Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)(=[O:18])=[O:17])[CH3:34])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of (R)-{[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (example 1-5, prepared by the method analogous to the one described for example 1-1, 48.6 mg, 0.100 mmol) in acetonitrile (3 mL) was added potassium carbonate (27.6 mg, 0.200 mmol) and methyl iodide (9.5 μL, 0.150 mmol). After being heated at 70° C. under an argon atmosphere for 6 hours, the reaction mixture was cooled to room temperature, filtered through a glass funnel and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloro-methane) to afford {(R)-4-[(3,5-bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (42.6 mg, 83%) as a white solid. MS cald. (calculated) for C20H21F6N3O4S 513, obsd. (observed) (ESI+) [(M+H)+] 514.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:16][CH2:17][CH3:18].[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: CCOc1cc(N2CCNCC2)ccc1Cl
Agent: Cl
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. 1-(4-Chloro-3-ethoxyphenyl)piperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (4% to 15% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-3-ethoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (25 mg): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.66 (dd, 0.4H), 8.57-8.54 (m, 1H), 7.29-7.19 (m, 4H), 6.49-6.40 (m, 2H), 5.45 (s, 0.7H), 5.43 (s, 1.3H), 4.10-4.04 (m, 2H), 3.81-3.69 (m, 4H), 3.23-3.16 (m, 4H), 1.50-1.45 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:29][C:28]1[CH:30]=[CH:31][C:25]([Br:24])=[CH:26][C:27]=1[F:32])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Br)cc1F

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dry CHCl3 under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g, 12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3 mmol). Reaction was refluxed for 6 hours, cooled and concentrated. Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH (2×200 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound. (5.5 g, 82%) APCI (AP−): 515.1, 517.1 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11](=[CH2:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=1[O:17][CH3:18])[CH3:2].[CH3:19][NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH2:16][CH:11]([C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([CH2:1][CH3:2])=[C:4]([O:17][CH3:18])[CH:5]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:24])[CH3:27]
Reactant: CCOC(=O)CCNC
Reactant: C=C(C(=O)OC)c1cc(OC)c(CC)c(OC)c1
Product: CCOC(=O)CCN(C)CC(C(=O)OC)c1cc(OC)c(CC)c(OC)c1
Yield: 59.5 %

Procedure:
A solution of 78.4 g (313 mmol) of methyl 2-(4-ethyl-3,5-dimethoxy-phenyl)-acrylate and 47.7 g (364 mmol) of ethyl 3-methylamino-propionate was stirred at room temperature for 48 hours. Chromatography of the reaction mixture (silica gel, ethyl acetate/hexane 1:1) and crystallization from hexane gave 71.1 g (59%) of methyl 3-[(2-ethoxycarbonyl-ethyl)-methyl-amino]-2-(4-ethyl-3,5-dimethoxy-phenyl)-propionate as colorless crystals of m.p. 74-75°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][CH:6]=1.C1C(=O)N([I:19])C(=O)C1>CC#N>[I:19][C:6]1[NH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1nc(C)c[nH]1
Solvent: CC#N
Product: CCOC(=O)c1nc(C)c(I)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 4-methyl-1H-imidazole-2-carboxylate (compound 239.1, 100 mg, 0.65 mmol) in CH3CN (10 mL). NIS (218 mg, 0.97 mmol) was added to the reaction. The reaction mixture was stirred for overnight at room temperature, then concentrated under reduced pressure. The residue was dissolved with 30 mL of EtOAc, then was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 80 mg (44%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: Brc1nccs1
Product: c1csc(N2CCOCC2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
2-Bromothiazole (4.592 g) was added to morpholine (24 ml), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil (4.531 g, yield; 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.CNCCNC.[Na+].[I-:22]>O1CCOCC1.[Cu]I>[I:22][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)Cc1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)Cc1ccc(I)cc1
Temperature: 120 °C
Reaction time: 70 h

Procedure:
To 6.00 g (23.4 mmol) N-(1-(4-bromophenyl)propan-2-yl)acetamide (I44.1) in 65 mL dioxan are added 0.45 g (2.34 mmol) CuI, 0.50 mL (4.70 mmol) N,N′-dimethylethylendiamine and 7.02 g (46.9 mmol) NaI. The reaction mixture is stirred at 120° C. for 70 h. The mixture is allowed to cool to r.t. and half of the solvent is removed in vacuo. EtOAc and diluted aq. ammonia solution are added and the layers are separated. The aq. layer is once more extracted with EtOAc. The organic layers are combined, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is triturated with diethylether and dried at 50° C. in vacuo.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]2[C:8]([C:10]3[C:15]([OH:16])=[CH:14][C:13]([CH2:17][OH:18])=[CH:12][C:11]=3[C:19](=[O:20])[C:3]=2[CH:2]=1)=[O:9].Cl>CS(C)=O.C(N(CC)CC)C>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[C:19](=[O:20])[C:11]=2[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cc(CO)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O
Reaction time: 0.25 h

Procedure:
To aloe-emodin (5.0 g) in dry dimethyl sulphoxide (55 ml) and triethylamine (77 ml) was added a solution/suspension of sulphur trioxide-pyridine complex (29.4 g) in dry dimethyl sulphoxide (100 ml), dropwise with stirring, over 15 minutes. The addition was slightly exothermic and gave a dark brown solution, which was stirred at room temperature for 2-3 hours, then poured onto dilute hydrochloric acid (1000 ml, 0.5M), stirred for 15 minutes, then left to stand for 15 minutes. The suspension was filtered (slow), washed with water (400 ml) and pulled dry to leave a brown solid. Dried at 50° C. in a vacuum oven, m.p. 198°-200° C.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+:10](C)[C:11]3[CH:16]=CC=CC=3)[S:9][C:5]=2[CH:4]=1.NCC[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:10][CH2:11][CH2:16][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[S:9][C:5]=2[CH:4]=1
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Reactant: NCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2sc(=NCCN3CCCCC3)sc2c1

Procedure:
A solution of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (8.39g), N-(2-aminoethyl)piperidine (2.56g) and anhydrous sodium carbonate (1.06g) in 200 ml of anhydrous dimethylformamide is heated at 120° C under a nitrogen atmosphere for three hours. The reaction mixture is poured into 1000 ml of water and extracted with three 300 ml portions of dichloromethane. The combined organic extracts are washed with two 500 ml portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield an oil. This oil is chromatographed on silica gel (1000 ml) eluting with (1) pentane (1000 ml), (2) chloroform (1000 ml), and finally methanol/chloroform (1:4, 2000 ml). The solid product from elution (3) is recrystallized from pentane to yield 4g of the title compound, melting point 42-44° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:14][C:13](=[O:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]2[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[C@@H:14]([CH3:25])[C:13](=[O:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]2[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([C@@H]2CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc([C@@H]2[C@@H](C)C(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1, 0.85 g, 2.5 mmol) in THF (20 mL) was added LiHMDS (2.5 mL, 2.5 mmol) at −78° C. After 30 mins, MeI (0.187 mL, 3.00 mmol) was added. The reaction mixture was stirred at −78° C. for 1.5 hr. It was warmed up to 0° C. for 30 min and then warmed up to RT for 30 min. The reaction mixture was quenched with 2 mL of AcOH and 100 mL of NH4Cl. The product was extracted with EtOAc (3×100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 30% EtOAc/Hexane to give (2S,3S,4R)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2,4-dimethyl-5-oxopyrrolidine-1-carboxylate (intermediate J2, 0.55 g, yield of 62%) as off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.29 (s, 1H), 7.14 (d, 1H), 6.95 (d, 1H), 3.93 (s, 3H), 3.91 (m, 1H), 2.58 (m, 1H), 2.40 (m, 1H), 1.59 (s, 9H), 1.38 (d, 3H), 1.17 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (1 eq.) in DCM was added TEA (3 eq.). The reaction was cooled to 0° C. Acetyl chloride (1 eq.) was filtered through a pad of alumina then added dropwise in solution in DCM to the reaction at 0° C. The reaction was stirred at 20° C. for 4 h. The crude was diluted with DCM, washed twice with water, then twice with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford (2-acetylamino-ethyl)-carbamic acid tert-butyl ester. The compound was used as such without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[NH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[N:14]=1.C(#N)C>C(Cl)Cl>[CH3:20][O:19][C:17]1[CH:16]=[C:15]([CH3:21])[N:14]=[C:13]([NH:12][C:10]([NH:9][S:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[O:11])[N:18]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccco1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccco2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.10 g of 2-furansulfonyl isocyanate in 40 ml of methylene chloride was added 1.60 g 2-amino-4-methoxy-6-methylpyrimidine. The resulting mixture was stirred for 1 hour at room temperature, then refluxed for 15 minutes, and the solvent was removed under vacuum. The solid obtained was allowed to stand under ethyl ether containing a trace of acetonitrile for one day, and was then filtered and dried to give the desired product melting at 185°-188° (dec).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][CH2:22][CH2:23]Cl)[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:20][CH2:19][O:21][CH2:22][CH3:23])[C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCCCl
Reactant: Brc1c(-c2ccccc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(-c2ccccc2)c(Br)c2ccccc21
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 0.48 g, 12.0 mmol) was added to a solution of 3-bromo-2-phenyl-1H-indole (2.72 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) by small portions, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 30 min. To the reaction mixture was added 2-chloroethyl ethyl ether (1.65 mL, 15.0 mmol), and the mixture was stirred at 70° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (2.60 g, yield 76%) as a red oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]2[NH:11][C:12]3[C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[N:14][C:13]=3[C:8]2=[CH:7][CH:6]=1>O1CCCC1.CO>[CH3:3][O:4][C:5]1[N:10]=[C:9]2[NH:11][C:12]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[N:14][C:13]=3[C:8]2=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1nc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)c3[nH]c4nc(OC)ccc4c3n2)cc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Aqueous sodium hydroxide (1.0 N, 0.66 mL, 0.66 mmol) was added to a solution of methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (80 mg, 0.22 mmol) in a mixture of tetrahydrofuran (3 mL) and methanol (1 mL). After 1 hr, the organic solvents were removed on the rotary evaporator. The residue was diluted with water to bring most of the solid into solution and sufficient 1.0 N aqueous HCl was added to bring the pH of the mixture to about 3. After stirring for 0.5 hr, the precipitate was collected, washed with water, and dried under vacuum over solid sodium hydroxide to give 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylic acid (74 mg, 0.212 mmol, 96% yield) as an orange solid. MS (ESI) m/z 350.2 (M+H). 1H NMR (DMSO-d6) δ ppm 8.52 (1H, d, J=8.54 Hz), 8.17 (1H, s), 8.09 (2H, d, J=8.85 Hz), 7.07 (2H, d, J=8.85 Hz), 6.78 (1H, d, J=8.24 Hz), 4.02 (3H, s), 3.83 (3H, s).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:8][CH:9]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCCO)cc2)CC(C)(C)C1
Yield: 80.2 %

Procedure:
To a solution of ethyl({4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate 10 (0.580 g, 1.336 mmol) in anhydrous THF (25 mL) was added LiAlH4 (3.4 mL, 3.42 mmol, 1.0 M solution in THF) drop-wise under N2 atmosphere at room temperature. The resultant solution was stirred at RT for 0.5 h. The reaction mixture was quenched with EtOAc (10 mL) and continued the stirring for an additional 10 min. Reaction mixture was poured into 15% aqueous HCl (50 mL) and then extracted with EtOAc (4×30 mL). The combined organic layer was washed with brine (1×30 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel column chromatography using hexanes: EtOAc (19:1 to 4:1) as an eluent to afford 0.41 g (79%) of the title compound (15) as white foam. 1H NMR (400 MHz, DMSO-d6): δ 7.16-7.06 (m, 4H), 7.03 (d, J=8.4 Hz, 2H), 6.84 (d, J=6.4 Hz, 2H), 4.83 (t, J=5.6 Hz, 1H), 3.92 (t, J=5.2 Hz, 2H), 3.67 (q, J1=10.8 Hz, J2=5.2 Hz, 2H), 1.90 (s, 2H), 1.86 (s, 2H), 1.24 (s, 2H), 0.87 (s, 6H), 0.87 (6H). LCMS (APCI): m/z 405 (M+Na)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:33])=O.C(Cl)(=O)C(Cl)=O>>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([Cl:33])=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: O=C(Cl)C(=O)Cl
Product: O=C(Cl)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O

Procedure:
The [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid is reacted with a suitably selected chlorinating agent such as thionyl chloride, oxalyl chloride, and the like, preferably thionyl chloride; according to known methods; to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetyl chloride.
Reaction SMILES: [NH2-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.C[O-].[Na+].[C:24]([NH2:33])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:31]2[CH:30]=[CH:29][CH:28]=[CH:26][C:25]=2[C:24]([NH2:33])=[O:32])[CH2:5]1
Reactant: CN1CCC(O)C1
Reactant: NC(=O)c1ccccc1O
Agent: C[O-]
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccccc2C(N)=O)C1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To 85.6 g (2.2 moles) of sodium amide in 1.5 liter of dry toluene was added 202 g (2 moles) of 1-methyl-3-pyrrolidinol so as not to exceed a temperature of 50° C. The mixture was then heated to 70° C. for 4.5 hours. The mixture was cooled and 381 g (2 moles) of o-toluenesulfonylchloride was added at a rapid drop while maintaining a temperature of 20°-30° C. with an ice bath. The mixture was stirred at room temperature for 2.5 hours and washed with water. The toluene solution was dried with sodium sulfate and concentrated. The residue, dissolved in 500 ml of dimethylformamide, was added to a reaction mixture prepared by adding 119 g (2.2 moles) of sodium methoxide and 274 g (2.0 moles) of salicylamide to one liter of dimethylformamide and the mixture was worked up as in preparation 1. Yield of product was 170 g (38%), m.p. 116°-118° C.
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[N:3]=1)[O:10][CH2:9][C@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[O:7]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C@H:37]1[CH2:41][CH2:40][C@H:39]([NH:42][CH2:14][C@H:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:4]4[N:3]=[C:2]([CH3:1])[O:26][C:5]=4[C:6]=3[O:7]2)[CH2:38]1
Reactant: NC1CCC(c2c[nH]c3ccc(F)cc23)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)O[C@@H](CN[C@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)CO3
Temperature: 77.5 °C
Yield: 34.6 %

Procedure:
Toluene-4-sulfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclo-penta[a]naphthlen-8-ylmethyl ester (0.46 g, 1.2 mmole) and 3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.27 g, 1.2 mmole) were combined in 8 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen for 5 hours. After cooling to room temperature, the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (CH2Cl2 then 1% MeOH/CH2Cl2) afforded 0.175 g of the title compound as an off-white solid: m.p. 79-82° C.; MS (ESI) m/z 422 (M+H)+.