Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>O1CCCC1.CN(C)C1C=CC=CC=1>[CH3:26][O:25][C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:22]=1[O:23][CH3:24])[C:17]([NH:11][C:4]1[C:5](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[C:6]([OH:8])=[O:7])=[O:18]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cc(F)ccc2C(=O)O)cc(OC)c1OC
Reaction time: 5 h
Yield: 60.3 %

Procedure:
In a mixture of 20 ml of tetrahydrofuran and 1.6 g of dimethylaniline is dissolved 1.6 g of 4-fluoroanthranilic acid. To this solution is added slowly a solution of 2.3 g of 3,4,5-trimethoxybenzoylchloride in tetrahydrofuran under room temperature and the mixture is strred at room temperature for 5 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 2.1 g of N-(3,4,5-trimethoxybenzoyl)-4-fluoroanthranilic acid as colorless needles.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[NH4+:10].[OH-]>O.[O-]S([O-])(=O)=O.[Cu+2].O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH2:10])[CH:3]=[N:4][CH:5]=1
Reactant: [NH4+]
Reactant: COc1cncc(Br)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: O
Product: COc1cncc(N)c1
Temperature: 120 °C

Procedure:
A solution of 3-bromo-5-methoxypyridine (5.2 g, 27.5 mmol) and CuSO4.H2O (1.37 g, 5.5 mmol) in NH4OH (5 mL) was placed in a sealed tube and heated at 120° C. for 10 hours. The reaction mixture was then cooled to room temperature, diluted with H2O (40 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound that was used in the next step with no further purification.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)CCC>[F:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Fc1cccnc1N1CCNCC1
Temperature: 23 °C
Yield: 72.8 %

Procedure:
The product of Example 28A (3.3 g, 0.025 mol) in n-butanol (150 mL) at 23° C. was treated with piperazine (21.5 g, 0.25 mol) and then reflux for 3 days. The reaction mixture was allowed to cool to 23° C. and concentrated under reduced pressure. The residue was slurried with water and ethyl acetate. The ethyl acetate solution was separarted, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 3.3 g (73% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.80 (m, 4H), 3.38 (m, 4H), 6.84 (m, 1H), 7.47 (m, 1H), 7.98 (m, 1H); MS (ESI) m/e 182 (M+H)+.
Reaction SMILES: [K].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Br:8][C:9]([CH2:11]Br)=[CH2:10]>C1(C)C=CC=CC=1.O>[Br:8][C:9](=[CH2:10])[CH2:11][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7]
Reactant: C=C(Br)CBr
Reactant: O=C1CCCN1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(Br)CN1CCCC1=O
Temperature: 0 °C
Yield: 64 %

Procedure:
To a suspension of 5.0 g (40.6 mmol) of pyrrolidinone potassium salt prepared from Example 1 in 40 mL of toluene, solution of 5.24 mL (2 equiv.) of 2,3-dibromopropene in 10 mL of toluene was added dropwise for 1 hour in water bath and the reaction mixture was reacted at 60˜70° C. for 2 hours. Upon completion of the reaction, the mixture was cooled to 0° C. and filtered to remove solid. It was then concentrated under reduced pressure and purified by separation with silica gel column chromatography (ethyl acetate/n-hexane (1:1)) to obtain 5.30 g (64% yield) of 1-(2-bromoallyl)-pyrrolidin-2-one. To degassed solution of 1.0 g (4.90 mmol) of 1-(2-bromoallyl)-pyrrolidin-2-one prepared in the above in 50 mL of ethanol/benzene (1:1), 5 mol% (172 mg) of ditriphenylphosphine palladium dichloride, degassed solution of 7.35 mL of 2N sodium carbonate and 3-pyridyl-tributyltin, dimethyl borate, trimethyl borate lithium salt, boronic acid propanediol ring ester (2 equiv.), etc. were added. The mixture was reacted for 15 minutes at room temperature, followed by heating at reflux for 18 hours. After concentrating under reduced pressure, it was extracted with ethyl acetate for three times and washed with brine for two times. The concentrated solution was purified by separation with silica gel column chromatography (ethyl acetate followed by methylene chloride/methanol (20:1)) to obtain 810 mg (82% yield) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one. Ozones were added to solution of 100 mg (0.494 mmol) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one at −78° C. to obtain 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one, which was the same as synthesized in Example 20.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH:44]1[CH2:48][N:47]([CH2:49][CH3:50])[N:46]([CH2:51][CH3:52])[CH2:45]1>ClCCl>[CH2:51]([N:46]1[CH2:45][CH:44]([NH:43][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH2:48][N:47]1[CH2:49][CH3:50])[CH3:52]
Reactant: CC(C)=CCC/C(C)=C/COc1ccccc1C(=O)O
Reactant: CCN1CC(N)CN1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN1CC(NC(=O)c2ccccc2OC/C=C(\C)CCC=C(C)C)CN1CC
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
2-geranyloxybenzoic acid (1.36 g) was dissolved in dichloromethan (20 ml) and 1-hydroxybenzotriazole (0.80 g) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.14 g) were added thereto while being cooled with ice. After the resulting mixture was stirred for 30 minutes, 4-amino-1,2-diethyl pyrazolidine (0.71 g) was added thereto and the mixture was stirred for one night at room temperature. The reaction liquid was washed with brine and then dried over sodium sulfite anhydride. Thereafter, the solvent was evaporated under a vacuum. The residue was purified by silica gel column-m chromatography (chloroform:methanol=30:1), thereby yielding 1.71 g (87%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH3:18][O-:19].[Na+]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:19][CH3:18]
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a stirred solution of 7-Chloro-6-fluoro-5-nitroquinoxaline-2(1H),3(4H)dione (0.100 g, 0.385 mmol, as prepared above) in DMSO (1.0 mL) at room temperature, sodium methoxide (0.125 g, 2.31 mmol, Mallinckrodt) was added in one port. The resulting dark red solution was stirred overnight at room temperate. It was then diluted with water (5.0 mL) and acidified with concentrated HCl (6 drops) to pH ˜2. The precipitated solid was filtered, washed with water (5.0 mL), and dried under vacuum to obtain 0.116 g (110%) of pure (1H NMR) title compound as a yellow powder; m. p. darkens at 316° C.; 1H NMR (DMSO-d6): δ 3.821 (s, 3H), 7.275 (s, 1H), 12.079 (s, 1H) 12.121 (s, 1H). The NMR also indicates the presence of DMSO (reaction solvent).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH3:20])=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[NH:23][C:21]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([C:41]3[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=3)=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[O:19][CH3:20])=[O:22]
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(-c3cnn(C)c3)nc2)c2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide (Example 3, 0.050 g, 0.12 mmol) in 3 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 M, 0.24 mL, 0.24 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.037 g, 0.18 mmol), and bis(tri-tert-butylphosphine)palladium(0) (4.0 mg, 0.0078 mmol). The reaction was heated at 100° C. for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 470.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.59 (s, 1H), 8.26-8.23 (m, 1H), 8.12 (d, J=7.1 Hz, 1H), 8.07-7.89 (m, 3H), 7.85-7.82 (m, 1H), 7.70-7.61 (m, 3H), 4.52 (s, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.98 (br s, 1H), 3.57-3.51 (m, 1H), 2.16-2.13 (m, 2H), 1.79 (br s, 2H), 1.50-1.21 (m, 4H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1([CH3:31])[N:17]2[C:18](=[O:29])[C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)=[CH:20][CH:21]=[C:16]2[C:15](=[O:30])[NH:14]1>CO.O.NN>[NH2:3][CH2:12][C:13]1([CH3:31])[N:17]2[C:18](=[O:29])[C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)=[CH:20][CH:21]=[C:16]2[C:15](=[O:30])[NH:14]1
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)NC(=O)c2ccc(Nc3ccncn3)c(=O)n21
Agent: NN
Solvent: O
Solvent: CO
Product: CC1(CN)NC(=O)c2ccc(Nc3ccncn3)c(=O)n21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (5, 0.085 g, 0.29 mmol) in methanol (20 mL), hydrazine hydrate (2 mL) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water, separated, dried over sodium sulphate and concentrated under reduced pressure, which was purified by repeated washing with diethyl ether and hexane to obtain 3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 15) as an off-white solid. Yield: 0.008 g, 9%; MS (ESI) m/z 287.05[M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.76 (d, J=7.8 Hz, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 3.55 (d, J=13.6 Hz, 1H), 2.92 (d, J=13.7 Hz, 1H), 1.75 (s, 3H), 1.44 (s, 1H), 1.41-1.34 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH3:21][S:22]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1F)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1F)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a suspension of 60% sodium hydride (0.16 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.80 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methanesulfonylchloride (0.41 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.47 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.[CH3:31][O:32][NH2:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][O:32][CH3:31])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CONC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.5 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (96 mg, 0.228 mmol) obtained in Example 12 in methylene chloride (3 ml), O-methylhydroxyamine hydrochloride (23 mg, 0.273 mmol), 1-hydroxybenzotriazole (31 mg, 0.228 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.273 mmol) and 4-methylmorpholine (59 μl, 0.546 mmol) were added. The reaction solution was stirred for 5 days at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 65% ethyl acetate/hexane was concentrated under reduced pressure to obtain a white solid. The resulting solid was washed with ethylacetate-hexane, and then was collected by filtration, to obtain the title compound (66 mg, 0.147 mmol, 64%) as a white powder.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)([CH3:14])[CH3:13])=[CH:20][CH:19]=1
Reactant: CC(C)(CO)NCCCn1ccnc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(COCc1ccc(Cl)cc1)NCCCn1ccnc1
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol (1.5 g) in dimethyl acetamide (10 ml) was addled dropwise to a stirred suspension of sodium hydride (0.32 g of a 60% dispersion in mineral oil) in dimethyl acetamide (15 ml) at 30° C. under nitrogen. The mixture was stirred for 45 minutes at 30° C. and then a solution of 4-chlorobenzyl chloride (1.63 g) in dimethyl acetamide (5 ml) was added. After the addition, the mixture was heated at 100-105° C. for 30 minutes and then cooled to 25° C. Toluene (50 ml) was added and the mixture was washed with water. The toluene layer was extracted with 5M hydrochloric acid. The combined acid extracts were basified with concentrated sodium hydroxide solution with cooling and extracted with dichloromethane to give an oil which was distilled under high vacuum to give N-[2-(4-chlorobenzyloxy)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine, b.p. 180-185° C. at 0.3 mbar.
Reaction SMILES: SC1C=CC(S[C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:25])[C:16]([CH3:24])([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH3:17])=[CH:11][CH:10]=2)=CC=1.[SH:26][CH2:27][CH:28]([OH:33])[CH:29]([OH:32])[CH2:30][SH:31].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:33][CH:28]([CH:29]([OH:32])[CH2:30][SH:31])[CH2:27][S:26][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:25])[C:16]([CH3:17])([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH3:24])=[CH:13][CH:14]=1
Reactant: OC(CS)C(O)CS
Reactant: CC(C)(C(=O)c1ccc(Sc2ccc(S)cc2)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCC(O)C(O)CS)cc1)N1CCOCC1
Reaction time: 17 h

Procedure:
1.0 g (4.0 mmol) of 1-[4-(4-mercaptophenylthio)phenyl]-2-methyl-2-morpholine-4-yl-propane-1-one and 1.37 g (8.9 mmol) of 1,4-dimercapto-2,3-butanediol are dissolved in 50 ml of dry dimethylacetamide, 1.10 g (8.0 mmol) of potassium carbonate are added and the mixture is stirred for 17 h. The resulting suspension is poured into water and extracted with ethyl acetate, the combined organic phases are washed with water. The solvent is distilled off and the residual oil is purified by column chromatography on silica gel with ethanol-methylene chloride (5:95) as eluent. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.31 (s,6H), 1.55 (t,1 H), 2.57 (m,4H), 2.75 (m, 1H), 3.24 (m,5H), 3.70 (m,5H), 4.18 (s,1H), 7.53 (d,2H), 8.49 (d,2H).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:14][C:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:18])[CH2:16]O>>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:7]=1[O:8][CH2:14][C:15]([CH3:18])([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:16])[C:1]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)(CO)N1CCCC1
Product: COC(=O)c1ccc(OCC(C)(C)N2CCCC2)c(OC)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl vanillate and 2-methyl-2-(1-pyrrolidinyl)propanol (Example 188, Part A) by a essentially following the procedure outlined in Example 193, Part A.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(O)(=O)=O.[CH2:13]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[N+:1]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 78 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
70% Nitric acid (3.16 mL) was added dropwise to a suspension of trifluoromethanesulfonic acid (9.34 mL, 105.6 mmol) in dichloromethane (250 mL). The suspension was cooled in a dry ice-acetone bath and a solution of 4-benzyl-benzoic acid (10.19 g, 48 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was stirred for about 2 hours at−78° C. and an additional 2 hours at room temperature. The reaction mixture was poured into crushed ice. The separated organic layer was washed with dichloromethane (2×) and the combined organic layers were dried over (Na2SO4), and solvents were evaporated. Recrystallization of the crude product from methanollethyl acetate gave 4-(4-nitrobenzyl)-benzoic acid (9.27 g, 58%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:17]=[CH:16][C:12]=2[C:13]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)O)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)N2CCOCC2)cc1OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
2-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)benzoic acid (compound 204 1.6 g; 0.00454 mole), tetrahydrofuran (50 ml) and diimidazolecarbonyl (0.92 g; 0.0057 mole) are introduced into a 100 ml flask. The mixture is stirred at 20° C. for 2 hours. Morpholine (1 ml; 0.0113 mole) is then added and the mixture is maintained under stirring for six hours. The reaction mixture is poured into distilled water (150 ml) and the precipitate is filtered, washed with water (100 ml) and then dried in the air. 2-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)-1-morpholinocarbonylbenzene (1.3 g; yield: 68.4%) is thus obtained in the form of a white solid of m.p. 153° C. (compound 201).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:16][C:17]1C=CC=C[C:18]=1N1CCN(CCO)CC1>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:18][CH2:17][OH:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Reactant: O=C(c1ccccc1)N1CCNCC1
Product: O=C(c1ccccc1)N1CCN(CCO)CC1
Yield: 90 %

Procedure:
2-(4-Benzoyl-piperazin-1-yl)-ethanol (38A) is prepared from 1-benzoyl-piperazine as described for 28A.
Reaction SMILES: [F:1][CH:2]([F:40])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C@@H:26]3[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]3)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.[ClH:41]>O1CCOCC1>[ClH:41].[NH2:32][C@@H:29]1[CH2:28][CH2:27][C@H:26]([NH:25][C:23]([C:22]2[C:16]3=[N:15][C:14]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:40])[CH:5]=5)[N:9]([CH3:13])[N:8]=4)=[CH:19][N:18]=[C:17]3[NH:20][CH:21]=2)=[O:24])[CH2:31][CH2:30]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)c2cc(OC(F)F)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](N)CC4)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl cis-4-(2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate (54 mg, 0.1 mmol) in 3 mL of 1,4-dioxane was added 10 mL of concentrated HCl. The reaction mixture was stirred overnight at 25° C. After evaporation under the reduced pressure, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min). After concentration, the crude solid was treated with 1N HCl (2 mL), the mixture was stirred for 10 min then evaporated and dried to afford N-(cis-4-aminocyclohexyl)-2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide hydrochloride (13 mg, 29.5%) as yellow solid. LCMS: (M+H)+=456; 1H NMR (300 MHz, CD3OD): δ 8.96 (s, 1H), 8.22 (s, 1H), 8.01 (d, 1H, J=2.1 Hz), 7.56 (d, 1H, J=9.0 Hz), 7.26 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 6.76 (t, 1H, J=74.1 Hz), 4.16-4.14 (m, 1H), 4.11 (s, 3H), 3.17-3.15 (m, 1H), 2.15-2.11 (m, 2H), 1.91-1.78 (m, 4H), 1.60-1.48 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([Cl:21])=[O:17])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)c2c(c1OC)CCCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)c2c(c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 3,4-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.