Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]5[N:39]=[C:38]([S:40][CH2:41][C:42]6[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=6)[N:37]([CH3:50])[C:36]=5[CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]5[N:39]=[C:38]([S:40]([CH2:41][C:42]6[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=6)=[O:61])[N:37]([CH3:50])[C:36]=5[CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(SCc5cncn5CCC)n(C)c4c2)CCN3CC(C)C)cc1
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(S(=O)Cc5cncn5CCC)n(C)c4c2)CCN3CC(C)C)cc1
Temperature: -13 °C
Reaction time: 2.5 h
Yield: 3.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazol-6-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (260 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (133 mg) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 2.5 hours at −13° C. Dimethylsulfide (0.1 ml) was added to the mixture and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=2:5→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl) methyl)sulfinyl)benzimidazol-6-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (9 mg) (Compound 447) as yellow amorphous.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O.CCCCCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: O
Product: CN(c1nc(Cl)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-methylaminopiperidine (EXAMPLE 9, 5.34 g, 25.9 mmol), 2,6-dichloro-3-nitropyridine (5.0 g, 25.9 mmol), and potassium carbonate (4.3 g, 31.1 mmol) in 100 ml acetonitrile are stirred at 20°-25° for 20 hr. The mixture is poured in water and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to give the crude product. Chromatography (silica gel, 300 g; with 15-25% ethyl acetate in hexane) gives the title compound, NMR (300 MHz, CDCl3) 7.92, 7.19, 6.47, 4.23, 3.40, 2.86, 4.23, 3.40, 2.86, 2.57, 2.02 and 1.69-1.71δ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].C(OCC)(=O)C(OCC)=O.C(OC(=O)C(=O)CC(=O)COC1C=CC=CC=1)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:64]1[N:65]([CH2:77][CH:78]([NH:80][C:81](OC(C)(C)C)=O)C)[N:66]=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:64]2[CH2:81][NH:80][CH2:78][CH2:77][N:65]2[N:66]=1
Reactant: CC(=O)COc1cccc(F)c1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: CCOC(=O)C(=O)OCC
Product: Fc1cccc(OCc2cc3n(n2)CCNC3)c1

Procedure:
The compound was prepared from 1-(3-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[CH3:20][C:13]1[CH:12]=[C:11]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C=O)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
4-Hydroxybenzaldehyde (945 mg, 7.7 mmol), 4-fluoro-2-methyl-1-nitrobenzene (1.0 g, 6.4 mmol), and K2CO3 (1.77 g, 12.8 mmol) were stirred in 55 mL dimethylformamide at 100 degrees Centigrade for 18 hours. The reaction was cooled to room temperature, diluted with ethylacetate, extracted two times with 1N NaOH, and rinsed with brine. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.72 g crude 4-[(3-methyl-4-nitrophenyl)oxy]benzaldehyde, which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:38][CH:39]=3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1ccc(CN)cc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: CNC(=O)c1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc32)cc1

Procedure:
Example 127 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 4-(aminomethyl)-N-methylbenzamide to give the title compound (0.005 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]2([CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35][CH:34]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])[C:9]1=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(N=Cc1ccccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Yield: 64.2 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 2.6 mmol) prepared in example 24a was reacted with 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.3 g, 14.1 mmol) prepared in example 17a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white foam (Yield: 0.92 g, 65%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a cooled solution of 3-[(tert-Butyldimethylsilyl)oxy]-4-methoxybenzaldehyde 13 (17.5 g, 65.7 mmol) in methanol (100 mL) under nitrogen, sodium borohydride (2.98 g, 78.8 mmol) was added and stirred at room temperature for 30 min. After the reaction was complete as indicated by TLC (chloroform on silica gel plate), ice was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with water and dried. Removal of solvent in vacuo yielded on yellow oil 14 (73.5%). 1H NMR: δ 0.18 (s, 6H, 2×CH3), 1.00 (s, 9H, 3×CH3), 1.90 (br s, 1H, OH), 3.82 (s, 3H, OCH3), 4.56 (s, 2H, CH2OH), 6.94 (br s, 3H, Ar—H). Anal. Calcd for C14H24O3Si: C, 62.64, H, 9.01. Found: C, 62.59, H, 9.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[NH:10][N:9]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[NH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Yield: 28.5 %

Procedure:
3-(2-Chloro-phenyl)-6-nitro-1H-indazole (8.82 g, 32.23 mmol) was dissolved in 400 mL EtOH and 120 mL water, and the mixture was heated to 85° C. with stirring. After stirring for 40 minutes, Fe (9.0 g, 161.15 mmol) and NH4Cl (8.62 g, 161.15 mmol) were added, and the reaction mixture was stirred for 16 hours at 85° C. The reactuion mixture was filtered through Whatman filter paper, and the filtrate was concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (hexanes/EtOAc 0-50%) to give 2.24 g of 3-(2-Chloro-phenyl)-1H-indazol-6-ylamine, MS (M+H)=245.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:35])(=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:34])(=[O:35])[N:22]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(Cl)c1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 3-chloro-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 24).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][CH:9]([NH2:8])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1
Reactant: COc1ccc(CC(CCC(C)C)NC(=O)OC(C)(C)C)cc1OCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(N)CCC(C)C)cc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of N-t-butoxycarbonyl-1-(3-methylbutyl)-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (89.69 g) in 156 ml of dichloromethane, 156 ml of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol =30:1-20:1), to thereby obtain 59.65 g of 1-(3-methylbutyl)-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[F:19])[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 590.1 %

Procedure:
A mixture of 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g, 2.1 mmol), zinc dust (8.14 g, 125 mmol) and ammonium chloride (6.66 g, 125 mmol) in THF (160 mL) and MeOH (160 ml) was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was partitioned between EtOAc (50 ml) and a mixture of water and saturated NaHCO3 (aq) (1:1; 50 ml). The mixture was extracted with EtOAc (2×50 ml). The combined organic extracts were dried (Na2SO4) and evaporated to yield 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (3.18 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, 1H), 7.24-7.19 (m, 1H), 7.00 (s, 1H), 6.94-6.92 (m, 1H), 6.74-6.69 (m, 1H), 5.54 (brs, 2H); MS (ESI) m/z: 257.0 (M+H+).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.O>O1CCCC1>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([B:1]([OH:6])[OH:2])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:25][CH2:26]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Temperature: -78 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
Triisopropyl borate (0.64 mL, 2.8 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.602 g, 1.9 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (7 mL) at −78° C. under a nitrogen atmosphere followed by dropwise addition of n-butyllithium (1.4 mL, 2.2 mmol). The resulting mixture was stirred at −78° C. for 2 h and at room temperature for another 16 h. Water (2.0 mL) was added and the mixture stirred for 30 min and evaporated to dryness. The residue was pre-adsorbed onto silica and purified by column chromatography on silica using methylene chloride/methanol, (9:1 to 1:9), as the eluent. The product was re-crystallized from water to give 311 mg (58% yield) of the title compound as white crystals: mp 215-218° C.; 1H NMR (DMSO-d6, 400 MHz) δ 8.47 (br s, 2H), 8.05 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 3.77 (m, 2H), 3.40 (m, 2H), 3.13 (m, 2H), 2.71 (s, 3H), 2.65 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 133.7, 133.3, 124.7, 49.8, 41.6, 41.4; MS (TSP) m/z 285 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([OH:17])([CH2:12][CH:13]([OH:16])[CH2:14]O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:17][CH2:14][CH:13]([OH:16])[CH2:12]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(O)(CC(O)CO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC2(CC1)CC(O)CO2
Reaction time: 8 h

Procedure:
The product of step c) (5.2 g, 0.021 mol) was dissolved in dry pyridine (60 ml), placed under nitrogen and cooled with an ice-bath. Tosyl chloride (4.8 g, 0.025 mol) was dissolved in pyridine (30 ml) and added dropwise. The reaction was heated at 110°. After 5 hours another 2.2 g (0.011 mol) tosyl chloride was added in 20 ml pyridine at room temperature and the heating was continued overnight.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1)=O.[BH4-].[Na+].[NH4+].[Cl-].CC(C)=O>CCO.C(Cl)Cl>[OH:2][CH2:3][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1
Reactant: CC[C@@H](C(N)=O)N1CC(C(=O)OC)CC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 2 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, a solution of 133 g (583 mmoles, 1 eq) of (2S)-2-(4-methoxycarbonyl-2-oxo-1-pyrrolidinyl)butanamide 11 in 200 ml of EtOH is added to 300 ml of EtOH, and the mixture cooled down to 0° C. 66.2 g (1.74 mole, 12 eq) of solid NaBH4 are then added by portions over 1.5 hour, all the while maintaining the temperature between 2 and 4° C. After 2 hours, the temperature is raised to 12° C. for 1 hour, and lowered again to 2-4° C. 240 ml of a saturated solution of NH4Cl are added dropwise over 1 hour, followed by 120 ml of acetone, and the mixture is left overnight at room temperature. The mixture is filtered, the precipitate washed with 3×70 ml of EtOH and the combined organic fractions concentrated to dryness to give 148 g of crude 6. It is suspended in 300 ml of CH2Cl2 and stirred for 30 min, filtered, washed with 2×100 ml of CH2Cl2 and dried to give 114 g of pure 6, 98%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.[Cl-].[NH4+]>O1CCCC1.CS(C)=O>[Br:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: BrCCCCBr
Reactant: CC(C)(C)c1cc(Br)ccc1N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
5.7 g (0.14 mol) of sodium hydride are suspended in 200 mL of tetrahydrofuran. 10 g (44 mmol) of 4-bromo-2-tert-butylaniline are added, along with 200 mL of dimethyl sulfoxide, added slowly. The mixture turns blue and, after 30 minutes, 13 mL (0.14 mol) of 1,4-dibromobutane are added and the reaction medium is stirred at room temperature for 13 hours. The reaction medium is then poured into saturated ammonium chloride solution and extracted with ethyl acetate, and the organic phase is then washed twice with water, dried and then concentrated to dryness. The residue is purified by chromatography on silica gel (eluent: 90/10 heptane/ethyl acetate). 6.4 g of 1-(4-bromo-2-tert-butylphenyl)pyrrolidine are obtained (yield=52%) in the form of a thick yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].[OH-].[Na+].C(=O)(O)[O-].[Na+]>Cl>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:19]=2)[CH:8]=[C:9]([OH:11])[CH:10]=1
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cc(O)cc(-c2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
3,5-Dihydroxybenzoic acid (21.4 g, 0.14 mol) and o-phenylenediamine (10 g, 0.093 mol) were refluxed in 4M hydrochloric acid (200 mL) at 135° C. for 24 hours under nitrogen. The mixture was cooled to room temperature and then neutralized to pH 6 with sodium hydroxide and then to pH 8 with sodium bicarbonate. The precipitated tan-colored product was isolated by filtration and recrystallized from methanol/water (1:4) to yield tan-colored needles (6.2 g). 1H NMR (DMSO-d6):δ 6.36 (1H, t), 7.04 (2H, d), 7.19 (2H, m), 7.47 (1H, d), 7.62 (1H, d), 9.56 (O—H,2H, s), 12.71 (N—H, 1H, s).
Reaction SMILES: [CH2:1]([CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:16]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22]([C:26]1[CH:27]=[C:28]([CH2:37][CH2:38][C:39]([NH:41][NH2:42])=[O:40])[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC=CC=1>O>[C:33]([C:30]1[CH:29]=[C:28]([CH2:37][CH2:38][C:39]([NH:41][N:42]2[C:19](=[O:21])[CH2:20][CH:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:16]2=[O:18])=[O:40])[CH:27]=[C:26]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:31]=1[OH:32])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 70 °C
Yield: 84.4 %

Procedure:
A mixture of 2-tetradecylsuccinic anhydride (17.2 g, 52.5 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (15.4 g, 52.5 mmol) and 40 ml of toluene was refluxed for about one hour under a nitrogen atmosphere with the azeotropic removal of water. The bulk of the solvent was then allowed to distill off. Residual solvent was removed by placing the heated mixture (140° C.) under vacuum for 15 minutes. The bath used to heat the mixture was cooled to 70° C. and the vacuum was released. The resulting viscous melt was dissolved in 120 ml of acetone and suction filtered to remove mechanical impurities. The filtrate was diluted to 700 ml with acetone. This solution was cooled in an ice/water bath to precipitate the product which was collected by vacuum filtration. The filtrate was then re-cooled in a -20° C. acetone/dry ice bath to obtain additional product which was also collected by filtration. The collected solids were combined, air dried on a sheet of paper and finally high vacuum dried to give 25.3 g of a white solid having a melting range of 70°-77° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:22][C:21]3[C:16](=[C:17]([O:29]C)[C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[C:20]=3[O:23]C)[CH2:15]2)=[CH:6][CH:5]=1.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:32][N:2]([CH3:1])[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:22][C:21]3[C:20](=[O:23])[C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[C:17](=[O:29])[C:16]=3[CH2:15]2)=[CH:6][CH:5]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)N(C)C)cc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CC(CCCOc3ccc(C(=O)N(C)C)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a mixture of N, N-dimethyl-4-[3-(4,5,6,7-tetramethoxyindan-2-yl)propoxy]benzamide (700 mg), 2,6-pyridinedicarboxylic acid (792 mg), THF (14 ml), and water (7 ml) was dropwise added a solution of CAN (3.44 g) in water (7 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (438 mg) as crystals.