Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:19])C.[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.II.[OH-].[Na+].Cl>CN(C=O)C.O>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]([S:27][C:24]1[CH:23]=[CH:22][C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:25]=1)=[C:7]([CH3:19])[N:6]2[CH2:5][C:4]([OH:3])=[O:20])(=[O:18])[CH3:17]
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1c(Sc1ccc(-c3ccccc3)cc1)c(C)n2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of (4-acetylamino-2-methyl-indol-1-yl)-acetic acid ethyl ester (0.27 g) and biphenyl-4-thiol (0.19 g) in DMF (5 ml) was added iodine (0.25 g). After stirring at RT overnight 1M NaOH (3 ml) was added and the reaction stirred at RT for a further 12 hours. The reaction was poured into water, the pH adjusted to 3 using 1M HCl and the organics extracted with EtOAc. The EtOAc extractions were combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to give crude material. Purification using RPHPLC gave the title compound as a pink solid (0.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=[N:13][N:12]=1.[CH3:20][O:21]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH2:16]([N:15]1[CH:14]=[N:13][N:12]=[C:11]1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([CH:5]=1)[CH:20]=[O:21])[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc(-c2nncn2CC(C)C)c(OC)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(OC)c(-c2nncn2CC(C)C)cc1C=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
Ex-109E: To a solution of 3-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole (Ex-109D, 0.78 g, 2.98 mmol) was added dichloromethyl methyl ether (0.4 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 9.0 mL, 9.0 mmol) over 10 min at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min and ambient temperature overnight. The reaction mixture was poured into ice. The aqueous solution was extracted with dichloromethane and isopropyl alcohol (33%, v/v, in dichloromethane). The combined dichloromethane and isopropyl alcohol were washed with brine, dried over sodium sulfate and concentrated. The aqueous solution was treated with sodium hydroxide to pH 12 and extracted again with isopropyl alcohol (33%, v/v, in dichloromethane) to give additional product. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) afford 5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (0.24 g, 28%): 1H NMR (CDCl3) δ 10.30 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 6.51 (s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 3.58 (d, J=7.2 Hz, 2H), 1.91–1.80 (m, 1H), 0.77 (d, J=6.5 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:29]([O:31]CC)=[O:30])([CH3:13])[C@@H:11]([OH:46])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].[Cl-].[NH4+]>C(O)C.O1CCCC1>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:29]([OH:31])=[O:30])([CH3:13])[C@@H:11]([OH:46])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@@H]12)CCCCCC(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@]12C[C@H](CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 50 %

Procedure:
Ethyl 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoate (11.1 mg, 0.0168 mmol) was dissolved in a mixed solvent of ethanol (0.5 ml) and tetrahydrofuran (0.5 ml). To this solution, 1N aqueous NaOH (0.5 ml) was added and the resulting mixture was heated under reflux for 5 hours. After cooling, saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified using a silica gel plate (developing solvent: hexane/ethyl acetate=1/1) to give 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid (5.3 mg, Yield 50%).
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH2:10][O:11][CH2:12][C:13]2([CH2:20][CH3:21])[CH2:18][O:17][P:16](Cl)[O:15][CH2:14]2)([CH2:8][CH3:9])[CH2:4][O:3]1.[CH2:22]([NH:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([P:2]1[O:7][CH2:6][C:5]([CH2:10][O:11][CH2:12][C:13]2([CH2:20][CH3:21])[CH2:18][O:17][P:16]([N:26]([CH:27]3[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30][C:31]([CH3:33])([CH3:34])[CH2:32]3)[CH2:22][CH2:23][CH2:24][CH3:25])[O:15][CH2:14]2)([CH2:8][CH3:9])[CH2:4][O:3]1)[CH:27]1[CH2:28][C:29]([CH3:35])([CH3:36])[NH:30][C:31]([CH3:34])([CH3:33])[CH2:32]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCC1(COCC2(CC)COP(Cl)OC2)COP(Cl)OC1
Product: CCCCN(C1CC(C)(C)NC(C)(C)C1)P1OCC(CC)(COCC2(CC)COP(N(CCCC)C3CC(C)(C)NC(C)(C)C3)OC2)CO1

Procedure:
If 1,3-bis(2-chloro-5-ethyl-1,3,2-dioxaphosphorinan-5-yl)-2-oxapropane is reacted with 4-butylamino-2,2,6,6tetramethylpiperidine in a procedure analogous to Example 2, 1,3-bis[2-(N-butyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino)5-ethyl-1,3,2-dioxaphosphorinan-5-yl]-2-oxapropane is obtained as a viscous resin (Compound No. 22, formula below, R3 =H); FD-MS: 730 (M+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([O:15][CH3:16])=[O:14]>CO.[Pt](=O)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]1
Reactant: COC(=O)c1ccnc(-c2ccc(F)cc2Cl)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(F)cc2Cl)C1
Reaction time: 9 h
Yield: 200.2 %

Procedure:
Methyl 2-(2-chloro-4-fluorophenyl)isonicotinate hydrochloride (2.35 g, 7.78 mmol) was dissolved in methanol (50 mL) and platinum(IV) oxide (0.177 g, 0.78 mmol) was added. The reaction mixture was hydrogenated in a Büchi hydrogenator at 5 bar and room temperature for 9 h. The catalyst was removed by filtration and the solvent was evaporated. The residue was dissolved in methanol (50.0 mL) and platinum(IV) oxide (144 mg, 0.63 mmol) was added. Hydrogenation was continued at 5 bar and room temperature for 4 h. The catalyst was removed by filtration and the solvent was evaporated. Crude methyl 2-(2-chloro-4-fluorophenyl)piperidine-4-carboxylate hydrochloride (2.4 g, 100%) was obtained as a yellow solid. MS m/z 272 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:38][C:39]1[C:40]([CH3:45])=[N:41][O:42][C:43]=1[CH3:44]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][C:39]4[C:40]([CH3:45])=[N:41][O:42][C:43]=4[CH3:44])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: Cc1noc(C)c1CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5c(C)noc5C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 4-(chloromethyl)-3,5-dimethylisoxazole (35 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-Chloro-N2-(4-(1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. 1H NMR (400 MHz, MeOD-d4) 8.12 (s, 1H), 7.75 (d, 1H), 7.03 (s, 1H), 6.27 (s, 1H), 4.25 (s, 2H), 3.69-3.67 (m, 2H), 3.27-3.20 (m, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.10-1.95 (m, 4H); ESMS m/z 525.1 (M+H+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.155 g, 62%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.333 g, 0.74 mmol) and methylamine (0.231 g, 7.4 mmol). mp 229-231° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:17]([CH2:19][N:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:21][C:22]([OH:24])=O)#[N:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:15]([CH3:16])[C:22](=[O:24])[CH2:21][N:20]([CH2:19][C:17]#[N:18])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: N#CCN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CN[C@@H](CN1CCCC1)c1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C(=O)CN(CC#N)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.7 %

Procedure:
[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]methylamine (3.03 g, 10.7 mmol) and N-(cyanomethyl)-N-(3,4-dichlorophenyl)glycine (2.77 g, 10.7 mmol) were dissolved in 100 mL of dimethylformamide. Triethylamine (4.47 mL, 32.1 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 4.73 g, 10.7 mmol) dissolved in 10 mL of dimethylformamide was added to the mixture at room temperature. The reaction was maintained at that temperature for 2 hours, before it was determined to be complete by LCMS (Eclipse XDB C18 (4.6×250 mm); trifluoroacetic acid: 1-99% B for 10 min, ES) Rt=8.4 min and m/e 525 [M+1]+. The reaction mixture was treated with 100 mL of 50% H2O and 50% saturated sodium bicarbonate solution and was allowed to stir at room temperature for one hour. After transferring the mixture to a 1 L separatory funnel, the aqueous layer was extracted three times with 200 mL portions of ethyl acetate. The organic layers were combined and washed once with 100 mL of H2O and once with 100 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated using rotary evaporation and then placed under high vacuum to give 6.1 g of N1-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(cyanomethyl)-N2-(3,4-dichlorophenyl)-N1-methylglycinamide, which was carried onto the next step as crude material. MS (ES) m/e 525 [M+H]+.
Reaction SMILES: ClC1N=CC(C2N=CN(CCCC[N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])C=2)=CC=1.N1C=C(C2C=CC(Cl)=NC=2)N=C1.C(=O)([O-])[O-].[K+].[K+].BrCCCCN1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[C:18]1(=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[NH:17]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccc(Cl)nc2)c1
Agent: Clc1ccc(-c2c[nH]cn2)cn1
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
2-(4-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione. To a solution of 5-(1H-imidazol-4-yl)-2-chloro-pyridine (15.14 g, 84.1 mmoles) in DMF (336 ml) was added potassium carbonate (58.1 g, 420.6 mmoles) and N-(4-bromobutyl)phthalimide (59.3 g, 210.3 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 48 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (1.5 L). The precipitate was filtered and rinsed with water (2×500 ml) and was pumped on for 1 hour. The material was than rinsed with diethyl ether (15×500 ml) and than was pumped on to yield 2-14-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione (25.16 g, 78%). MH+(381)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15](Br)=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:49](=[O:50])[C:48]1[CH:52]=[CH:53][C:45]([Cl:44])=[CH:46][CH:47]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Br)ccc2n1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(c1nc2ccccc2n1Cc1ccccc1)N(CCCN1C(=O)c2ccccc2C1=O)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 2-{3-[1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione (260 mg, 0.56 mmol) and triethylamine (0.47 ml, 3.36 mmol) in DCM (3 ml) at 0° C., was added 4-chlorobenzoylchloride (0.36 ml, 2.8 mmol, 5 eq). The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate and saturated sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layers was combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give N-[1-(1-Benzyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-chloro benzamide (182 mg, yield 54%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][C@@H:16]4[CH2:18][C@H:13]3[CH2:14][N:15]4C(OC(C)(C)C)=O)[CH:9]=[N:10][CH:11]=2)=[CH:2]1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1(OC)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][C@@H:16]4[CH2:18][C@H:13]3[CH2:14][NH:15]4)[CH:9]=[N:10][CH:11]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(-c2ccsc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: c1cc(-c2cncc(N3C[C@@H]4C[C@H]3CN4)c2)cs1
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a stirred solution of (1S,4S)-5-(5-(3-thienyl)-3-pyridyl)-2-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane (0.63 g, 1.4 mmol) in anisole (3.0 mL) at 0-5° C. under a nitrogen atmosphere, trifluoroacetic acid (2.0 mL, 26 mmol) was added dropwise over a 10 min period. After 0.5 h at 25° C., the solution was adjusted to pH 5 using 10% NaOH, followed by extraction with diethyl ether (1×15 mL) to remove the anisole. The aqueous portion was adjusted to pH 11 using 10% NaOH, followed by extraction with diethyl ether (3×25 mL). The combined diethyl ether extracts were dried (Na2SO4) filtered and concentrated under vacuum. Purification of the residue by column chromatography on silica gel, using chloroform:methanol:triethylamine (40:5:1) as eluent, gave a light yellow oil (124 mg, 34%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:16]([F:29])([F:30])[F:15])[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccccc2C(F)(F)F)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2-trifluoromethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 70% overall yield. mp 123-124°. FDMS m/e=419 (M+ of free base). α[D]589=−7.0 (c=0.66, methanol).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[OH2:9]>C(O)(=O)C>[CH3:5][C:6]1[CH2:7][C:8](=[O:9])[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ccccn1
Reactant: O
Solvent: CC(=O)O
Product: CC1=NN(c2ccccn2)C(=O)C1

Procedure:
0.5 g (4.44 mmol) of 2-hydrazinopyridine and 0.58 g (4.44 mmol) of acetoacetic ester are stirred in 15 ml of glacial acetic acid for 2 hours at 90° C. The mixture is then diluted with water and the precipitated crystals are filtered off with suction, washed again with water and dried under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=CC=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]2)=[C:15]([F:39])[CH:14]=1.NN>C(O)C>[CH2:31]([N:28]([CH2:29][CH3:30])[C:26]([CH:25]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][NH:3][C:2](=[O:1])[CH:10]([CH2:5][CH3:4])[CH2:9][CH3:8])=[CH:14][C:15]=2[F:39])[CH2:24][CH2:23]1)=[O:27])[CH3:32]
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(CN3C(=O)c4ccccc4C3=O)cc2F)CC1
Agent: NN
Solvent: CCO
Product: CCC(CC)C(=O)NCc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.3 %

Procedure:
A solution of 2-{4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-fluoro-phenyl]-piperazin-1-yl}-N,N-diethyl-2-phenyl-acetamide (0.09 g, 0.16 mmol) in ethanol (3 mL) was added hydrazine (50 μL) and the mixture stirred at rt. After 6 h, the solvent was removed and the residue treated with 2-ethyl-butyryl chloride (30 μL) as described in previous examples to provide 0.04 g of the title compound. MS: 497.6. 1H NMR (CDCl3): 7.47-7.43 (m, 2H), 7.37-7.29 (m, 3H), 6.96-6.91 (m, 2H), 6.88-6.84 (m, 1H), 5.72-5.67 (br, 1H), 4.37 (d, J=5.3, 2H), 4.23 (s, 1H), 3.49-3.36 (m, 2H), 3.31-3.15 (m, 2H), 3.14-3.05 (m, 4H), 2.74-2.63 (m, 4H), 1.89-1.82 (m, 1H), 1.68-1.58 (m, 2H), 1.53-1.43 (m, 2H), 1.10-1.01 (m, 6H), 0.91-0.86 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:14])/[C:10](=O)[CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:14])/[C:10](=[N:16]\[OH:17])/[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC(=O)/C(C)=C/c1ccc(F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCC(=N/O)/C(C)=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.6 %

Procedure:
To a solution of Example 1D (1.96 g, 10.2 mmol) in pyridine (40 mL) was added hydroxylamine hydrochloride (1.06 g, 15.3 mmol) in one portion. The reaction was stirred at ambient temperature for 12 hr, and then concentrated in vacuo. The residue was partitioned between EtOAc and 1M aq HCl. The separated organic phase was washed with 1M aq HCl and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; 5% to 30% EtOAc/hexanes; SF40-115 g column) and the late eluting component was isolated to afford the title compound as a white solid (0.16 g, 7.6% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 7.44-7.34 (m, 2H), 7.25-7.15 (m, 2H), 6.36 (s, 1H), 2.36 (q, J=7.4 Hz, 2H), 1.98 (d, J=1.5 Hz, 3H), 1.05 (t, J=7.4 Hz, 3H). MS (DCI+): 208 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)([O-:9])=[O:8].Br[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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.C(OCC)(=O)C.COCCOC.O>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Water (0.6 mL), sodium carbonate (70 mg), 2-nitrophenylboronic acid (44 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then sodium carbonate (23 mg), 2-nitrophenylboronic acid (37 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours and 50 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 91-80% hexane/ethyl acetate] to obtain 68 mg of tert-butyl 4-(2-nitrophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light green solid.