Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([O:23][CH2:24][O:25][CH:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:27])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[OH:21])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[CH2:3]([C:7]1[N:8]([O:23][CH2:24][O:25][CH:26]([Si:28]([CH3:30])([CH3:29])[CH3:31])[CH3:27])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)CBr
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2O)n1OCOC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OCC)n1OCOC(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93750.5 %

Procedure:
To a mixture of NaH (80% oil dispersion, 33 mg, 1.1 mmol, previously washed with hexanes), in DMF (4 ml) was added dropwise a solution of 2-n-butyl-5-(2-Hydroxy-4-methoxybenzoyl)-1-trimethylsilylethyloxymethoxy-1H-imidazole-(404 mg, 1.00 mmol) in DMF (3 ml) at 0° under argon. The cooling bath was removed and the mixture stirred for 10 min. at ambient temperature. Ethyl bromoacetate (125 μl, 1.10 mmol) was added neat and the reaction stirred for 2 h. The mixture was partitioned between water and EtOAc and the layers separated. The aqueous layer was further extracted (EtOAc, 2x) and the combined organic extract was washed with water (5x) and brine. Evaporation under reduced pressure, after drying (MgO4 anhydrous) afforded the title compound as a reddish oil (475 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li:20]CCCC>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Li:20])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [Li]CCCC
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=CC2
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Li]C1C=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reaction time: 3 h
Yield: 98 %

Procedure:
5,6-dimethoxy-3-phenyl-1H-indene (1.26 g, 4.99 mmol) was dissolved in a mixture of 15 mL of toluene and 25 mL of hexane and 3.06 mL of 1.6 M n-BuLi were added dropwise via syringe over a 3 min period. The solution developed a yellow-light green precipitate during addition of n-BuLi. The reaction mixture was stirred for 3 h and then filtered, washed with 60 mL of hexane and dried in vacuum to afford the desired product as a yellow solid (1.24 g) in 98 percent yield.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[OH:8][C:9]1[C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(OC)ccc1O
Yield: 74.6 %

Procedure:
10% palladium-carbon (48 mg) was added to 480 mg of methyl 3-benzyloxy-6-methoxy-picolinate. After the replacement of the atmosphere by nitrogen, 25 ml of methanol was added thereto. Further, after the replacement of the atmosphere by hydrogen, the mixture was vigorously stirred to allow a reaction to proceed. One hr after the initiation of the reaction, the reaction mixture was filtered, followed by purification by chromatography on silica gel (chloroform-methanol) to give 240 mg (yield 76%) of the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:15])[CH2:12][CH2:13]Cl.S(=O)(=O)(O)O>>[OH:10][C:8]1[CH:7]=[CH:6][C:5]2[C:11](=[O:15])[CH:12]=[CH:13][O:3][C:4]=2[CH:9]=1
Reactant: O=C(CCCl)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccoc2cc(O)ccc12
Temperature: 25 °C
Yield: 88 %

Procedure:
To a cooled (5° C.) solution of 2N sodium hydroxide (10.0 L) was added the compound of step A (244.1 g) in one portion. The solution was warmed to room temperature over 2 hours using a warm water bath then recooled to 5° C. and the pH adjusted to 2 with 6M sulfuric acid (1.2 L). The mixture was extracted with 3×3.0 L of ethyl acetate, washed with brine (1×2.0 L) dried over sodium sulfate and filtered. Concentration in vacuo gave a tan solid. Trituration with hexanes, and filtration afforded 173.7 g (58% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:11]=[C:12]([NH:22][C:23]([C@H:25]([NH:34]C(=O)OC(C)(C)C)[CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])[CH:13]=[C:14]4[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:16]=2[C:15]=34)=[CH:4][CH:3]=1>Cl>[NH2:34][C@H:25]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:23]([NH:22][C:12]1[CH:13]=[C:14]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:16]3=[C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:9][C:10]([CH:11]=1)=[C:15]23)=[O:24]
Reactant: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@@H](CCc4ccccc4)NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)cn1
Agent: Cl
Product: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@H](N)CCc4ccccc4)cc4c3c2C=NNC4=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A suspension of tert-butyl [(1R)-1-({[2-(6-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]amino}carbonyl)-3-phenylpropyl]carbamate 267 (c) in 5 mL of 4M HCl in dioxanes was stirred at room temperature for two hours. The mixture was then filtered and the solid material washed thoroughly with ethyl ether. The title compound was obtained as a yellow solid in 48% yield after purification by reverse-phase HPLC.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Mg]Br>>[CH3:22][C@@H:8]1[CH2:9][C:10]2[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[CH:11]=2)[C@@H:17]2[C@@H:7]1[C@H:6]1[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]1
Reactant: C[Mg]Br
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
androsta-4,6-dien-3,17-dione 17 ketal (XXXVIII) is reacted with methyl magnesium bromide in the presence of cuprous chloride to produce 7α-methylandrost-4-ene-3,17-dione 17 ketal (XXXIX)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34][C:35]3[CH:48]=[CH:47][C:38]4[C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][O:41][C:37]=4[CH:36]=3)[CH:28]=2)=[C:22]([CH3:49])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:20]2[CH:21]=[C:22]([CH3:49])[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34][C:35]4[CH:48]=[CH:47][C:38]5[C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][O:41][C:37]=5[CH:36]=4)[CH:28]=3)=[C:24]([CH3:26])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(=O)OC(C)(C)C)CC5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
4-[(Methylsulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester (134 mg, 0.48 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (200 mg, 0.48 mmol) and cesium carbonate (470 mg, 1.43 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting solution was mixed with 30 mL of ethyl acetate. The organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) successively, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by elution system B to obtain the title compound methyl (S)-2-(6-((4′-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3j (101 mg, yield 35.0%) as a colorless slime.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[C:22]([CH3:30])[N:23]3[C:28]=2[C:27]([CH3:29])=[CH:26][CH:25]=[CH:24]3)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[CH3:30][C:22]1[N:23]2[C:28]([C:27]([CH3:29])=[CH:26][CH:25]=[CH:24]2)=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]2=[O:31])[CH:21]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(3,8-Dimethyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (10 mg, 0.023 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (1.1 mg, 0.046 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product. LCMS (ESMS): m/z 406.27 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][CH:5]([C:15]([CH:19]([NH:27][C:28](=[O:44])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:43])[N:36]([CH2:40][CH2:41][CH3:42])[CH2:37][CH2:38][CH3:39])[CH:30]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:18])[PH2:16]=[O:17])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[OH-].[Na+]>CO>[CH2:40]([N:36]([CH2:37][CH2:38][CH3:39])[C:35]([C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[C:28]([NH:27][CH:19]([C:15]([OH:18])([PH2:16]=[O:17])[CH:5]([C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])[CH2:4][C:3]([OH:45])=[O:2])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:44])=[O:43])[CH2:41][CH3:42]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)NC(Cc2ccccc2)C(O)([PH2]=O)C(CC(=O)OC)C(=O)Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)C(=O)c1cccc(C(=O)NC(Cc2ccccc2)C(O)([PH2]=O)C(CC(=O)O)C(=O)Nc2ccccc2)c1
Yield: 80.3 %

Procedure:
A solution of 14 mg of 3-{[1-(3-dipropylcarbamoyl-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoylmethyl}-N-phenyl-succinamic acid methyl ester (compound I-17) in 1 ml of MeOH and 3 mg of NaOH was warmed to 45° for 3 h. The solution was evaporated, the residue partitioned between 1N aqueous hydrochloric acid and CH2Cl2, the organic layer was washed with water, dried and evaporated to give 11 mg of 3-{[1-(3-di-propylcarbamoyl-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoylmethyl}-N-phenyl-succinamic acid (compound 1-53).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].CN1CCOCC1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A solution of 0.120 g (purity: 76% corresponds to 0.25 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 1E) in 2 ml N,N-dimethylformamide was treated at room temperature with 0.052 g (0.27 mmol, 1.1 eq.) of 3,4-dichlorophenyl isocyanate and 0.136 ml (1.24 mmol, 5 eq.) of 4-methylmorpholine. The reaction was stirred at room temperature overnight. To the solution was added 5 mg (0.02 mmol, 0.1 eq.) of 3,4-dichlorophenyl isocyanate. After 1 h, no starting material was left; the solution was slowly added to a solution of sat. aq. sodium hydrogencarbonate, followed by extraction with ethyl acetate (3 times). The organic phases were washed with a solution of sat. aq. sodium hydrogencarbonate and with 10% aq. sodium chloride solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum. The crude product was purified by flash chromatography (20 g SiO2-column, dichloro-methane/methanol 2:98, 5:95, 1:9, 1:4) to give 0.061 g (51%) of the title compound as white solid. MS: 483.4 (MH+, 2Cl).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:7])=[O:5].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]I)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:6]([CH3:7])([C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ICCc1ccccc1OCc1ccccc1
Product: CCOC(=O)C(C)(CCc1ccccc1OCc1ccccc1)C(=O)OCC

Procedure:
2-Methylmalonic acid diethyl eater and 2-(2-benzyloxyphenyl)ethyl iodide were used in the same manner as working example 52 (S) to give the subject compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:13]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:11])=[C:6]([Cl:12])[CH:5]=2.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[Cl:1][C:2]1[N:3]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:4]2[C:9]([C:10]=1[C:25](=[O:28])[CH2:26][CH3:27])=[CH:8][C:7]([Cl:11])=[C:6]([Cl:12])[CH:5]=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)cc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)Cl
Product: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12

Procedure:
The same procedure was used for the synthesis of the 3-propionyl derivative 4.47 (FIG. 6A). 2,5,6-Trichloro-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.39, FIG. 6A) was acylated under Friedel-Crafts conditions with propionyl chloride and deprotected in two steps to yield the desired 2,5,6-trichloro-3-propionyl-1-(β-D-ribofuranosyl)indole (4.47, FIG. 6A).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH:21]([CH2:24][CH3:25])[CH2:22][OH:23]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(N)CO
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: CC[C@@H](CO)Nc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 350 μl (5 equivalents) of (+/−)-2-amino-1-butanol, and the mixture is then heated at 120° C. for approximately 2 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 95-5-0.3 mixture for eluent. 40 mg of expected product are obtained.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[Cl:29])[CH2:9][CH2:8][CH2:7]1)=[O:4].[OH-].[Na+].Cl>CO>[C:3]([CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:20][C:19]=2[Cl:29])[CH2:9][CH2:8][CH2:7]1)([OH:4])=[O:2]
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(N3CCCC3)cc2Cl)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1CCCN(C(=O)c2ccc(N3CCCC3)cc2Cl)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
5-Methoxycarbonylmethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (183 g) is suspended in methanol (2 liters), and thereto is added a 5N sodium hydroxide (171 ml), and the mixture is stirred at 60° C. for four hours. To the mixture is added a 5N sodium hydroxide (60 ml), and the mixture is stirred at 70° C. for one hour. The mixture is acidified with hydrochloric acid, and concentrated under reduced pressure to remove the methanol. The crystals are collected by filtration, washed with water, and dried to give 5-carboxymethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (142 g).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The product from Example 92B and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. MS (ESI+) m/z 410 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:29]1([C:34]([Cl:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:34]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:35])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCCC4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 32 mg (0.24 mmol) of cyclopentylcarbonyl chloride are reacted together by general method F. 30.5 mg (52.8% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1C=CC=CC=1.C(OCC)C>[N:1]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: C1COCCN1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture was stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:16]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[N:17][CH:18]=[CH:19][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:22](=[O:23])[C:21]([C:16]2[C:15]([Cl:14])=[N:20][CH:19]=[CH:18][N:17]=2)([CH3:26])[CH3:25])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](NC(=O)C(C)(C)c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottomed flask was added tert-butyl(cis-3-aminocyclobutyl)carbamate (0.4903 g, 2.63 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (Intermediate 29, 0.634 g, 3.16 mmol), HATU (1.301 g, 3.42 mmol, GenScript Corp), and triethylamine (1.465 ml, 10.53 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (5.26 ml) to stir at room temperature for 24 h. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.8210 g, 2.226 mmol, 85% yield). LCMS showed product peak at 1.86 min (m+1=313.0, product-tbutyl group). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 7 H) 1.49 (s, 5 H) 1.82 (qd, J=9.00, 2.35 Hz, 2 H) 2.34-2.47 (m, 2 H) 2.69 (s, 3 H) 3.48-3.65 (m, 1 H) 3.72-3.87 (m, 1 H) 7.04 (d, J=6.85 Hz, 1 H) 7.63 (d, J=6.46 Hz, 1 H) 8.42 (d, J=2.54 Hz, 1 H) 8.65 (d, J=2.35 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([O:62][CH3:63])[C:16]=1[CH:17]=[CH:18][CH:19]([S:29]([CH:32]([CH:42]=[CH:43][C:44]1[C:49]([O:50][CH3:51])=[CH:48][C:47]([O:52][CH3:53])=[CH:46][C:45]=1[O:54][CH3:55])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([NH2:41])[CH:34]=1)(=[O:31])=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([NH2:28])[CH:21]=1>O1CCCC1>[CH3:63][O:62][C:56]1[CH:57]=[C:58]([O:60][CH3:61])[CH:59]=[C:15]([O:14][CH3:13])[C:16]=1/[CH:17]=[CH:18]/[CH:19]([S:29]([CH:32](/[CH:42]=[CH:43]/[C:44]1[C:45]([O:54][CH3:55])=[CH:46][C:47]([O:52][CH3:53])=[CH:48][C:49]=1[O:50][CH3:51])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([NH:41][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:34]=1)(=[O:31])=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([NH:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:21]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)c(OC)c1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-(4-nitrobenzamido)-4-methoxybenzylsulfone in 72% yield. m.p. 206-208° C. NMR (DMSO-d6) δ 3.80(s, 3H), 3.81(s, 6H), 3.83(s, 3H), 4.18(s, 2H), 6.08(s, 2H), 7.14-7.23(d, 1H vinylic), 6.97-7.86(m, aromatic), 9.05(s, 1H).