Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Ga+3:4].[O-]CC.[O-]CC.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([O:19]C(=O)COCCOC)=[O:18].COCCOCC(O)=O.C(OC(=O)C)(=O)C.[Ga]>O.Cl>[Ga+3:4].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([O-:19])=[O:18]
Reactant: COCCOCC(=O)OC(=O)COCCOC
Agent: CC[O-]
Agent: COCCOCC(=O)O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCCOCC(=O)[O-]
Temperature: 60 °C

Procedure:
To gallium ethoxide (1.06 gram, 0.00517 mol, AlfaAesar 41907) was added methoxyethoxyacetic anhydride (4.16 gram, 0.0167 mol, made by the reaction of methoxyethoxyacetic acid and acetic anhydride). The contents of the reaction mixture were heated to 60° C. for 18 hours to give a viscous liquid mixture of the product and the by-product the ethylester of methoxyethoxyacetic acid. The mixture was soluble and stable in water and in dilute aqueous hydrochloric acid. The product mixture containing the ester and gallium salt left a 6.09% ceramic oxide residue as measured by TGA in air. IR(thin film) 2984, 2931, 2894, 1753, 1603, 1457, 1204, 1145, 1101 cm−1.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([N:7]1[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]1[CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CNCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
tert-Butyl (3S)-3-methylpiperazine-1-carboxylate (380.0 g, 1.897 mol) and benzyl bromide (248 mL, 2.09 mol) were mixed in acetonitrile (440 mL). Triethylamine (300.0 mL, 2.152 mol) was carefully added and the mixture was refluxed overnight. After the mixture was cooled down to room temperature, the solid was filtered out. The filtrate was concentrated. The residue was combined with the solid and dissolved in methylene chloride. The methylene chloride solution was washed with 1N NaOH and dried over magnesium sulfate. After the solvent was removed, the residue was directly treated with 6 N HCl at 0° C., and 3 hours later, the solution was basified by slowly adding solid sodium hydroxide. The resulting mixture was extracted with methylene chloride and the extracts were dried over magnesium sulfate. After removal of the solvent, 330 g (91.4%) of product was obtained. The product was used directly for next step. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.30 (m, 5H), 4.05 (d, 1H), 3.15 (d, 1H), 2.92 (m, 1H), 2.83 (m, 2H), 2.67 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.36 (bs, 2H), 2.06 (m, 1H), 1.14 (d, 3H). MS (EI) 191.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH:5]([OH:7])=[O:6].[CH:8](O)=[O:9]>C(OC(=O)C)(=O)C>[CH3:1][C:2]([CH:4]1[C:8](=[O:9])[O:7][C:5]1=[O:6])=[O:3]
Reactant: CC(C)=O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C1C(=O)OC1=O
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To acetic anhydride (350 ml) at 0° acetone dicarboxylic acid (200 g, 1.37 mole) was added slowly over 1/2 hour with vigorous stirring. After stirring 3 hours, a white solid was filtered and washed with ether (100 ml). Drying the solid 3 hours at 50° C. (0.1 mm) gave acetone dicarboxylic acid anhydride (149 g), m.p. 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:27](=[O:28])[NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.3 g of phenyl isocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 3 hours. The dichloromethane was distilled off under reduced pressure, and the residue was purified by means of column chromatography with the use of silica gel (developing solvent of acetonehexane), thereby producing 3.0 g (yield of 72%) of the subject compound in white crystals, m.p. 135°-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5](N)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[I-:17].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[I:17][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: [I-]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Product: Cc1ccc(I)c(C(=O)O)c1

Procedure:
20 G. of 5-methyl-anthranilic acid are suspended in 200 ml. of 3-N hydrochloric acid at 0° C. A solution of 10 g. of sodium nitrite and 20 ml. of water is added dropwise thereto with stirring and the mixture is further stirred for 25 minutes at 0° C. A solution of 26.5 g. of potassium iodide, 30 ml. of 3-N hydrochloric acid and 30 ml. of water is then added dropwise at 5°-10° C. The mixture is stirred for an additional 30 minutes at room temperature and for 2 hours at reflux. The mixture is cooled and sodium thiosulfate is added until the solution is yellow (5 g.). The crystalline 2-iodo-5-methyl-benzoic acid obtained is removed by filtration under vacuum and washed neutral with water. The crude acid is dissolved in ether, washed well with sodium thiosulfate solution and water, dried over sodium sulfate and evaporated, and there are obtained light-brown crystals having a melting point of 100°-112° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: O=C1CCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 150 °C

Procedure:
A mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 2-pyrrolidinone (153 mg, 1.8 mmol), potassium carbonate (83 mg, 0.6 mmol), copper powder (126 mg, 1.2 mmol) were heated in a microwave reactor at 150° C. for 1 minute. The reaction mixture was diluted with 2-pyrrolidinone (1 g, 12 mmol) and heated for a further 20 minutes at 200° C. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E217). MS (ES+) m/e 378 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH3:17])=[CH:11][CH:10]=1.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1
Reactant: CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(-c2ccc(Br)cc2F)cc1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
29 g of 2-fluoro-4-bromo-4'-propionylbiphenyl was dissolved in 72 ml of trifluoroacetic acid and stirred. 24 g of triethylsilane was dropwise added thereto at room temperature over a period of 30 minutes. After this was stirred for 2 hours, 900 ml of an aqueous saturated sodium hydrogencarbonate solution was dropwise added thereto so that the excess trifluoroacetic acid was decomposed. This was extracted with chloroform and then washed three times with water, and chloroform was removed by distillation. The residue was distilled under reduced pressure (b.p. 140° to 145° C./2 mmHg) to obtain 23.4 g of 2-fluoro-4-bromo-4'-propylbiphenyl.
Reaction SMILES: Br.[OH:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.O>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(O)cc1)C1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(O)cc1)C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 9.7 g of 4-(4-hydroxybenzoyl)piperidine hydrobromide, 6.4 g of sodium bicarbonate and 7.0 g of 3-(2-bromoethyl)indole in 90 ml of dimethylsulfoxide is stirred overnight under nitrogen at 50° C. After cooling to ambient temperature, water is added dropwise, precipitating a gummy brown solid. The supernatant solution is decanted from the solid, triturated with water, collected, and dried. Recrystallization from an ethanol-water mixture gives an off-white solid, mp 212°-214° C. (dec.) of 3-{2-[4-(4-hydroxybenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([NH2:9])=[N:6][C:7]=1[I:8].O.O.[Sn](Cl)Cl.O.[F-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[N:6][C:7]=1[I:8]
Reactant: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(I)nc1N
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-chloro-6-iodo-3-nitropyridin-2-amine (18.9 g, 63.1 mmol) in EtOH (100 mL) was added tin (II) chloride dihydrate (57 g, 252 mmol). The mixture was heated at 70° C. for 0.5 h. The r×n was warmed to rt and treated with a slurry of 150 mL water and 60 g KF and stirred for 0.5 h. The mixture was then partitioned between ethyl acetate (300 mL) and water (300 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and filtered through a 100 g pad of silica gel. The filtrate was concentrated and dried under vacuum to give an off-white solid, which was used in next step without further purification. LC-MS: calculated for C5H5ClIN3 269.47, observed m/e: 269.99 (M+H)+ (Rt 1.35/5 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)C12CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)C12CCNC2
Reaction time: 24 h
Yield: 102.1 %

Procedure:
To a solution of an optically-active compound of 6-benzyl-3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (10.0 g) in tetrahydrofuran/methanol (50 ml/50 ml) was added 20% palladium hydroxide carbon (2.0 g), and the mixture was hydrogenated under 4 atmospheres for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the titled compound (7.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 120.8 %

Procedure:
To a solution of 2-chloro-1-[(3-fluorobenzyl)oxy]-4-nitrobenzene from Example 3A (8.70 g, 25.1 mmol) in ethanol (150 mL) was added zinc powder (10.1 g, 154 mmol), and the mixture was heated to 60° C. A solution of ammonium chloride (3.30 g, 61.8 mmol) in water (30 mL) was added dropwise, and the reaction was stirred for additional 2 h at this temperature. The mixture was filtered through Celite®, and the solvent was removed in vacuo. The residue was triturated with water, and the precipitate was collected by suction filtration, washed with water and dried to yield 7.63 g (98%) of the aniline.
Reaction SMILES: [NH:1]([CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[NH2:2].[N:18]1[CH:23]=NC=N[CH:19]=1>C(O)C.C(OC)(C)(C)C>[CH3:17][N:15]([CH2:14][CH2:13][C:7]1[C:6]2[CH:5]=[C:4]([CH2:3][N:1]3[N:2]=[CH:23][N:18]=[CH:19]3)[CH:12]=[CH:11][C:10]=2[NH:9][CH:8]=1)[CH3:16]
Reactant: c1ncncn1
Reactant: CN(C)CCc1c[nH]c2ccc(CNN)cc12
Solvent: COC(C)(C)C
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Yield: 157.2 %

Procedure:
A solution of [2-(5-Hydrazinomethyl-1H-indol-3-yl)-ethyl]-dimethyl-amine (3.1 g, 85% purity, 11.9 mmol) and 1,3,5-triazine (0.69 g, 8.5 mmol) in ethanol (50 ml) is refluxed over night. The solution is then diluted with tert-butyl methylether (TBME), and the precipitated ammonium salts are filtered off. Removal of the solvent on the rotavapor produces 3.6 g of an oil which is chromatographed on silica (CH2Cl2: MeOH:NH4OH 98:2:1 to 95:5:1 v:v:v) to give 1.75 g (55%) of the product, dimethyl-[2-(5-[1,2,4]triazol-1-ylmethyl-1H-indol-3-yl)-ethyl]amine (Rizatriptan). HPLC retention time: 4.0 min.
Reaction SMILES: [Cl:1]CCl.[OH-].[Na+].Cl.C[O:8][C:9]1[CH:10]=[C:11](/[C:15](=[CH:22]/[CH3:23])/[CH:16]([CH3:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[CH3:20][N:18]([CH3:19])[CH2:17][CH:16](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:22]\[CH3:23])[CH3:21]
Reactant: C/C=C(/c1cccc(OC)c1)C(C)CN(C)C
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C/C=C(/c1cccc(O)c1)C(C)CN(C)C
Yield: 73 %

Procedure:
The base was released with dichloromethane/sodium hydroxide solution from (5), which was prepared according to Example 5, and after drying the solution dichloromethane was removed by distillation. Hydrochloride (6), which had a melting point of 80° C., was obtained in a yield of 73% theoretical from the base obtained, under the conditions given in Example 2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)O1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.O1CCOCC1>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Temperature: 150 °C
Yield: 78.9 %

Procedure:
The product of Example 9A (182 mg, 0.76 mmol), N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (Aldrich, 500 mg, 1.9 mmol), dichlorobis(triphenylphosphine)palladium (II) (Aldrich, 53 mg, 0.076 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 6.5 mg, 0.019 mmol) were combined with 1 mL each of ethanol, p-dioxane, and 1 M aq. sodium carbonate. The mixture was heated in a sealed tube to 150° C. at 330 watts for 10 min in an Emry™ Creator microwave. The mixture was cooled to room temperature, filtered through Celite®, and concentrated onto silica. The product was purified by column chromatography (SiO2, 5% methanol containing 1% NH4OH—CH2Cl2) to provide the title compound (203 mg, 79%). 1H NMR (300 MHz, CD3OD) δ 1.96 (m, 1H), 2.09 (m, 1H), 2.16 (m, 1H), 2.16 (s, 3H), 2.38 (m, 1H), 2.64 (td, J=6.5, 3.6 Hz, 1H), 3.33-3.53 (m, 6H), 3.97 (dd, J=13.9, 8.1 Hz, 1H), 5.54 (m, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.69-7.78 (m, 2H), 7.91-7.98 (m, 2H), 8.11 (d, J=9.3 Hz, 1H) ppm; MS (DCI/NH3): m/z 339 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(C(C)C)C(C)C)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[N:27][C:26]=2[N:31]=[C:32](SC)[S:33][CH3:34])=[C:21]([CH3:37])[CH:20]=1.O>C(#N)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]3[N:27]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:32]([S:33][CH3:34])[N:31]=3)[N:28]=[CH:29][CH:30]=2)=[C:21]([CH3:37])[CH:20]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2ccnnc2N=C(SC)SC)c(C)c1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(SC)nc2c(-c3ccc(OC)cc3C)ccnn12
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Ethyl bromoacetate (0.87 mL) and i-Pr2EtN (1.36 mL) were added to a solution of methyl N-[4-(4-methoxy-2-methylphenyl)-3-pyridazinyl]-(methylsulfanyl)methaneimidothioate (1.25 g) in acetonitrile (10 mL), and the mixture was heated under stirring at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, which was added with water, extracted with ethyl acetate, and washed with water. After that, it was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (628 mg) as a red brown oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH2:29][OH:30].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([NH:29][OH:30])=[O:24])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(NO)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A mixture of 1-benzyl-3-(5-hydroxycarbonyl-2-furyl)-1H-indazole (0.40 g, 1.257 mmol), DMF (cat., 2 drops) and SOCl2 (5 mL) was heated to reflux for 2 h. After cooling, the excess SOCl2 was removed under reduced pressure and the almost black oil was dissolved in DME (8 mL). A portion of this acid chloride solution (2 mL, approx. 0.314 mmol) was mixed with a solution of NH2OH.HCl (0.20 g, 2.88 mmol) and K2CO3 (excess) in H2O (2 mL) and allowed to stir at rt overnight A precipitate formed while stirring. The reaction mixture was poured onto water (50 mL) and extracted four times with EtOAc. The combined organic material was dried (MgSO4) and concentrated under reduced pressure to give the crude product (77.4 mg, 74%) as an orange/brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][CH:16]([CH3:18])[CH3:17]>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CBr
Reactant: Cc1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(C)C)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a stirred solution of 3-hydroxy-5-methylisoxazole (5.0 g, 50.5 mmol) in acetone (125 mL) at room temperature under argon was added K2CO3 (13.9 g, 101 mmol) and the reaction mixture was heated at 60° C. After 30 min, 1-bromo-2-methylpropane (10.4 g, 75.7 mmol) was added dropwise over 2 min. After 16 h the reaction mixture was cooled, filtered and concentrated. Purification by chromatography (silica, 70 to 100% ethyl acetate in heptane) gave the title compound (700 mg, 9%) as a volatile yellow liquid.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>C(Cl)(Cl)Cl>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][O:1][C:9]=12
Reactant: [O-][n+]1cccc2occc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccnc2ccoc12
Yield: 50 %

Procedure:
To a solution of Furo[3,2-b]pyridine 4-oxide in CHCl3 (5 mL) was added POCl3 (5 g, 33 mmol). The mixture was refluxed for 2 hours. After cooling, the mixture was quenched with ice water and neutralized with NaHCO3. Extracted with CHCl3 (3×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography to afford 7-Chloro-furo[3,2-b]pyridine (0.74 g, 50%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (m, 1H), 7.92 (m, 1H), 7.28 (m, 1H), 7.04 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[O:28][C:24]=2[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[O:28][C:24]=2[CH:23]=1
Reactant: CC1(C)OB(c2cc3ccc(Cl)cc3o2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccc(Cl)cc4o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL) was added 2-(6-chloro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, crude), and K3PO4 (140 mg, 0.66 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) under nitrogen atmosphere. After stirring 1 h at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-chloro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (60 mg, 43%).
Reaction SMILES: [OH:1][CH:2]([CH:8]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH:10]=[CH2:11])[CH2:3][C:4]([O:6]C)=[O:5]>[OH-].[K+].CO>[OH:1][CH:2]([CH:8]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:9][CH:10]=[CH2:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CCC(C(O)CC(=O)OC)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C(O)CC(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 3-hydroxy-4-cyclopentylhept-6-enoate (4.00 g, 17.7 mmol) was dissolved in a 2 N potassium hydroxide-methanol solution (53 mL), and the solution was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure. To the residue, water and diethyl ether were then added, and the aqueous layer was neutralized with 2 N hydrochloric acid. Diethyl ether was added thereto. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a yellow oil substance (4.00 g (including the residual solvent)).