Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Br[CH:16]([CH3:20])[C:17](Cl)=[O:18].[C:21]([OH:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([S:28][CH:16]([CH3:20])[C:17]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18])(=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: CC(Br)C(=O)Cl
Reactant: OC(=S)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(SC(=O)c1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
33g (0.20 mol) of DL-phenylalanine was neutralized with 100 ml of 2N-NaOH solution and to the resulting solution were simultaneously added dropwise 34.2g (0.20 mol) of 2-bromo-propionylchloride and 110 ml of 2N-NaOH solution over about one hour while stirring and ice-cooling. During the reaction, the reaction mixture was maintained in a slightly alkaline condition. After completion of the addition, the ice-bath was removed and the mixture was stirred at room temperature for a further 2 hours. The filtrate which had been prepared by neutralizing 33.7g (0.24 mol) of thiobenzoic acid with 122 ml of 2N--KOH solution and filtering the thus obtained solution was added to the reaction mixture. The mixture was stirred at room temperature overnight and then acidified with hydrochloric acid while ice-cooling to form oil. The oil was extracted with ethyl acetate and the extract was washed with water, dried over anhydrous sodium sulfate, and then allowed to be placed under reduced pressure to remove the ethyl acetate. During removal of the ethyl acetate, crystals started to precipitate. After completion of the evaportion, benzene was added to these crystals and they were recovered by filtration and washed with benzene to give 25.0g of N-(2-benzoylmercaptopropionyl)phenylalanine. (m.p. 173° - 175°C)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:14][O:13][N:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of 5-bromo-indanone (100 g, 0.474 mol) in ethanol (650 ml) under argon was added methoxylamine hydrochloride (198 g, 2.38 mol) and pyridine (125 ml). The mixture was refluxed for 2.5 hours, cooled to room temperature and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was then extracted with ethyl acetate and the organic phase dried (sodium sulphate) and then concentrated in vacuo. The crude material was recrystallised from isopropanol to furnish the title compound, (110 g, 97%), as a brown solid; 1HMR (CDCl3) 7.52 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1Hz), 3.97 (3H, s), 2.99 (2H, m), 2.99 (2H, m), 2.85 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[N:38][CH:39]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:40][C:36]1[CH:37]=[N:38][CH:39]=[C:34]([N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)[CH:35]=1)=[C:3]([CH3:27])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[N:5]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (85.0 mg, 0.210 mmol) and 5-morpholinopyridin-3-amine in toluene to give tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.3 Hz), 7.70 (1H, d, J=2.2 Hz), 7.29 (1H, ddd, J=10.0, 2.5, 1.2 Hz), 6.90 (1H, d, J=12.9 Hz), 6.80 (1H, ddd, J=13.8, 8.8, 2.6 Hz), 6.57 (1H, t, J=2.3 Hz), 3.85 (4H, dd, J=5.6, 4.0 Hz), 3.52-3.63 (4H, m), 3.27-3.35 (4H, m), 3.10-3.17 (4H, m), 2.07 (3H, s), 1.50 (9H, s). Mass Spectrum (ESI) m/e=541.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O.C(O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccccc1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccccc1NN=C(C(C)=O)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of 2-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (673 mg, 9.76 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(2-methoxyphenyl)hydrazono]pentane-2,4-dione (1500 mg, 79%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)(=O)=O.[CH3:15][CH2:16]O>>[CH2:15]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[N:9][CH:8]=1)[CH3:16]
Reactant: CS(=O)(=O)OCc1ccc(C#N)nc1
Reactant: CCO
Product: CCOCc1ccc(C#N)nc1

Procedure:
(6-Cyanopyridin-3-yl)methyl methanesulfonate (199 mg, 0.94 mmol) in 2 mL anhydrous EtOH was heated at 85° C. in a sealed tube for 3.5 h. The mixture was concentrated and purified by silica gel chromatography (elution with 0-25% EtOAc/Hex) to afford 5-(ethoxymethyl)picolinonitrile (104 mg).
Reaction SMILES: BrCCC(C)CC(C)(C)C.CC(CC(C)(C)C)CC=O.[CH3:21][C:22]([CH3:46])([CH2:24][CH:25]([CH3:45])[CH2:26][CH:27]([O:37]C(N1C=NC=N1)=O)[CH2:28][CH2:29][CH:30]([CH3:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:23]>[Cu]>[CH3:46][C:22]([CH3:23])([CH2:24][CH:25]([CH3:45])[CH2:26][CH:27]([OH:37])[CH2:28][CH2:29][CH:30]([CH3:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:21]
Reactant: CC(CCC(CC(C)CC(C)(C)C)OC(=O)n1cncn1)CC(C)(C)C
Agent: [Cu]
Agent: CC(CC=O)CC(C)(C)C
Agent: CC(CCBr)CC(C)(C)C
Product: CC(CCC(O)CC(C)CC(C)(C)C)CC(C)(C)C

Procedure:
2,2,4,9,11,11-Hexamethyl-6-dodecanol (b.p. 104°-110° at 0.18 mm of mercury pressure ) was prepared by reacting 1-bromo-3,5,5-trimethylhexane with 3,5,5,-trimethylhexanal and converted into 1-[2,2,4,9,11,11-hexamethyl-6-dodecyloxycarbonyl]-1,2,4-triazole of formula: ##STR19## following the procedures of Example 18. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH2:11][CH:10]2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:15](=[O:17])[CH:10]3[CH2:11][CH2:12][C:13](=[O:14])[N:9]3[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CCC(=O)N1Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CN2C(=O)CCC12
Temperature: 5 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 25.37 g of (±)-1-[(3-chlorophenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid in sieve dried dichloromethane (20 ml), 13.09 g of thionyl chloride was added, and the resultant solution was stirred and refluxed with the exclusion of moisture for 6 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5° C. and 40 g of aluminum chloride was added in portions with exclusion of moisture and vigorous stirring. The reaction was slightly exothermic and a solid began to precipitate. The flask was heated intermittently with a steam bath to increase the rate of the reaction. After each heating, the gas evolution was allowed to subside. When heating did not produce gas evolution, ice chips were added to quench the reaction. Water was then added to the mixture and the phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phase was dried (Na2SO4). The mixture was vacuum filtered and concentrated to a solid to which ethyl acetate was added and the resultant mixture was vacuum filtered to give 11.56 g of a solid. The solid was dried overnight under vacuum.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.CO.[C:32]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:32][N:25]1[N:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:29]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[O:27][C:26]1=[O:28]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
(S)-5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (280 mg, 0.68 mmol) obtained in Step 1 was suspended in THF (5.0 mL), and the mixture was stirred at 55° C. for 5 hours after adding methanol (0.082 mL, 2.04 mmol), triphenylphosphine-supported resin (Triphenylphosphine, polymer-supported; 3.08 mmol P/G, 1.02 g, 3.06 mmol), and diethyl azodicarboxylate (40% toluene solution, 0.92 mL, 2.04 mmol). The resin was separated by filtration, and the filtrate was collected, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-3-methyl-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (305 mg, quantitative).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][NH2:9].[C:17](#[N:20])[CH:18]=[CH2:19]>C(O)(=O)C>[C:17]([CH2:18][CH2:19][N:9]([CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:2][N:1]([CH2:4][CH2:3][C:2]#[N:1])[CH2:12][CH2:11][C:10]#[N:5])[CH2:6][CH2:7][C:8]#[N:9])#[N:20]
Reactant: C=CC#N
Reactant: NCCCN(CCCN)Cc1ccccc1
Solvent: CC(=O)O
Product: N#CCCN(CCC#N)CCCN(CCCN(CCC#N)CCC#N)Cc1ccccc1

Procedure:
4.43 g of acetic acid was added to 4.00 g of N,N-bis(3-aminopropyl)benzylamine and 100 mL of acrylonitrile and the mixture was heated under reflux for 14 hours. After the reaction mixture was concentrated, 150 mL of water was added thereto and the mixture was neutralized by 4.60 g of 28% ammonia water, followed by extraction of the mixture with ethyl acetate (150 mL). After the organic layer was washed with water, it was dried with anhydrous magnesium sulfate. The solvent was distilled off to give 6.59 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[CH2:6][CH2:7][N:8]([CH2:31][CH2:32]Cl)[C:9]1[CH:29]=[C:28]([Cl:30])[C:12]2[O:13][C:14]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:15]=3[S:16](=[O:19])(=[O:18])[CH2:17][C:11]=2[CH:10]=1.O.Cl.[CH3:36]O>>[CH3:36][O:27][C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:14]2[O:13][C:12]3[C:28]([Cl:30])=[CH:29][C:9]([N:8]4[CH2:7][CH2:6][N:4]([CH2:3][CH2:1][OH:2])[CH2:32][CH2:31]4)=[CH:10][C:11]=3[CH2:17][S:16](=[O:19])(=[O:18])[C:15]=2[CH:20]=1)=[O:26]
Reactant: CO
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Agent: Cl
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(CCO)CC3)cc(Cl)c1O2
Temperature: 70 °C

Procedure:
Ethanol amine (0.25 mL, 4.17 mmol) was added to a solution of Example 102j (0.5 g, 1.04 mmol) in methanol (5 mL) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 120° C. for 4 h. It was brought to room temperature, treated with, chilled water, dilute HCl to neutral pH and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated, treated with methanolic HCl solution, and refluxed at 70° C. for 3 h. The reaction mixture was concentrated, treated with aqueous sodium bicarbonate solution to neutral pH and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 5% methanol/chloroform) to obtain the title compound. Yield: 0.337 g, (67.13%); 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.05-3.15 (m, 4H, 2CH2), 3.40-3.45 (m, 8H, 4CH2), 3.70 (s, 1H, OH), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (EI+) 481 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:31]2[CH:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([CH2:21][O:20][CH3:19])=[CH:27][CH:26]=3)[N:29]=[CH:30]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COCc1ccc(-c2c[nH]cn2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(-c2cn(-c3cc(C(=O)OC)c([N+](=O)[O-])cc3C(F)(F)F)cn2)cc1
Yield: 95.2 %

Procedure:
A mixture of 1.00 g (3.74 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.775 g (4.12 mmol) of 4-(4-methoxymethyl-phenyl)-1H-imidazole in 10 ml of tetrahydrofuran are refluxed for 2 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase separated and washed with brine, dried over Na2SO4 and concentrated to dryness. The residue is purified by flash chromatography on silica (40-63 μm particle size) with ethyl acetate/hexane 2:3, yielding 1.55 g of 5-[4-(4-methoxymethyl-phenyl)-imidazol-1-yl]-2-nitro-4-trifluoromethyl-benzoic acid methyl ester acid as a yellow powder, m.p.=135-137° C. 1H-NMR (DMSO-d6, 400 MHz): 3.30 s, 3H; 3.95 s, 3H; 4.42 s, 3H; 7.35 d, J 10.4 Hz, 2H; 7.82 d, J=10.4 Hz, 2H; 8.02 s, 1H; 8.05 s, 1H; 8.30 s, 1H; 8.72 s, 1H.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>C1CCCCC1.C(OCC)C>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: Br
Reactant: OCCCCCCCCCCO
Solvent: C1CCCCC1
Solvent: CCOCC
Product: OCCCCCCCCCCBr
Temperature: 30 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
87.8 g (0.50 mol) of 1,10-decanediol, 165.1 g of 48% strength hydrobromic acid and 2.5 l of high-boiling petroleum ether (b.p. 100-140° C.) were heated under reflux with vigorous stirring for 4 hours. A further 80.0 g of 48 strength hydrobromic acid were added, and the mixture was boiled for 5 hours. After cooling to 30° C., the phases were separated. The organic phase was washed first with a solution of 100 g of Na2CO3 in 500 ml of water and then with 2×500 ml of water. Removal of the solvent was followed by chromatography on 700 g of silica gel. The byproduct 1,10-dibromodecane was eluted with cyclohexane/diethyl ether (20:1). Chromatography with cyclohexane/diethyl ether (2:1) afforded 103.9 g (0.44 mol, 87%) of 10-bromo-1-decanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([NH:16][NH2:17])=[O:15])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19](N(CC)CC)[CH3:20].C(Cl)(=O)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:19]([CH3:20])=[N:17][N:16]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NN)ccn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(-c2ccnc(NC(=O)OC(C)(C)C)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of tert-butyl[4-(hydrazinocarbonyl)-2-pyridyl]carbamate (1.01 g, 4.0 mmol) and triethylamine (0.832 mL, 6.0 mmol) in tetrahydrofuran (20 mL) was added acetyl chloride (0.341 mL, 4.8 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hr. To this reaction mixture were added triethylamine (2.77 mL, 20 mmol) and p-toluenesulfonyl chloride (1.53 g, 8.0 mmol), and the resulting mixture was heated under reflux for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran), and washed with diethyl ether/methanol to give the title compound (448 mg, yield 41%) as pale-brown crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[N+:1]([O-:4])=[O:2])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
10.0 mL of conc. HNO3 at 0° C. was slowly treated with 20.0 mL of conc. H2SO4, then 7.6 g (40 mmol) of 3,5-difluoro-benzoic acid ethyl ester. The reaction mixture was warmed up to room temperature and stirred overnight. This mixture was poured into a beaker containing ice. The resulting mixture was extracted with ethyl acetate, washed with cold water and evaporated to produce 7.4 g (32 mmol, 80%) of 3,5-difluoro-2-nitro-benzoic acid ethyl ester. LCMS: 232 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:12])([F:13])[F:14])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h
Yield: 96.5 %

Procedure:
Dissolve 5-chloro-2-(trifluoromethyl)benzoic acid (10 g, 0.044 mol) in MeOH (150 mL). Add thionyl chloride (50 g, 0.421 mol) slowly. Heat the resulting mixture to 70° C., and stir for 12 hours. Concentrate the mixture under reduced pressure. Pour the residue into water (100 mL), and extract the aqueous with EtOAc (2×200 mL). Dry the combined organics over sodium sulfate, and concentrate under reduced pressure to give the title compound (11.5 g, 96.5%) as an oil. 1H NMR (300 MHz, CDCl3,) δ 7.78 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.57 (dd, J=2.1, 8.7 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:18])[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cc1csc([C@H](N)Cc2c[nH]c3ccccc23)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1csc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-2-(1H-indol-3-yl)-1-(4-methylthiazol-2-yl)ethylamine (500 mg, 1.94 mmol) and 4-dimethylamino-4-phenylcyclohexanone (421 mg, 1.94 mmol) in anhydrous tetrahydrofuran (40 mL) was mixed with sodium sulphate (1.00 g) and stirred for 3 h at room temperature. After adding, acetic acid (291 mg, 287 μL, 4.85 mmol), sodium triacetoxyboron hydride (574 mg, 2.71 mmol) was added and the mixture stirred overnight at room temperature. The mixture was then filtered, the filtrate concentrated to low volume in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (876 mg) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol [95:5→9:1 and 1% ammonia in each case (33% in water)]. The non-polar diastereoisomer (450 mg) was purified once again by flash chromatography (38 g, 20×2.5 cm) with dichloromethane/methanol (300:9) and 1% ammonia (33% in water). The polar diastereoisomer (262 mg) was also purified once again by flash chromatography (18 g, 20×2.0 cm) with dichloromethane/methanol (24:1) and 1% ammonia (33% in water).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]=3[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]3=[C:10]([O:25][CH3:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)cc(OC)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-(4-bromophenyl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4(7H)-one (200 mg, 0.51 mmol, 1.00 equiv) in tetrahydrofuran (2 mL), PPh3 (290 mg, 1.11 mmol, 2.17 equiv), methanol (18 mg, 0.56 mmol, 1.11 equiv). To the resulting mixture was then added DEAD (180 mg, 1.03 mmol, 2.03 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined. The resulting mixture was washed with water (1×10 mL). The resulting mixture was dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (Petroleum Ether-1:100) to yield 6-(4-bromo-phenyl)-3-ethyl-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine as a white solid. MS (m/z): 409 [MH+].