Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:25][S:26][CH3:27])([CH3:24])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[C:8](CCS([O-])(=O)=O)[CH:9]=[C:10]([CH2:12]CS([O-])(=O)=O)[CH:11]=1.[C:28](=[O:31])([O-])[O-].[K+].[K+].CN(C)C=[O:37]>>[CH3:1][C:2]([S:25][S:26][CH3:27])([CH3:24])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:28][OH:31])[CH:9]=[C:10]([CH2:12][OH:37])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CSSC(C)(C)CSCc1cc(CCS(=O)(=O)[O-])cc(CCS(=O)(=O)[O-])c1
Reactant: CN(C)C=O
Agent: [K+]
Product: CSSC(C)(C)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
IBD monomer (177 mg, 0.602 mmol) in anhydrous N,N-dimethylformamide (1.75 mL) was added to (5-((2-methyl-2-(methyldisulfanyl)propylthio)methyl)-1,3-phenylene)bis(methylene)dimethanesulfonate (119 mg, 0.251 mmol) at ambient temperature. Potassium carbonate (173 mg, 1.253 mmol) was added and the reaction was allowed to stir at ambient temperature for 20 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The extracts were washed with brine and then dried with anhydrous sodium sulfate, filtered and concentrated on high vacuum. The crude product was purified by flash silica gel chromatography (neat DCM 2% MeOH/DCM). Fractions containing product were combined, concentrated and purified by semi-prep RP-HPLC (C18, A=DI water B=ACN, 20 mL/min). Fractions containing desired product were combined, extracted with dichloromethane, dried with anhydrous magnesium sulfate, filtered and concentrated to yield the desired product (46 mg, 21%). 1H NMR (400 Hz, CDCl3): δ 8.19 (d, J=8.0 Hz, 2H), 7.77 (m, d, J=4.4 Hz, 2H), 7.50 (s, 2H), 7.34 (s, 1H), 7.31 (s, 2H), 7.19 (m, 4H), 7.03 (t, J=7.2, 7.6 Hz, 2H), 6.77 (s, 2H), 5.14 (m, 4H), 4.40 (m, 2H), 3.91 (s, 6H), 3.70 (m, 2H), 3.63 (m, 2H), 3.41 (m, 2H), 2.65 (s, 2H), 2.29 (s, 3H), 1.26 (s, 6H). MS (m/z), Calcd. 893.2 (M+Na)+. found 893.2 (M+Na)+, 911.2 (M+H2O+Na)+, 929.2 (M+2H2O+Na)+, 945.1 (M+2H2O+K)+. See FIG. 30.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Na+].[CH2:13]1[S:15][CH2:14]1>O.[N+]([O-])([O-])=O.[Ag+]>[OH-:9].[SH:15][CH2:14][CH2:13][N+:1]1[CH:2]=[CH:3][C:4]([CH2:7][S:8]([OH:11])(=[O:9])=[O:10])=[CH:5][CH:6]=1
Reactant: C1CS1
Reactant: O=S(=O)([O-])Cc1ccncc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)Cc1cc[n+](CCS)cc1
Product: [OH-]
Reaction time: 1 h
Yield: 31.4 %

Procedure:
A solution of silver nitrate (1.31 g, 7.68 mmol) in water (4 ml) was added to a stirred solution of sodium 4-pyridylmethylsulfonate (1.50 g, 7.68 mmol) in water (15 ml). The resulting hazy solution was treated with ethylene sulfide (0.51 ml, 8.58 mmol) added dropwise over 2 minutes. The resulting gummy mixture was let stand at room temperature 30 minutes and the supernatant decanted. The residue was mixed with water (10 ml) and vigorously bubbled with hydrogen sulfide for 10 minutes. The mixture was vigorously stirred an additional 1 hour and the silver sulfide precipitate removed by centrifugation. The supernatant was concentrated under vacuum to ca. 5 ml and charged onto a column of Dowex 50W-X4 (hydrogen form, 200-400 mesh, 1.5×33 cm). The column was eluted with water at 6.0 ml fractions/2.0 minutes. Fractions 19 to 27 were combined and evaporated under vacuum to an off-white solid. The solid was mixed with a few mls of methanol and filtered to afford the title compound as an off-white solid (303 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (14.1 g, 100 mmol) and 3-aminophenol (11.2 g, 102 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (26.5 g, 191 mmol) and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate-hexane (1:1, 250 mL) and washed with water (250 mL×2) and saturated brine (100 mL), successively. The collected aqueous layer was extracted with ethyl acetate-hexane (1:1, 250 mL). The collected organic layer was dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad filled with two layers of silica gel and celite, and the filtrate was concentrated. The obtained yellow syrup-like substance was recrystallized from ethyl acetate and hexane to give the title compound (21.8 g, 95%) as yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][NH:23][CH3:24]>C(O)C>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1)[CH3:24]
Reactant: CNC
Reactant: COC(=O)c1cccc2oc(-c3ccc(CBr)cc3)nc12
Solvent: CCO
Product: COC(=O)c1cccc2oc(-c3ccc(CN(C)C)cc3)nc12
Temperature: 30 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
Methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate (100 mg, 0.29 mmol) and dimethylamine (26 mg, 0.58 mmol) were added into ethanol (30 ml) and the mixture was stirred at 30° C. for 12 h. The resulting mixture was evaporated under reduced pressure. 60 mg of methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxylate solid was obtained, yield: 44.5%. LC-MS (ESI) m/z: 311 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[O:12][CH3:13].[CH2:15](I)[CH3:16]>CN(C)C=O>[CH2:15]([N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[C:11](=[O:14])[O:12][CH3:13])[CH3:16]
Reactant: CCI
Reactant: COC(=O)Nc1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC)c1ccccc1C
Reaction time: 4 h

Procedure:
5.1 g (0.2 mol) of sodium hydride are added a little at a time to 30 g (0.18 mol) of methyl N-(o-methylphenyl)-carbamate (Example 1a) in 200 ml of dimethylformamide. After the evolution of gas has ceased, 30 g (0.2 mol) of ethyl iodide are added dropwise, the reaction mixture being lightly cooled in a water bath. A white solid is precipitated. After about 4 hours, the reaction mixture is diluted with water and the aqueous phase is extracted three times with ether. The organic phase is dried over MgSO4 and evaporated down. The residue is distilled. 32.5 g (0.17 mol=93%) of the title compound are obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O>C1COCC1>[CH3:13][CH:12]([CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)[NH2:14]
Reactant: CC(=Cc1c[nH]c2cc(F)ccc12)[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 92.2 %

Procedure:
α-Methyl-6-fluorotryptamine was prepared by the dropwise addition of an anhydrous THF solution of 6-fluoro-3-(2-nitropropenyl)-1H-indole (560 mg, 2.54 mmol) to a stirred mixture of LiAIH4 (480 mg, 12.7 mmol) in THF (40 mL) at 0° C. The reaction slurry was allowed to stir under N2 from 0° C. to ambient room temperature over 3.5 hours. The reaction solution was again cooled to 0° C. prior to the dropwise addition of H2O to quench excess LiAIH4. The reaction suspension was filtered through a pad of Celite to remove Al salts. The filtrate was concentrated under reduced pressure, diluted with EtOAc (200 mL), washed with NaCl (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to provide 450 mg of α-methyl-6-fluorotryptamine as a viscous oil; 1H NMR (CDCl3) δ 8.30 (1H, br s), 7.52 (1H, m), 6.98-7.04 (2H, m), 6.87 (1H, t), 3.29 (1H, m), 2.87 (1H, dd), 2.64 (1H, q), 1.25 (3H, d); MS (ESI): 193 (MH+); TLC (SiO2 plate, 100% DCM) Rf=0.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: OCCCCc1ocnc1-c1ccc(Cl)s1
Reactant: COc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1OCCCCc1ocnc1-c1ccc(Cl)s1
Reaction time: 1 h

Procedure:
To a mixture of 4-(5-chloro-2-thienyl)-5-oxazolebutanol (800 mg), 2-methoxyphenol (770 mg), tributylphosphine (1.24 g) and tetrahydrofuran (10 ml) was added dropwise a toluene solution of diethyl azodicarboxylate (40%, 2.61 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(5-chloro-2-thienyl)-5-[4-(2-methoxyphenoxy)butyl]oxazole was obtained as an oil (420 mg, 37%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1ccc(O)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)O)c(Cl)c1Cl

Procedure:
To 20.7 g (0.1 mole) off 2,3-dichloro-4-hydroxybenzoic acid was added 8 g of sodium hydroxide dissolved in 150 ml water. The solution was warmed to 60° and 12.6 g (0.1 mole) of dimethyl sulfate added. The mixture was then heated at 70° for 2 hours, cooled, acidified and filtered to yield 16.7 g. (75%) of the product, m.p. 224°-226°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:17]([CH3:21])([CH3:20])[CH:18]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1([CH:18]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)([CH3:21])[CH3:20])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C=O)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C1CCCCC1)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A suspension of p-chlorobenzamide (5.31 g, 35.10 mmol), 2-cyclohexyl-2-methylpropanal (4.5 g, 35.10 mmol), and benzotriazole (4.18 g, 35.10 mmol) in toluene (100 mL) was treated with p-toluenesulfonic acid (334 mg, 1.76 mmol). The solution was heated at reflux under Dean-Stark conditions for 10 hours, then cooled gradually to ambient temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (elution with 10% EtOAc/hexane) to provide 5.3 g of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 25 °C

Procedure:
To a solution of ethyl 8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (25.0 g, 104.9 mmol) in DMF (500 mL), potassium carbonate (58 g, 420 mmol) and benzyl bromide (14.9 mL, 126 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate to give titled material.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH:57]([Mg]Br)([CH3:59])[CH3:58].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42]([OH:43])[CH:57]([CH3:59])[CH3:58])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: CC(C)[Mg]Br
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)C(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 213 mg (0.273 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formyl pyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in 5 ml of tetrahydrofuran, 0.5 ml (0.5 mmol) of 1.0 mol/L isopropyl magnesium bromide-tetrahydrofuran solution was added under an argon gas atmosphere, and the reaction solution was stirred at room temperature for 0.5 hour. Then, 0.5 ml (0.5 mmol) of 1.0 mol/L isopropyl magnesium bromide-tetrahydrofuran solution was further added and the reaction solution was stirred at room temperature for 0.5 hour. After completion of the reaction, the reaction solution was poured into saturated ammonium chloride aqueous solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-80/20 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 174 mg of the title compound as a white solid (yield: 77%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=2)[CH:8]=1)[OH:6])C.[OH-].[K+].C(O)(C(F)(F)F)=O>CCO>[C:21]([C:18]1[NH:17][C:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:5]([OH:6])[C:4]([OH:31])=[O:3])=[CH:8][C:9]=2[C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=2)=[O:15])=[N:20][CH:19]=1)#[N:22]
Reactant: CCOC(=O)C(O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C(O)C(=O)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of [4-[(5-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-hydroxy-acetic acid ethyl ester (as prepared in the previous step)(30.0 mg, 71 μmol) in 0.2 mL of EtOH at RT was added a 2N KOH solution (71 uL, 14.2 μmol) and the reaction stirred for 2 h. The pH was then adjusted to 2 with a 2 M TFA solution and the title compound was purified by RP-HPLC, eluting with a linear gradient of 20% to 50% CH3CN in 0.1% TFA/H2O over 10 min to give 20 mg (71%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.24 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.40 (dd, J=8.4, 2.1 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 5.78 (m, 1H), 5.15 (s, 1H), 2.33 (m, 2H), 2.10 (m, 2H), 1.62 (t, J=6.3, 6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O2, 395.2 (M+H). found 395.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH2:10]2)=[CH:5][C:4]=1C)#[CH:2].[C:19](O)(=O)C1C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1)[CH3:29]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:35]3[CH:36]=[CH:37][C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:39])=[CH:33][CH:34]=3)=[CH:4][C:5]=2[CH3:19])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=C(O)c1ccccc1
Reactant: C#Cc1ccc(C2(OCC(C)(C)C)CC2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and ethyl-4-iodo benzoate (Reagent A, 86.0 mg, 0.31 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (78 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 60.0 mg (50%) of the title compound as an orange solid.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:13]([C:12]1[CH:18]=[CH:19][C:9]([C:6]#[C:7][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
4-Ethynylbenzaldehyde (10 g) obtained by the same method as the synthesis method described in the literature (Tetrahedron Letters, 2007, Vol. 48(33), pp. 5817-5820), PdCl2(PPh3)2 (3.4 g), CuI (1.5 g), and triethylamine (32 mL) were added to a THF (0.25 L) solution of ethyl 4-iodobenzoate (20 g). The mixture was stirred for 3 hours at room temperature, and the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/chloroform=80/20→0/100) to obtain ethyl 4-[(4-formylphenyl)ethynyl]benzoate (yellow solid) (16 g, 69%).
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 488 mg (0.82 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde, and 2.5 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 35 minutes. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 274 mg of a blackish brown crystal (yield: 93.6%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].Br[CH2:6][C:7]([NH:9][C:10]1[C:27]([OH:28])=[C:26]2[C:13]([CH2:14][CH:15]3[C:24]([C:25]2=[O:29])=[C:23]([OH:30])[C:22]2([OH:31])[CH:17]([CH:18]([N:37]([CH3:39])[CH3:38])[C:19]([OH:36])=[C:20]([C:33]([NH2:35])=[O:34])[C:21]2=[O:32])[CH2:16]3)=[C:12]([N:40]([CH3:42])[CH3:41])[CH:11]=1)=[O:8]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:39][N:37]([CH3:38])[C@H:18]1[C@H:17]2[C@:22]([OH:31])([C:23]([OH:30])=[C:24]3[C@H:15]([CH2:16]2)[CH2:14][C:13]2[C:26](=[C:27]([OH:28])[C:10]([NH:9][C:7](=[O:8])[CH2:6][NH:4][O:3][CH3:2])=[CH:11][C:12]=2[N:40]([CH3:41])[CH3:42])[C:25]3=[O:29])[C:21](=[O:32])[C:20]([C:33]([NH2:35])=[O:34])=[C:19]1[OH:36]
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reactant: CON
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Product: CONCC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 21.2 %

Procedure:
The compound of the example is prepared by the procedure of example 1 using 1.5 g of methoxyamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 0.5 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.1 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[CH:23]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[N:6][C:7]=1F.[NH:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.CN1CCOCC1.O>CN1CCCC1=O>[Cl:1][C:2]1[C:7]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]2)=[N:6][C:5]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[CH:23]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(F)n2)c1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Temperature: 100 °C
Yield: 80.5 %

Procedure:
A mixture of 1-(5-chloro-6-fluoro-2-pyridyl)-6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridine (0.155 mmol; 54.9 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.466 mmol; 93.2 mg), and N-Methylmorpholine (1.55 mmol; 159 mg; 0.172 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water. The precipitate was collect by filtration and dried on high vacuum to afford tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (66.6 mg, 80%), which was used without further purification.