Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:13])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (60 mg, 0.1415 mmol), 4-dimethylaminopyridine (8.6 mg, 0.0704 mmol) and piperidine (24 mg, 0.2823 mmol) were dissolved in methylene chloride (5 ml), WSC-HCl (81 mg, 0.4225 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (62 mg, 0.1265 mmol, 89%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)nc2)CC1
Yield: 69 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (525 mg) described in Preparation Example 106 and 5,5-dimethyloxazolidin-2-one (242 mg) described in Preparation Example 43, the title compound (393 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH:25]C(C)(C)C)(=[O:24])=[O:23])[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:49]([O:48][C:46]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:20])[CH3:21])=[CH:17][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:8]=1)(=[O:23])=[O:24])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 3-(3-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (68.8 mg, 0.159 mmol; see step (f)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine and dried over anhydrous MgSO4, concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (69.8 mg, 0.471 mmol) and butyl chloroformate (202.8 μL, 1.59 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the title compound in 59% yield, over two steps, (44.4 mg, 0.093 mmol).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccn3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3ccccn3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-pyridyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.31 g, 0.65 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(2-pyridyl)-1(2H)-isoquinolinone dihydrochloride (0.27 g, 93.1%) as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=O)=[CH:4][CH:3]=1.B.C1COCC1.Cl.O>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][C:12]3[C:13](=[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: CCCCCOc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2
Yield: 58.1 %

Procedure:
N-2-(4-Hydroxyphenyl)ethyl-3-pentyloxyphthalimide (412 mg, 1.17 mmol) was dissolved in THF (1 ml), and a 1.0M THF solution (4 ml) of BH3·THF (4.0 mmol) was added to this solution. The mixture was stirred with refluxing under heating for 8 hours. A 3N aqueous hydrochloric acid solution (10 ml) was added to the reaction mixture. The mixture was further stirred for 0.5 hour at the same temperature, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml×3), and washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give N-2-(4-hydroxyphenyl)ethyl-7-pentyloxyisoindol-1-one (232 mg, 0.68 mmol, 59%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccccc1)c1ccc(Cl)cc1
Product: O=C(NCC(c1ccccc1)c1ccc(Cl)cc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-phenyl-ethylamine. LCMS (MH+): m/z=404.0, tR (minutes, Method D)=0.91
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[NH:11][C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H-].[Na+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39]Br)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:9]([CH2:39][CH2:38][CH2:37][CH:34]3[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]benzimidazole (550 mg, 1.84 mmol) and anhydrous N,N-dimethylformamide (59 ml). To this solution was added sodium hydride (60% in mineral oil, 81.04 mg, 2.03 mmol). The resulting mixture was stirred at room temperature for 60 minutes, and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (620 mg, 2.03 mmol) was added. The resulting mixture was heated to 100° C. and stirred at this temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous fraction was extracted twice with brine. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1)C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[CH:22][C:23]=3[O:28][CH3:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: COc1cc(CCC(=O)O)ccc1OCc1cccc(SC2CCCC2)n1
Yield: 59 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (33 mg, 0.14 mmol) obtained in Step C of Preparation Example 27 and 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester (36 mg, 0.15 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 69%).
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:11][S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)Cc1ccccc1
Yield: 72.1 %

Procedure:
The general method of procedure A was followed with phenylmethanesulfonamide (51.3 g), acetone (30 ml), 1N sodium hydroxide (31.5 ml), and 4-chlorophenyl isocyanate (5.07 g) in acetone (30 ml). The reaction mixture was filtered and the filtrate acidified with 1N HCl (31.5 ml). The solid product was washed with water and dried in vacuum at 60° C. to provide 7.73 g of white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=[O:19])[CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:27]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=[O:19])[NH:27][CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: COC1CC(=O)NCC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 15.6 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6S)-6′-chloro-2-(3-chlorophenyl)-6-methoxyspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (156 mg, 0.4 mmol) was reacted with NaN3 (52 mg, 0.8 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.8 mL) (Aldrich) in acetonitrile (10 mL) to give rac-(3S,4R,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (25.3 mg): HRMS (ES+) m/z Calcd for C20H18Cl2N2O3+H [(M+H)+]: 405.0767, found: 405.0765 and rac-(3R,4R,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione: HRMS (ES+) m/z Calcd for C20H18Cl2N2O3+H [(M+H)+]: 405.0767, found: 405.0768.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]=1[NH:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:3].[OH-].[K+].Cl>CO.O>[NH2:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[NH:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:3]
Reactant: CCOC(=O)c1ccc(C(N)=O)c(NC2CCCC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(C(=O)O)cc1NC1CCCC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A suspension of ethyl 4-(aminocarbonyl)-3-(cyclopentylamino)-benzoate (333 mg, 1.21 mmol) and potassium hydroxide (135 mg, 2.41 mmol) in methanol (6 mL) and water (2 mL) was stirred at 55° C. for 1 h. After cooling to room temperature, water was added and the pH adjusted to 4 with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to provide 4-(aminocarbonyl)-3-(cyclopentylamino) benzoic acid (260 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6): 13.02 (br s, 1H), 8.17 (d, 1H), 7.97 (br s, 1H), 7.66 (d, 1H), 7.34 (br s, 1H), 7.21 (d, 1H), 7.04 (dd, 1H), 3.81 (m, 1H), 1.99 (m, 2H), 1.64 (m, 4H), 1.42 (m, 2H). MS (EI) for C13H16N2O3: 249 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].N.[Na].CO>O1CCCC1.C(O)(C)C>[CH3:19][O:18][C:13]1[CH2:14][C:15]2[CH2:16][CH2:17][CH:8]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH3:7])[CH2:9][C:10]=2[CH2:11][CH:12]=1
Reactant: CCCN(CCC)C1CCc2cc(OC)ccc2C1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)O
Product: CCCN(CCC)C1CCC2=C(CC=C(OC)C2)C1
Yield: 89.5 %

Procedure:
A solution of N,N-dipropyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine (17.6 g, 0.067 mole) in tetrahydrofuran (188 mL) and isopropanol (188 mL) was added with stirring to liquid ammonia (500 mL) cooled by a dry ice-isopropanol bath. Sodium (29.4 g, 1.3 g-atom) was added in small pieces over 0.5 hr. After the blue colour disappeared (ca. 2 hr), methanol (120 mL) was added and the ammonia was allowed to evaporate after removal of the cooling bath. The residue was diluted with water (1000 mL) and extracted three times with diethyl ether. The ether extracts were dried (MgSO4) and concentrated, giving a yellow oil (15.8 g) of 1,2,3,4,5,8-hexahydro-6-methoxy-N,N-dipropyl-2-naphthalenamine, NMR (CDCl3) δ 0.85 (t, 6H), 3.5 (s, 3H) and 4.6 (m, 1H).
Reaction SMILES: [CH2:1]([CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH2:1]([CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:9]([O:11][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C(Cc1ccccc1)c1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)C(Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
To a solution of α-benzylindole-3-acetic acid (12 g) in methanol (200 mL), was added 2 mL of concentrated H2SO4 ; the mixture was stirred at reflux temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to a volume of about 50 mL, then diluted with 200 mL of toluene. The toluene solution was washed with water, saturated NaHCO3 solution, and again with water. On evaporation, if afforded 12.3 g (97.6% crude yield) of product as a light brown viscous oil. The crude product slowly crystallized on standing at room temperature. It was triturated with heptane to give fine white crystals, m.p. 62°-68° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.C(O)CCC>O1CCOCC1.CN(C=O)C>[CH2:23]([NH:30][C:4]1[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 2.13 mmol), benzylamine (0.233 mL, 2.13 mmol) and DIEA (0.750 mL, 4.31 mmol) in dioxane (12 mL)/nBuOH (12 mL)/DMF (3 mL) was stirred at 70° C. for 2 h. It was concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give N-benzyl-2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.993 g).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Br:16][CH2:17][CH2:18]Br.[I-].[K+]>C(O)C>[C:1]1([N:7]2[CH2:13][C:11](=[O:12])[N:10]([CH2:18][CH2:17][Br:16])[C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCBr
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN(c2ccccc2)C(=O)N1CCBr

Procedure:
A mixture of 1-phenylhydantoin (5 g, 28.3 mmoles), 85% potassium hydroxide (2.06 g, 31.2 mmoles), 1,2-dibromoethane (11.72 g, 62.4 mmoles) and potassium iodide (catalytic amounts) in 100 ml of ethanol was refluxed for 67 hours. The solid was filtered, the mother liquors were evaporated and the crude product was purified by silica gel column chromatography eluting with increasing mixtures of ethyl acetate in hexane. By crystallization from acetone/hexane 1.56 g of the title compound were obtained, m.p. 146°-147° C.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][S:53][CH2:52][CH2:51]1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][S:53][CH2:52][CH2:51]1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCN1CCSCC1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCSCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(2-chloroethyl)thiomorpholine hydrochloride (prepared as describe in WO 2009058859) as the alkylating reagent in Step 1. The product was isolated as a white solid (3 mg, 0.85%). LCMS: m/e 659.37 (M+H)+, 2.38 min (method 13). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 5.32-5.19 (m, 1H), 4.77 (s, 1H), 4.65 (s, 1H), 3.11-2.98 (m, 1H), 2.89 (m, 5H), 2.75 (m, 5H), 2.67-2.57 (m, 1H), 2.31-2.16 (m, 1H), 2.14-1.85 (m, 6H), 1.71 (s, 7H), 1.59-1.40 (m, 6H), 1.38-1.15 (m, 8H), 1.08-0.96 (m, 10H), 0.94 (s, 3H)
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH2:27])=O)[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:28])[CH2:23][CH2:24][C:25]#[N:27])[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC(N)=O)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC#N)C1
Temperature: 0 °C
Yield: 55.9 %

Procedure:
To a mixture of 4-((3S)-3-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)-4-oxobutanamide (5.5 mg, 0.014 mmol) and triethylamine (9.6 μL, 0.069 mmol) in tetrahydrofuran (0.2 mL) stirring at about 0° C. was added trifluoroacetic anhydride (4.8 μL, 0.034 mmol). The resulting mixture was kept cold and stirred for 2 h. The mixture was concentrated then purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3 mg (57%) of the desired product. LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.2.