Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1>N1C=CC=CC=1>[CH3:20][O:19][C:18]1[C:13]([NH:12][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])(=[O:10])=[O:9])=[N:14][CH:15]=[C:16]([CH3:21])[N:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: COc1nc(C)cnc1N
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I
Temperature: 70 °C
Yield: 44.4 %

Procedure:
2-Iodobenzenesulphonyl chloride (obtained as described in J Org Chem, 1977, 42, 3265) (12.1 g) was added to a solution of 2-amino-3-methoxy-5-methylpyrazine (5.6 g) in pyridine (100 ml) and the solution was heated at 70° C. for 8 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the extracts were washed with 2M hydrochloric acid (200 ml) and water (200 ml). The extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ether to give N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (7.2 g), m.p. 136-138° C.; 1H NMR (d6 -DMSO): 2.3 (s,3H), 3.9 (s,3H), 7.3 (dt,1H), 7.5-7.65 (m,2H), 8.05-8.15 (m,2H), 10.7-10.8 (br s, 1H).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl.N1C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:1](=[O:2])[CH3:3])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of Pyridine (3 mL) and AcCl (1.017 g, 13.043) in DCM (15 mL) was added the solution of 4-nitrobenzenamine (1.5 g, 10.870 mmol) in pyridine (3 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was washed with water (10 mL×3), dried under reduced pressure to afford N-(4-nitrophenyl)acetamide as yellow powder (1.9 g, yield: 97%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH3:18])[S:16](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[ClH:36].N1C=CC=CC=1>ClC(Cl)CCl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:18][Cl:36])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reactant: Cl
Solvent: ClCC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 100 °C
Yield: 17.3 %

Procedure:
2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide (0.96 g.) was dissolved in 1,1,2-trichloroethane (15 cc), and pyridine (0.32 g.) and pyridine hydrochloride (0.12 g.) were added thereto. The mixture was heated at 100° C., for 3 hours, cooled, washed with water, dried and then concentrated. The residue was subjected to a chromatography of silica gel in which chloroform was used as the eluant. The eluate was concentrated to yield, as the residue, crystals (0.09 g.) of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-chloromethylpenam-3-carboxylate, m.p. 104°-105° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1>O>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 120 °C
Yield: 165.4 %

Procedure:
A mixture of 1-methyl-piperazine (1.3 g, 1.2 mmol) and 4-fluoro benzoic acid methyl ester (500 mg, 0.32 mmol) was stirred with heating at 120° C. for 20 hrs. Cold water then added, filtered the solid precipitated to afford 124 mg (16.4% yield) of 4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester. 1H NMR (CDCl3): δ 8.0 (d, 2H), 6.9 (d, 2H), 3.9 (s, 3H), 3.4 (t, 4H), 2.6 (t, 4H), 2.4 (s, 3H).
Reaction SMILES: C(#N)C.[OH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:21][CH3:22].Br[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[CH:24]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:7][C:6]=1[O:21][CH3:22])([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(CCNC(=O)OC(C)(C)C)ccc1OC(C)C
Temperature: 65 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a 250 mL round bottom flask containing acetonitrile (18.7 mL) was added tert-butyl 4-hydroxy-3-methoxyphenethylcarbamate (1.0 g, 3.74 mmol), 2-bromopropane (0.51 g, 4.11 mmol), and potassium carbonate (1.5 g, 11.22 mmol). The resulting suspension was stirred at 65° C. for 18 hours. A second addition of 2-bromopropane (0.51 g, 4.11 mmol) was performed and heating was continued for another 18 hours. The reaction mixture was concentrated reaction in vacuo. The resulting oil was dissolved in EtOAc and washed with H2O, aqeuous saturated sodium bicarbonate and brine, then dried with sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc in Heptane) to afford tert-butyl 4-isopropoxy-3-methoxyphenethylcarbamate (0.81 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.84 (d, J=8.03 Hz, 1H), 6.67-6.75 (m, 2H), 4.37-4.70 (m, 2H), 3.86 (s, 3H), 3.27-3.46 (m, 2H), 2.68-2.81 (m, 2H), 1.45 (s, 9H), 1.37 (d, J=6.02 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reaction time: 0.5 h

Procedure:
A mixture of 20 g of 6-methoxy-1H-indole, 41.75 g of the hydrate of 4-piperidone hydrochloride and 205 ml of 2 N methanolic potassium hydroxide solution was refluxed under an inert atmosphere for 81/2 hours and the mixture was slowly diluted with water to a volume of 1.2 liters. Crystallization began and the mixture was stirred for 30 minutes and then was filtered. The recovered product was rinsed with water and dried at 50° C. under reduced pressure over a desiccant to obtain 23.05 g of 6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[C:14](=[O:23])[C:13]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]([OH:20])[C:18]([CH3:21])([N:15]2[C:14](=[O:23])[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:12]([CH3:11])[O:17][CH2:16]2)[CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)c2cc(F)cc(F)c2)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.4 %

Procedure:
3,5-Difluorobromobenzene (2.9 g) was added to a suspension of magnesium (0.41 g) in tetrahydrofuran, under an inert atmosphere at 20° C., slowly, to initiate reaction, then at a rate to maintain gentle reflux. After refluxing for 1 hour, the mixture was added to a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (2.59 g) in tetrahydrofuran at -78° C. The solution was warmed to ambient temperature and stirred for 18 hours. Ammonium chloride and ethyl acetate were added and the organic phase dried (magnesium sulphate) and evaporated to give 1-(3,5-difluorophenyl)-2-methyl-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-propan-1-ol (1.32 g), m.p. 87.6-89.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[C:19]12(C3C=CC(Br)=CC=3O)[CH2:28][CH:23]3CC(C[CH:21]([CH2:22]3)[CH2:20]1)C2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:15]12([C:4]3[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=3[O:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH2:18][CH:21]3[CH2:22][CH:23]([CH2:28][CH:19]([CH2:20]3)[CH2:16]1)[CH2:17]2
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 9.17 g (29.9 mmol) of 2-(1-adamantyl)-4-bromophenol (Compound F), 0.75 g (3.0 mmol) of pyridinium p-toluenesulfonate, 3.77 g (4.1 ml, 44.8 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a bright yellow solid. Purification by flash chromatography (preabsorbed onto silica with chloroform, eluted with 2% ethyl acetate in hexane) yielded the title compound as a nearly white solid. PMR (CDCl3): d 1.6-2.2 (21H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.4 Hz), 7.05 (1H, d, J=8.7 Hz), 7.23 (1H, dd, J=8.7, 2.5 Hz), 7.30 (1H, d, J=2.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:31])=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=2)[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1.CCCCCC>[F:30][C:21]1[CH:20]=[C:19]([C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8]([C:5]2[N:6]=[CH:7][C:2]3[NH:1][C:33](=[O:35])[O:31][C:3]=3[CH:4]=2)=[O:9])[CH:24]=[CH:23][C:22]=1[O:25][C:26]([F:27])([F:29])[F:28]
Reactant: Nc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc2oc(=O)[nH]c2cn1
Temperature: -78 °C

Procedure:
To a cooled (−78° C.) and stirred mixture of ((S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxypicolinamide (200 mg, 0.00045 mol) in THF (5 mL) was added TEA (0.31 mL, 0.002 mol, Spectrochem, India) and triphosgene (270 mg, 0.0009 mol, Spectrochem, India). The reaction mixture was stirred for 2 h at same temperature, slowly warmed to rt and stirred overnight. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 (5 mL), extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography, silica gel (60-120 mesh) using 50-60% EtOAc in petroleum ether as the eluent, followed by further purification using Prep TLC plates, mobile phase 50% EtOAc in hexanes to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (d, J=7.2 Hz, 1H), 9.00 (s, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.44-7.35 (m, 1H), 7.35-7.31 (m, 3H), 7.26-7.21 (m, 1H), 6.64 (d, J=7.6 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:12][CH2:13][CH2:14][Cl:15]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:7][CH2:6]1
Reactant: COCCN1CCNCC1
Reactant: ClCCCBr
Solvent: CCO
Product: COCCN1CCN(CCCCl)CC1

Procedure:
144 Grams of N-(2-methoxyethyl)-piperazine and 157.5 grams of 3-bromo-1-chloropropane were dissolved in 500 milliliters of ethanol and refluxed for 2 hours. The ethanol was evaporated, the residue dissolved in water, the aqueous solution made alkaline with sodium hydroxide solution, the solution extracted with ether, the ether solution separated, washed with water, dried and evaporated. 110 grams of 4-(2-methoxyethyl)-1-(3-chloropropyl)piperazine was thus obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=2)/C#N)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23]([O:26]C(=O)C)(=O)[CH3:24].[N:30]1C=CC=C[CH:31]=1>>[C:23]([O:21][C:18]1[CH:19]=[CH:20][C:15](/[C:14](/[C:31]#[N:30])=[CH:11]/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][C:17]=1[F:22])(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)c(F)c2)cc1OC
Reactant: c1ccncc1
Product: COc1ccc(/C=C(\C#N)c2ccc(OC(C)=O)c(F)c2)cc1OC
Yield: 92 %

Procedure:
Compound 59 (1.20 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (1.26 g, yield: 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])=[O:9])[CH:5]=1
Reactant: CCCNC
Reactant: COC(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
5-(2-Oxo-pyrrolidin-1-yl)-isophthalic acid monomethyl ester (D63) (1.0 g, 3.8 mmol) was dissolved in DMF (7 ml) and treated with N-methyl propylamine (0.42 g, 5.7 mmol), HOBt (0.62 g, 4.56 mmol) and EDC (1.02 g, 5.32 mmol) and the resulting solution was stirred overnight at room temperature. It was then evaporated to dryness and the residue was partitioned between EtOAc and dil.HCl. The organic phase was separated, washed with dil.HCl (×2), dil.NaHCO3 (×3) and brine (×1). It was dried (MgSO4) and evaporated to leave the crude product which was purified by silica chromatography eluting with DCM/MeOH to afford the pure title compound (D64) (0.40 g, 33%).
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.Cl[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH:28]=[O:29]>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:22]2[N:26]([CH3:27])[N:25]=[CH:24][C:23]=2[CH:28]=[O:29])=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cn1ncc(C=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
Under cooling in an ice bath, potassium tert-butoxide (217 mg) was added to a tetrahydrofuran (2.8 mL) solution of 4-chlorobenzyl alcohol (217 mg), and the obtained solution was then stirred for 20 minutes. Under cooling in an ice bath, 5-chloro-1-methyl-1H-pyrazol-4-carbaldehyde (200 mg) was added to the reaction solution, and the obtained solution was then stirred for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 60:40), so as to obtain the title compound (127 mg) in the form of a colorless oily substance.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29]C)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Yield: 86 %

Procedure:
A 2.0 g 4.9 mmol) sample of the methyl ester product compound from Example 1 was dissolved in 80 ml of ethanol and treated with 80 ml of 10% NaOH at ambient temperature for 3 days. The ethanol was removed in vacuo and the aqueous phase acidified to pH 1 with hydrochloric acid which caused the product to precipitate; filtration and drying in vacuo gave 1.65 g (86%) of colorless compound: mp 134°-135° C.; NMR (DMSO-d6) δ0.85 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H), 1.23-1.39 (m, 4H), 1.53-1.68 (m, 4H), 2.59 (t, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 5.37 (s, 2H), 5.37 (s, 2H), 7.18-7.26 (m, 2H), 7.28-7.37 (m, 3H), 7.42-7.48 (m, 1H), 7.53-7.60 (m, 1H), 7.70-7.75 (m, 1H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][C@@H:16]([NH:15][C:13]([C:8]2[NH:9][C:10]([CH2:11][CH3:12])=[C:6]([Cl:5])[N:7]=2)=[O:14])[C@H:17]([NH:4][CH:1]([CH3:3])[CH3:2])[CH2:18]1)=[O:23])([CH3:28])([CH3:27])[CH3:26].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]([CH3:3])[CH3:2])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 12 %

Procedure:
Isopropylamine (372 μL, 4.37 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (162 mg, 0.437 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Isopropylamine (37.2 μL, 0.437 mmol), sodium cyanoborohydride (82.4 mg, 1.31 mmol) and acetic acid (150 μL, 2.62 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 24 mg of the cis isomer of the title compound (15%) as a pale yellow oily substance and 20 mg of the trans isomer of the title compound (12%) as a pale yellow oily substance.
Reaction SMILES: [CH:1]1[C:18]2[C:5](=[C:6]([CH:19]=O)[C:7]3[C:16]([CH:17]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24]>CCO.CCOCC>[CH:1]1[C:18]2[C:5](=[C:6]([CH2:19][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])[C:7]3[C:16]([CH:17]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2cc2cc3ccccc3cc12
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccccc2cc2cc3ccccc3cc12
Yield: 50.1 %

Procedure:
Using the reductive amination procedure described in Example 1, naphthacene-5-carbaldehyde (3A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 50.1% yield of 2-[(5-naphthacenylmethyl)amino]-2-methyl-1,3-propanediol methanesulfonte, mp 197.5°-199°, (EtOH/Et2O), (C, H, N, S).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH:31]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:33])[CH3:32]>CN(C=O)C>[CH:31]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:18]2[C:19]3[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]([CH2:15][CH2:14][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:17]2[CH3:27])=[O:40])=[CH:37][CH:36]=1)([CH3:33])[CH3:32]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(OC(C)C)cc1

Procedure:
1-(4-Isopropoxybenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 4-isopropoxybenzoyl chloride following the procedure described above in Example 1.