sealed in a pressure tube and heated to 100° C. for 48 hours. The reaction mixture was concentrated in vacuo to provide 5-bromo-6-chloro-1H-indole-3-sulfonic acid as a pyridinium salt, which was used directly in the next step without further purification. A mixture of 5-bromo-6-chloro-1H-indole-3-sulfonic acid (100 mg, 0.32 mmol), 4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-ol (114 mg, 0.39 mmol), 2 N aqueous potassium carbonate solution (0.64 mL, 1.29 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.0 mg, 0.016 mmol) in EtOH (5 mL) was sealed and heated to 130° C. for 2 hours. The reaction mixture was diluted with water (10 mL) and washed with EtOAc (2×10 mL). The aqueous layer was concentrated in vacuo and purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); HOLD at 100.0% H2O/0.0% MeCN for 1.0 min. 100.0% H2O/0.0% MeCN linear to 5.0% H2O/95.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.) to provide the title compound (2.3 mg, 2%). MS (ES−) 398.0 (M−H)+. Retention time=2.28 minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH:1]1(C(O)=O)[CH:6]([C:7]([OH:9])=[O:8])[CH:5]([C:10]([OH:12])=[O:11])[CH:4](C(O)=O)[CH:3](C(O)=O)[CH:2]1C(O)=O.C(O)(=O)C1C(=CC=CC=1)C(O)=O>>[CH:5]1([C:10]([OH:12])=[O:11])[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1C(C(=O)O)C(C(=O)O)C(C(=O)O)C(C(=O)O)C1C(=O)O
Agent: O=C(O)c1ccccc1C(=O)O
Product: O=C(O)C1C=CC=CC1C(=O)O

Procedure:
Cyclohexane-1,2,3,4,5,6-hexacarboxylic acid can be prepared by partially hydrogenating phthalic acid to form 3,5-cyclohexadiene-1,2-dicarboxylic acid, reacting the product with maleic anhydride to form bicyclo-2,2,2, 7-octane-2,3,5,6-tetracarboxylic acid, and catalytically oxidizing this intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5]([C:11](OCC)=[O:12])[C:6](OCC)=[O:7].[CH:20]([NH2:22])=[NH:21]>>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[C:11](=[O:12])[NH:22][CH:20]=[N:21][C:6]=1[OH:7]
Reactant: CCOC(=O)C(Cc1ccccc1Cl)C(=O)OCC
Reactant: N=CN
Product: O=c1[nH]cnc(O)c1Cc1ccccc1Cl

Procedure:
Condensation of diethyl o-chlorobenzylmalonate with formamidine yielded 5-(o-chlorobenzyl)-6-hydroxy-4(3H)-pyrimidinone which, by reaction with phosphorus oxychloride, yielded 4,6-chloro-5-(o-chlorobenzyl)pyrimidine, melting point 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:22]([CH:24]1[CH2:26][CH:25]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=O>CN1C(=O)CCC1>[CH2:30]([O:29][C:27]([CH:25]1[CH2:26][CH:24]1[C:22]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]([N:11]3[CH2:17][C:16]4([CH3:19])[CH2:18][CH:12]3[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]4)=[O:10])=[CH:3][C:2]=2[N:1]=1)=[O:28])[CH3:31]
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)c(N)c2)C1
Reactant: CCOC(=O)C1CC1C=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CC1c1nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 8.4 %

Procedure:
To a solution of (3,4-diaminophenyl)-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)methanone (500 mg, 1.74 mmol) in dry NMP (25 mL) at room temperature under an inert atmosphere of nitrogen was added approx. 500 mg of molecular sieve 4 Å followed by ethyl 2-formyl-1-cyclopropanecarboxylate (0.51 mL, 3.86 mmol). The mixture was stirred for 16 hrs at 50° C. The reaction was quenched by the addition of water (100 mL) followed by extraction with diethyl ether (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo. The resulting oil was purified by preparative HPLC, dried in vacuo at 50° C. affording 60 mg (8%) of the title compound as a solid. MS-ESI m/z 410; 1H NMR (400 MHz, CDCl3) δ 0.88-1.06 (m, 6H), 1.07-1.20 (m, 4H), 1.25 (t, 3H), 1.27-1.34 (m) and 1.49-1.66 (m, 3H), 1.36-1.48 (m, 2H), 1.72-1.84 (m, 2H), 2.36-2.48 (m, 1H), 2.66-2.76 (m, 1H), 3.18-3.27 (m, 1H), 3.30 (d) and 3.65 (d, 1H), 4.00-4.06 (m) and 4.57-4.65 (m, 1H), 4.14 (q, 2H), 7.18-7.30 (m, 2H), 7.57 (d, 1H), 10.37 (br s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Yield: 89.9 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-3 using 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 250 mg, 1.20 mmol), 4-fluoro-3-(trifluoromethyl)phenol (430 mg, 2.40 mmol), K2CO3 (479 mg, 3.60 mmol) in CH3CN (5 mL) to afford 380 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.75 (s, 1H), 8.82 (d, J=5.4 Hz, 1H), 7.92 (m, 1H), 7.86-7.81 (m, 3H), 7.31 (t, J=9.6 Hz, 1H), 6.90 (d, J=5.1 Hz, 1H); MS (m/z): 353.14 (M+H)+.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][CH2:35][C:36](O)=[O:37])(OCC1C=CC=CC=1)=O>>[NH2:34][CH2:35][C:36]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:37]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: NCC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 2 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-glycine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-4.01 (m, 1H), 3.85 (s, 2H), 3.55-3.40 (m, 1H), 3.38-3.22 (m, 1H), 1.91-1.40 (m, 10H), 1.38-0.90 (m, 5H). 31P NMR (CD3OD, 300 MHz): δ 39.92. LCMS m/z: [M+H]+=293.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:14][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=2)=[CH:18][CH:17]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCCCCCCCCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCCCCCCCCCCOCc2ccc(Br)cc2)cc1
Yield: 87 %

Procedure:
To a solution of 851 mg (21.3 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (60 ml) was added 1.21 g (6.94 mmol) of 1,10-decanediol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, 4.23 g (16.9 mmol) of 4-bromobenzyl bromide was added to the solution, and the mixture was reacted at room temperature for 18 hours. To the solution at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:1) yielded 3.09 g (6.04 mmol) of 1,14-bis(4-bromophenyl)-2,13-dioxatetradecane.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1.N([O-])=O.[Na+].[I-:24].[K+]>O.OS(O)(=O)=O>[I:24][C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc(I)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (500 mg, 1.85 mmol) was dissolved in H2O (5 mL) and concentrated H2SO4 solution (0.5 mL) then cooled to 0° C. and treated with a solution of sodium nitrite (NaNO2) (140 mg, 2.04 mmol) in H2O (2 mL) dropwise. Potassium iodide (460 mg, 2.78 mmol) in 1N H2SO4 solution (0.5 mL) was added over 10 minutes (reaction becomes dark red). The resulting solution was warmed to room temperature and stirred 18 hours. The reaction was quenched with NaHSO3 and water (pH 2.5) then extracted with ethyl acetate (4×30 mL). After drying (Na2SO4), the solution was filtered and concentrated to a yellow oil which was chromatographed on Silica gel to provide a yellow oil. (260 mg, 37%). (TLC 30% ethyl acetate/hexanes Rf 0.70). (A 5.4 g scale performed as above yielded 5 g, 67%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23]C(=O)C2C=CC=CC=2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:44]([CH3:46])([CH3:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:42]=2[Se:41]1)(=O)C.[OH-].[Na+].Cl>C1COCC1.CO>[OH:23][C:16]1[CH:17]=[CH:18][C:19]2[C@@H:20]3[C@H:11]([C@H:8]4[C@@:6]([CH2:22][CH2:21]3)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]4)[C@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]([CH3:45])([CH3:46])[C:43]4[CH:47]=[CH:48][CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:42]=4[Se:41]3)[CH2:13][C:14]=2[CH:15]=1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCN4[Se]c5c([N+](=O)[O-])cccc5C4(C)C)Cc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)c2cccc([N+](=O)[O-])c2[Se]N1CCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 22 h
Yield: 99 %

Procedure:
N-{8-[17β-acetoxy-3-benzoyloxyestra-1,3,5(10)-trien-7α-yl]octyl}-3,3-dimethyl-7-nitrobenzisoselenazoline (115 mg, 0.15 mmol) is dissolved in 2 ml of THF and 1 ml of methanol. To the obtained mixture is then added an aqueous solution of NaOH (1 ml, 1N, 1.0 mmol). The reaction medium is stirred at room temperature for 22 hours, then neutralized with an aqueous solution of HCl (1N). The mixture is extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous solution of NaCl, dried over MgSO4 and evaporated. The residue is purified by silica gel column chromatography (eluent:EtOAc:cyclohexane, 1:3) to provide the expected product (95 mg, 94%) as a deep red solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]=1[F:24].[CH:27]([Sn](CCCC)(CCCC)CCCC)=[CH2:28].CCOC(C)=O.[Na+].[Cl-]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:27]=[CH2:28])=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]=1[F:24]
Reactant: Cc1ccc(Nc2ccc(Br)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Nc2ccc(C)cc2CC(=O)N(C)C)c(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
5-Methyl-2-(2′-fluoro-4′-bromo-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide prepared by method outlined in example 3 (0.8 g, 1.7 mmol), Pd(PPh3)4 (0.1 g, 0.09 mmol), and vinyl tributylstannane (0.6 g, 1.9 mmol) in DMF (5 mL) is heated to 120° C. under nitrogen overnight. After cooling, the reaction is portioned between EtOAc and saturated aqueous solution of NaCl. The separated organic layer is washed twice with fresh saturated aqueous solution of NaCl. The EtOAc layer is dried and concentrated under reduced pressure. The residue is purified by flash chromatography to give 5-Methyl-2-(2′-fluoro-4′-vinyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14].[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>CCOC(C)=O>[CH2:31]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])(=[O:36])=[O:35])[CH2:32][CH3:33]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(N)c3)n2)cc1F
Reactant: CCCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C

Procedure:
The title compound was obtained following procedure and work up described for example 67, step 1, but starting from methyl 4-{5-[3-amino-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate, prepared as in example 67, Steps 1 and 2, (200 mg; 0.49 mmol) and 1-propanesulfonyl chloride (280 mg; 2 mmol). The title compound was obtained as a yellow powder after column chromatography (EtOAc:cHex from 10:90 to 100:0). LC/MS (Method B): 517.4 (M+H)+. HPLC (Method A) Rt. 6.37 min (purity: 96.5%).
Reaction SMILES: ClC1N=C(C2C=C(C=CC=2)C=O)C=CN=1.C(OC([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([Cl:42])[N:37]=3)[CH:31]=2)[CH:25]([C:43]([OH:45])=[O:44])[CH2:24]1)=O)(C)(C)C>>[Cl:42][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=2)[CH2:29][N:26]2[CH2:27][CH2:28][NH:23][CH2:24][CH:25]2[C:43]([OH:45])=[O:44])[CH:41]=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C(=O)O)C1
Agent: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 4-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 433.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:41]1[CH2:46][CH2:45][S:44][CH2:43][CH2:42]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:41]2[CH2:46][CH2:45][S:44][CH2:43][CH2:42]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCSCC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 51 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and thiomorpholine (0.80 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-42. Mol. Wt.: 499.5808 (C28H25N3O4S); Rf: 0.43 (ethyl acetate:n-hexane=1:2); Yield: 51%; Mp.: 210-211° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 499.1566 (C28H25N3O4S+). Found, 499.1570. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2:39 (br, 4H, —CH2—), 2.45 (s, 3H, —CH3), 3.15 (s, 2H, —CH2N—), 3.23 (br, 4H, —CH2—), 7.45 (d, J=8.1 Hz, 2H, Ar—H), 7.88-7.91 (m, 2H, Ar—H), 8.07-8.19 (m, 4H, Ar—H), 8.27 (d, J=8.4 Hz, 1H, Ar—H), 8.73 (d, J=8.4 Hz, 1H, Ar—H), 10.00 (s, 1H, Ar—NH—), 10.61 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.89, 26.48, 53.13, 54.62, 61.92, 65.54, 127.72, 126.30, 126.40, 126.92, 127.69, 127.92, 127.98, 129.22, 129.43, 130.53, 132.30, 134.12, 134.41, 134.45, 140.21, 142.61, 166.27 (NCO), 168.89, 169.15 (NCO), 181.42 (CO), 183.84 (CO).