Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15]([OH:26])=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([O:24][CH3:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C1COCC1>[Pd].CO>[CH3:25][O:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:26])[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[CH:23]2
Reactant: COc1ccc2nc(O)c(C3=CCN(Cc4ccccc4)CC3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reaction time: 2 h

Procedure:
A mixture of 160 mg (0.462 mmol) 3-(1-benzyl-1.2.3.6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol and 20 mg palladium on charcoal (Pd/C 10%) in 30 mL MeOH was first of all hydrogenated for 17.5 h at 50° C. in a hydrogen atmosphere of 50 psi. Then 10 mL THF and 20 mg palladium on charcoal (Pd/C 10%) were added and hydrogenation continued for a further 2 h under the same conditions. Another 20 mg palladium on charcoal (Pd/C 10%) were added and the mixture was hydrogenated overnight at 50° C. in a hydrogen atmosphere of 60 psi. Then the reaction mixture was filtered, washed with DMF and the filtrate was evaporated down. The residue was added to EtOAc, triturated with PE and filtered. The precipitate was washed with DIPE and dried.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.OS(O)(=O)=O.O.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:18])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cnc1N
Yield: 73.9 %

Procedure:
A slurry of 2-amino-5-bromopyridine-3-carboxylic acid (7 g, 32.2 mmol) in methanol (150 mL) and H2SO4 (7 mmol) was heated to reflux for 48 h. The reaction mixture was concentrated to ca. 40 mL. Water (100 mmol) was added to the residual oil, and the mixture neutralized with sodium carbonate. Ethyl acetate (400 mL) was added and the organic layer was washed with saturated aqueous sodium chloride then dried (Na2SO4) and concentrated to give the title compound (5.5 g, 73.9% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=1>CN(C)C=O>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:60]=[C:61]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=1
Reactant: Nc1cccc(-c2nc3ccccc3[nH]2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4nc5ccccc5[nH]4)c3)c(=O)oc12
Temperature: 25 °C

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.050 g, 0.23 mmol) and HATU (0.095 g, 0.25 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-benzimidazol-2-yl)-benzenamine (0.048 g, 0.23 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 1541F: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:23][O:24][CH2:25][CH2:26][Br:27]>CC#N>[Br-:27].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:26][CH2:25][O:24][CH3:23])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: COCCBr
Solvent: CC#N
Product: COCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 42.4 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0597 g, 0.203 mmol) and 2-bromoethyl methyl ether (0.030 mL, 0.319 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0372 g, 42.8%). EI-MS m/z 352 (M+) Rt (1.69 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([C:22](=[O:24])[CH3:23])[C:5]([OH:21])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH3:9].[Br:26][CH2:27][CH2:28]Br>>[Br:26][CH2:27][CH2:28][O:21][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:25])[C:4]=1[C:22](=[O:24])[CH3:23]
Reactant: BrCCBr
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCCc1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccc(F)cc1
Yield: 64 %

Procedure:
Example 1d (110 mg, 0.30 mmol) was reacted with 1,2-dibromoethane (3.0 eq.) as described under General Procedure F to afford the title compound (86 mg, 64%) as light cream oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.14 (m, 2H), 6.99-6.93 (m, 2H), 4.28 (t, J=6.2 Hz, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.64 (s, 3H), 3.50 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.49 (s, 3H), 2.19 (s, 3H), 2.05-2.02 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:43])([CH3:42])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:44]1([C:50]2[CH:55]=[CH:54][C:53](B3OC(C)(C)C(C)(C)O3)=[CH:52][N:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][Si:2]([CH3:43])([CH3:42])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:53]3[CH:52]=[N:51][C:50]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:55][CH:54]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2c(I)cnn12
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 80 °C
Yield: 61 %

Procedure:
To a pressure tube were charged benzyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (1 g, 2.85 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 g, 4.1 mmol), Pd(PPh3)4 (164 mg, 0.14 mmol), DME (20 mL) and 2 M Na2CO3 (10 mL). The mixture was briefly degassed with Argon and the tube was capped and heated at 80° C. for 15 hours. On cooling, H2O (40 mL) and EtOAc (100 mL) and aqueous layer was extracted with EtOAc (3×) and combined organic layers were washed with brine once and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-30%) gave the title compound (1.33 g, 61%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10].C(OCC)(=O)C.O>CN(C)C=O>[CH:9]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:25][C:24]3[CH:26]=[C:27]([Br:1])[CH:28]=[CH:29][C:23]=3[O:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)N1CCC(C2Cc3ccccc3O2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
N-Bromo-succinimide (510 mg) is added to (4-(2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (830 mg) in N,N-dimethylformamide (20 mL). The mixture is heated to 50° C. and stirred at this temperature for 4 h. After cooling to room temperature over night, ethyl acetate and water are added and the mixture is extracted with ethyl acetate. The organic phase is washed with sodium thiosulfate solution and water and dried (Na2SO4). The solvent is evaporated and the residue is triturated with diisopropyl ether to afford the title compound as a white solid. Yield: 750 mg (71% of theory); LC (method 1): tR=1.43 min; Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29][CH2:30]CC)=[O:28])[CH2:4][C@@H:3]1[OH:33].S(=O)(=O)(O)O>CO>[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29][CH3:30])=[O:28])[CH2:4][C@@H:3]1[OH:33]
Reactant: CCCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Yield: 85.2 %

Procedure:
A solution of propyl 2β,3α-dihydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (100 mg) in methanol (10 ml) was heated at 100° C. with concentrated sulphuric acid (0.2 ml) for 48 h. The cooled mixture was evaporated, the residue brought to pH 10 by the addition of 0.88 ammonia solution and extracted with ethyl acetate (3×). The extracts were washed with water, dried and evaporated to give the title compound (80 mg), [α]D +22.4°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:18][CH:19]([CH:27]=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:30][NH2:31].C1COCC1>ClCCl>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:18][CH:19]([CH2:27][NH:31][CH3:30])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCC(C[C@H](NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 78 %

Procedure:
A stirred solution of 40 (6.1 g, 14.9 mmol) in dichloromethane (50 mL) was treated with 2 N methylamine-THF solution (10 mL) at 0° C. overnight. After removal of solvents, the residual oil was dissolved in methanol (80 mL) and placed in an ice-bath. To the above solution was added sodium borohydride in small portions over 30 min. The reaction solution was kept at 0° C. for 1 hour, and solvent was then evaporated. The residue was worked up with brine and dichloromethane. After separation, the organic phase was dried over anhydrous MgSO4, rotary evaporated and dried in vacuum. The crude amine 41 (5.4 g, 78%) was obtained as a light yellow glassy solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].S([O-])([O-])(=O)=O.[C:31](OC=O)(=[O:33])C>N1C=CC=CC=1>[O:24]=[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:25])[N:15]1[CH2:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][CH:31]=[O:33])[CH:4]=2)[NH:8][CH:7]=1
Reactant: CC(=O)OC=O
Reactant: NCc1ccc2[nH]cc(CCCN3C(=O)c4ccccc4C3=O)c2c1
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=CNCc1ccc2[nH]cc(CCCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Following the method described in Example 12 (i), a solution of 2-[3-[5-(aminomethyl)-1H-indol-3-yl]propyl]-1H-isoindole-1,3(2H)-dione, sulphate (0.75 g) was reacted with formic acetic anhydride (15 ml) in pyridine (27.5 ml) to give the title compound as a yellow solid (0.49 g) m.p. 150°-152° after crystallisation from ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:14][CH:13]=2)=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl[6-hydroxy-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.42 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (48 mg, 1.2 mmol) (60% in oil). The resulting mixture was stirred at 0° C. for 10 min. To the mixture was added methyl 2-bromoisobutyrate (0.22 g, 1.2 mmol), and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate (0.31 g, 59.6%) as crystals.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22]
Reactant: CCI
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Temperature: 70 °C
Yield: 57.1 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and ethyl iodide (0.1 mL, 0.75 mmol) and the resultant reaction mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in pet ether) to afford title compound as a solid (50 mg, 58%).
Reaction SMILES: C(OC([N:8]([CH2:18][CH2:19][O:20][CH3:21])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])=O)(C)(C)C.[ClH:22].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:22].[CH3:21][O:20][CH2:19][CH2:18][NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: COCCN(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCNc1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-[(tert-butoxycarbonyl)(2-methoxyethyl)amino]benzoic acid (0.57 g) and ethyl acetate (10 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (5.0 ml) under ice-cooling, followed by stirring at room temperature over one night. The solid precipitated was collected by filtration to obtain 3-[(2-methoxyethyl)amino]benzoic acid hydrochloride (0.38 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(O)(C(F)(F)F)=O>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17]2[CH2:23][CH:24]4[NH:28][CH:27]([C:16]3=2)[CH2:26][CH2:25]4)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc31)C1CCC(C2)N1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc(N)cc4)ccc31)C1CCC(C2)N1
Yield: 25 %

Procedure:
The product of step A was subjected to Boc-deprotection with TFA following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 1:9 methanol/dichloromethane) to give 2-(4-aminophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (25 mg, 25%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 8.16 (s, 1H), 7.49-7.65 (m, 4H), 6.62-6.67 (m, 2H), 5.24-5.25 (m, 1H), 4.51-4.53 (m, 1H), 3.68 (s, 3H), 3.34-3.50 (m, 1H), 2.97-3.05 (m, 1H), 2.34-2.45 (m, 2H), 2.20-2.27 (m, 1H), 1.96-1.98 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([C:6]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:9]([NH2:10])=[CH:8][C:7]=1[N:16]1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1)(=[O:5])=[O:4].O.Cl>[Fe].C(O)C>[CH3:1][N:2]([CH3:23])[S:3]([C:6]1[C:7]([N:16]2[CH:17]=[CH:18][C:19](=[O:22])[CH:20]=[CH:21]2)=[CH:8][C:9]([NH2:10])=[C:11]([NH2:13])[CH:12]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N)cc1-n1ccc(=O)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(N)c(N)cc1-n1ccc(=O)cc1
Yield: 95.1 %

Procedure:
First, a mixture containing 1.50 g of 4-dimethylsulfamoyl-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline, 1.49 g of iron powder, 9 ml of water, 36 ml of ethanol, and 0.45 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 45 minutes. The subsequent processes were conducted in the same way as in Reference Example 3 to give crude crystals. The crude crystals were recrystallized with methanol/isopropanol to give 1.30 g of crystals of 4-dimethylsulfamoyl-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][NH:9][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH2:11]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 94.4 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (700 mg) and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (960 mg) according to an analogous synthetic method to Example 152, the title compound (1.2 g) was obtained.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:29]=[C:28]([F:27])[CH:35]=[C:34]([F:36])[CH:33]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)cc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of intermediate 59 (0.50 g, 1.36 mmol), 3,5-difluorobenzylamine (0.481 mL, 4.07 mmol) and MeOH (0.1 mL) is heated at 100° C. for 3 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 0.28 g of the product 89. 1H NMR (CDCl3) δ 7.10-6.60 (m, 14H), 5.45-5.35 (m, 2H), 4.75-4.55 (m, 2H), 1.16 (s, 9H); MS: m/z 464 (M++1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][CH2:10][C:11](Br)=[O:12].CCN(CC)CC>C(Cl)Cl>[Br:9][CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)=[O:12]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 3-iodoaniline (2.19 g, 10.0 mmol) and 2-bromoacetyl bromide (0.87 mL, 3.40 g, 10.0 mmol) in DCM (100 mL) was added Et3N (1.39 mL) at 0° C. The reaction mixtures were stirred at room temperature for overnight. The reaction mixtures were diluted with DCM (100 mL), washed with water, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 10% EtOC in hexanes to 100% EtOAc to afford 2-bromo-N-(3-iodophenyl)acetamide (2.824 g, 83%). MS (ESI), 340, 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[C:31][Si](C)(C)C)[CH:27]=[CH:26][C:25]=3[OH:36])[C:5]2=[CH:4][CH:3]=1.[F-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[CH:31])[CH:27]=[CH:26][C:25]=3[OH:36])[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione was dissolved in methanol (10 mL). To the stirred solution, KF (Aldrich, 270 mg) was added and the mixture was stirred at rt overnight. The solvent was removed under reduced and the residue was treated with 6 mL of 5% MeOH in methylene chloride. The solid was filtered out and the filtrate was concentrated to about 2 mL and loaded on to an ISCO column. Chromatography (eluent with 5% MeOH in methylene chloride) gave a white solid. 30 mg. MS (H+), 477.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23]C#N>>[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23][C:13]1[NH:2][C:3](=[O:12])[C:4]2[C:5]([CH:11]=1)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Reactant: N#CCCN1CCCCC1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3CCCCC3CO)cc12
Yield: 9.9 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (3.17 g) and 3-(2-hydroxymethylpiperidin-1-yl)propionitrile (1.51 g), 3-[2-(2-hydroxymethylpiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (268 mg) was obtained.