Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][CH:7]=[N:8][OH:9])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[CH:18]1([C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:20][CH2:19]1.[O-]CC.[Na+]>CN(C)C=O.O1CCCC1>[CH:18]1([C:22]2[O:9][N:8]=[C:7]([CH2:6][O:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CC(=O)C1CCC1
Reactant: CC(C)(C)OCC=NO
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(COC(C)(C)C)noc1C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (1,1-dimethylethyl)oxyethanal oxime (1.71 g, 13.0 mmol) in N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.74 g, 13.0 mmol) while the flask was in a water bath. After approximately 10 minutes the flask was removed from the water bath and the solution was stirred for approximately 1 hour. The solution, containing the crude imidoyl chloride, was then poured into ether and washed twice with water followed by brine, and then was dried over magnesium sulfate and concentrated. Then to a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.66 g, 15.6 mmol) in tetrahydrofuran (8 mL) at 0° C. was added sodium ethoxide (21 wt % solution in ethanol, 5.82 mL, 15.6 mmol). The above imidoyl chloride was diluted with tetrahydrofuran (6 mL) then added to the solution containing the ketoester. A solid was seen to precipitate. After the addition the solution was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured into ether and washed twice with water followed by brine, dried over magnesium sulfate and concentrated to afford ethyl 5-cyclobutyl-3-{[(1,1-dimethylethyl)oxy]methyl}-4-isoxazolecarboxylate (3.13 g, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 4.53 (s, 2H), 4.22 (q, J=7 Hz, 2H), 4.17-4.05 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.03 (m, 1H), 1.95-1.86 (m, 1H), 1.26 (t, J=7 Hz, 3H), 1.17 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2cccs2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccs3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as light yellow solid. MS: 400.3 (M−H)−, 354.1, 281.2. NMR: (CDCl3, 1H, 300 MHz, δ, TMS) 1.13 (t, J=7.2, 3H), 2.34 (s, 3H), 2.41 (s, 3H), 2.93 (d×d, J=15.2, J=8.8, 1H), 3.12 (d×d, J=15.2, J=4, 1H), 3.30-3.38 (m, 1H), 3.49-3.57 (m, 1H), 4.01 (d×d, J=8, J=4.8, 1H), 4.94 (s, 2H), 6.78 (d×d, J=8, J=1.6, 1H), 6.82 (d, J=1.6, 1H), 7.08-7.14 (m, 2H), 7.40 (d×d, J=4.8, J=0.8, 1H), 7.64 (d×d, J=4.0, J=0.8, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cc[nH]c(=O)c1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CCN(C(=O)OC(C)(C)C)C4)c(=O)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
A suspension of 4-(4-chloro-2-methoxyphenyl)pyridin-2(1H)-one (126 mg, 0.534 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (234 mg, 0.641 mmol), CuI (122 mg, 0.641 mmol), 8-hydroxyquinoline (93 mg, 0.64 mmol) and Cs2CO3 (191 mg, 0.587 mmol) in DMSO (5 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135° C. with stirring overnight. The suspension was cooled, 40:9:1 CH2Cl2/MeOH/NH4OH was added, and the resulting suspension was stirred at 25° C. for 10 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution was dried over Na2SO4 and concentrate under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 0:100) gave the title compound (123 mg, 44%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.1 Hz, 1H), 7.42-7.35 (m, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.12-7.02 (m, 2H), 6.99 (d, J=1.8 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 6.44 (dd, J=7.2, 1.8 Hz, 1H), 4.65 (br s, 2H), 3.88 (s, 3H), 3.90-3.81 (m, 2H), 3.65 (s, 3H), 2.87-2.79 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:17]([C:20]([NH2:22])=[O:21])=[C:16]3[C:8]=2[C:9]2[CH2:10][CH2:11][CH:12]([C:23]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])[CH2:13][C:14]=2[NH:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:19]=[CH:18][C:17]([C:20]([NH2:22])=[O:21])=[C:16]3[C:8]=2[C:9]2[CH2:10][CH2:11][CH:12]([C:23]([NH:25][CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:24])[CH2:13][C:14]=2[NH:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc(C2=CCCCC2)c2c3c([nH]c12)CC(C(=O)NC1CCOCC1)CC3
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(C2CCCCC2)c2c3c([nH]c12)CC(C(=O)NC1CCOCC1)CC3
Reaction time: 1 h

Procedure:
A solution of 5-cyclohexenyl-N2-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide (Example 3-117, 28 mg, 0.066 mmol) in methanol (10 mL) was combined with 10% palladium on charcoal (80 mg) and shaken under an atmosphere of hydrogen (45 psi) for 1 h. The mixture was filtered, the solid was rinsed with methanol and the filtrates were concentrated to provide 5-cyclohexyl-N2-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide as an off-white solid (28 mg, quantitative). 1H NMR (400 MHz, methanol-d4) δ 7.46-7.50 (1H, m), 6.91 (1H, d, J=8.05 Hz), 3.89-3.98 (3H, m), 3.46-3.54 (2H, m), 3.13 (1H, dd, J=14.43, 4.16 Hz), 2.95-3.06 (2H, m), 2.87-2.94 (1H, m), 2.65-2.73 (1H, m), 2.15 (1H, dd, J=11.10, 3.05 Hz), 1.77-1.99 (8H, m), 1.47-1.61 (6H, m), 1.26-1.40 (2H, m). Mass spectrum m/z 424.3 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][P:8]([CH:13](O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6].C(Cl)[Cl:27].N1C=CC=CC=1>O>[CH2:5]([O:7][P:8]([CH:13]([Cl:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: ClCCl
Reactant: CCOP(=O)(OCC)C(O)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOP(=O)(OCC)C(Cl)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
8.7 g (0.073 mol) of thionyl chloride were added to a mixture of 22.96 g (0.07 mol) of 4-trifluoromethoxy-α-hydroxy-benzylphosphonic acid diethyl ester, 70 ml of methylene chloride and 5.6 g (0.07 mol) of pyridine at 20°-40° C. in the course of about 1 hour, while cooling slightly with water. The reaction mixture was then heated to 50° C. for 3 hours and was subsequently stirred for 12 hours without further action of heat. The mixture was poured onto about 100 g of ice-water and the organic phase was separated off and dried. After distilling off the solvent, the residue was concentrated under 2 mm Hg and at 45° C. 18.7 g (77.1% of theory) of 4-trifluoromethoxy-α-chloro-benzyl-phosphonic acid diethyl ester were obtained as a yellow viscous oil with a refractive index of nD22 : 1.4968.
Reaction SMILES: [S:1]1[C:5]([C:6]2([OH:19])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.C[O:25][C:26](=[O:49])[C@H:27]([C@@H:46]([CH3:48])O)[NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[S:1]1[C:5]([C:6]2([O:19][C@H:46]([CH3:48])[C@@H:27]([C:26]([OH:49])=[O:25])[NH2:28])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2
Reactant: OC1(c2cc3ccccc3s2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2cc3ccccc3s2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(benzo[b]thien-2-yl)-9H-fluoren-9-ol (Example 2n) and UW-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1C=CC=CC=1)[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:2].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[C:27]3[C:23](=[CH:22][C:21]([N:20]([CH3:30])[CH3:19])=[CH:29][CH:28]=3)[C:24](=[O:25])[O:9]2)=[CH:10][CH:11]=1)[CH3:13]
Reactant: CCN(Cc1ccccc1)c1ccc(C=O)cc1
Reactant: CN(C)c1cccc(C(=O)O)c1
Product: CCN(CC)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1

Procedure:
Employing a procedure similar to that described in Example 1, part A above, for interacting 7.2 g of 4-(N-ethylbenzylamino)benzaldehyde and 5.2 g of 3-dimethylaminobenzoic acid, there was obtained 7.5 g of 3-4-(N-ethylbenzylamino)phenyl]-6-dimethylaminophthalide (Formula II: R=CH3 ; X=H; Y=(C6H5CH2)(C2H5)NC6H4) as a viscous oil.
Reaction SMILES: C(O[C@@:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([C@H:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=O)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:5]([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)=[C:12]([S:14]([N:35]1[CH2:36][CH2:37][N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][CH2:34]1)(=[O:15])=[O:16])[CH3:13]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Solvent: ClCCl
Product: CC(=C(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCN(c2ccccc2)CC1
Yield: 8.6 %

Procedure:
In dichloromethane (15 ml) was dissolved (2R 3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (0.5 g). To the solution was added, under ice-cooling, 1-phenylpiperazine (0 27 g) The reaction mixture was stirred for 10 minutes under ice-cooling, which was then concentrated. The concentrate was subjected to a silica gel chromatography (eluent: hexane/ethyl acetate=1/2→ethyl acetate) for purification to give, as the first eluate, 1-[3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-buten-2-ylsulfonyl]-4-phenylpiperazine (isomer B, Compound 31, 0.05 g) as a pale brown solid substance and, as the second eluate, 1-[3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-buten-2-ylsulfonyl]-4-phenylpiperazine (isomer A, Compound 30, 0.18 g) as a pale brown solid substance.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:32])[C@H:21]([N:29]=[C:30]=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C>[CH3:18][O:19][C:20](=[O:32])[C@H:21]([NH:29][C:30]([O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:15][CH:14]=1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1ccc(OCCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc(OCCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
(4-Phenethyloxyphenyl)methanol 11(1.141 g, 5.0 mmol), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (1.036 g, 5.0 mmol) and DMAP (10 mg) were combined and heated until molten and stirred for 20 min. Upon cooling the residue was purified by chromatography to give about 2.1 g of (R)-2-(4-phenethyloxybenzyloxycarbonylamino)-3-phenyl-propionic acid methyl ester 12.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[CH:7]([O:15]C(=O)C)[CH2:6][CH:5]1[CH3:19])(=[O:3])[CH3:2].[OH-].[Na+].O>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[C@@H:7]([OH:15])[CH2:6][C@@H:5]1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC(C)N(C(C)=O)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2cc(F)ccc2[C@@H](O)C[C@@H]1C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
(Step 3) 1.4 g of 1-acetyl-7-fluoro-4-acetoxy-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 10 mL of ethanol, and 10 mL of a 1 N aqueous solution of sodium hydroxide was added to the solution. The mixture was stirred for 1.5 hours. After completion of the reaction, water was added to the reaction liquid, and the mixture was extracted with chloroform. Subsequently, the organic layer was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=1:1), and thus 400 mg (34%) of trans-1-acetyl-7-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)[CH3:14].N1CCCC1>CO.O>[CH2:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:19][CH2:20]1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CCN1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Solvent: O
Product: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 77.6 %

Procedure:
A solution of 5-nitro-1H-indole (0.67 g, 4.13 mmol), 1-ethylpiperidin-4-one (1.094 mL, 8.26 mmol) and pyrrolidine (1.025 mL, 12.40 mmol) in dry methanol (10 mL) was refluxed for 48 h. The reaction was brought to room temperature, diluted with water and product was extracted into CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated, crude was stirred with isopropanol: hexanes, (15 mL, 1:7) and the yellow precipitate was filtered and dried to obtain 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (0.87 g, 78%). 1H NMR (DMSO-d6) δ 11.87 (s, 1H), 8.69 (d, 1H, J=2.1 Hz), 8.01 (dd, 1H, J=2.4, 9.0 Hz), 7.65 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 6.18 (s, 1H), 3.16-3.12 (m, 2H), 2.64 (t, 2H, J=5.1 Hz), 2.54-2.42 (m, 4H, merged with DMSO-peak), 1.70 (t, 3H, J=7.2 Hz); ESI-MS (m/z, %): 272 (MH+, 100).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@@:3]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH2:5]2.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:26]=1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:52]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[ClH:52].[ClH:52].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][C:26]=1[CH2:27][NH:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@@:3]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH2:5]2
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccc(OC(F)(F)F)cc1CN[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1R*,2R*,5S*)-2-amino-8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octane (Description 9; 156 mg, 0.53 mmol) and 2-methoxy-5-(trifluoromethoxy)benzaldehyde (132 mg, 0.6 mmol) were dissolved in 1,2-dichloroethane (10 mL) and acetic acid (35 μL), and treated with sodium triacetoxyborohydride (127 mg, 0.6 mmol). The suspension formed was stirred at ambient temperature for 16 hours, then quenched with saturated aqueous sodium hydrogen carbonate solution (50mL). The mixture was extracted with dichloromethane (2×50 mL) and the extracts were dried (MgSO4), then concentrated. Purification of the residue gave the desired free base which was taken up in ethyl acetate (10 mL) and treated with ethereal hydrogen chloride (1M, 2 mL). The solid formed was recovered by filtration and recrystallized from methanol/diethyl ether to give the title compound as a white solid (178 mg, 0.3 mmol).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH:32]=2)=[N:28][C:27]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:43][CH2:42][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)[CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1)C(=O)O

Procedure:
: The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 2H, J=7.82 Hz), 7.86 (d, 2H, J=8.21 Hz), 7.68 (d, 2H, J=7.82 Hz), 7.45 (t, 1H, J=7.65 Hz), 7.41–7.40 (m, 1H), 7.31–7.30 (m, 1H), 7.19(d, 1H, J=8.40 Hz), 7.10–7.04 (m, 2H), 6.88–6.79 (m, 2H), 6.61 (dd, 1H, J=8.40 Hz, 1.65 Hz), 4.22 (t, 2H, J=5.87 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.08 Hz), 3.10–3.03 (m, 3H), 2.43 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C33H32NO6S 570.1950, found 570.1958.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)C1CC1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[NH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:31][N:32]=1>>[CH3:27][C:28]1[N:29]=[C:30]2[N:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:32]=1
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.87 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 48%).
Reaction SMILES: C(OC(N1CCC(NC2CCNCC2)CC1)=O)(C)(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]([CH2:40][CH:41]2[CH2:45][CH2:44][N:43](C(OCC3C=CC=CC=3)=O)[CH2:42]2)[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][CH:31]([N:34]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH2:40][CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C)CCN(CC1CCN(C(=O)OCc2ccccc2)C1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(NC2CCNCC2)CC1
Product: CN(C)CCN(CC1CCNC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared by using the same procedure as described for the preparation of 4-(piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in Example 4, Step 1 except 4-[(1-benzyloxycarbonyl-pyrrolidin-3-ylmethyl)-(2-dimethylamino-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester was used in place of 4-(1-benzyl-piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as light brown syrup. ESI MS m/z 355 (M+H+); 1H NMR (400 MHz, CDCl3) δ 4.15 (br s, 1H), 2.98 (d, J=7.5 Hz, 10.9 Hz, 1H), 2.90 (q, J=7.2 Hz, 1H), 2.71-2.50 (m, 6H), 2.40 (q, J=4.9 Hz, 1H), 2.31 (m, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.87-1.59 (m, 8H), 1.44 (s, 9H), 1.35 (m 2H).