Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(N2CCc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3C2)cc1
Reaction time: 6 h
Yield: 9.8 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added p-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (12.8 mg, 10%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3cccn3)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:13][S:14]([O:12][C:8]1[CH:7]=[C:6]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:11]=[CH:10][N:9]=1)(=[O:16])=[O:15]
Reactant: CC(C)CSc1cc[nH]c(=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CSc1ccnc(OS(C)(=O)=O)c1
Yield: 91.6 %

Procedure:
1.3 g of 4-isobutylthio-2-pyridone (m.p. 119° to 120° C.) and 0.7 ml of methanesulfonyl chloride were dissolved in 10 ml of methylene chloride, and cooled below 10° C. 1.5 ml of triethylamine was added dropwise to the solution with stirring. By stirring at room temperature for 4 hours, the reaction was completed. The reaction solution was poured into 100 ml of water, followed by addition of 100 ml of methylene chloride for separation. The methylene chloride layer was washed with water and saturated aqueous solution of common salt, then distilled to remove the solvent. The obtained residue was purified by silica-gel column chromatography (developer: benzene and n-hexane) to obtain 1.7 g of the objective 4-isobutylthio-2-pyridyl methanesulfonate (yield: 91.6%) as a colourless oil, which were allowed to stand to crystallization.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[N:6]([C:7](=[O:10])[CH2:8]Cl)[CH2:5][CH:4]([CH3:11])[O:3]1.C([O-])=[O:14].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1([CH3:12])[N:6]([C:7](=[O:10])[CH2:8][OH:14])[CH2:5][CH:4]([CH3:11])[O:3]1
Reactant: CC1CN(C(=O)CCl)C(C)(C)O1
Reactant: O=C[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: CC1CN(C(=O)CO)C(C)(C)O1
Reaction time: 96 h

Procedure:
Thirty-eight and three tenths g. of 2,2,5-trimethyl-3-chloroacetyl-1,3-oxazolidine, 15.6 g. of sodium formate, 24.4 g. sodium carbonate and 1 g. of tetrabutyl phosphonium bromide were combined in 100 ml. of water and allowed to stir for four days. The mixture was heated to reflux for two hours, cooled and extracted with 50 ml. of methylene chloride. The inorganic salts were filtered off and the aqueous phase extracted three times with 25 ml. portions of methylene chloride. The combined methylene chloride extracts were washed with water, dried over anhydrous magnesium sulfate and stripped under vacuum. Yield was 30.9 g. of product, m.p. 50°-53° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[OH:16])[C:5]([CH2:7][C:8](OCC)=[O:9])=O.O.[NH2:21][NH2:22]>C(O)C>[OH:9][C:8]1[NH:22][N:21]=[C:5]([C:4]2[CH:3]=[C:2]([OH:1])[C:15]([OH:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cc(O)[nH]n2)cc(O)c1O
Reaction time: 0.08 h

Procedure:
2.0 g of ethyl (3,4-dihydroxy-5-nitrobenzoyl)acetate are suspended in 50 ml of ethanol. After treatment with 0.4 g of hydrazine hydrate the mixture is held at the reflux temperature for 16 hours. After distillation of the solvent, the residue is held at the boiling temperature for 5 minutes with 50 ml of ethyl acetate. The separated precipitate is filtered under suction and the filtrate is concentrated to 10 ml. The crystals, which separate in the cold, are filtered under suction. There is obtained 5-(5-hydroxypyrazol-3-yl)-3-nitropyrocatechol in form of orange crystals of m.p. 228° (dec.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH3:14])=[N:7][NH:8]2.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH3:14])=[N:7][N:8]2[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc2[nH]nc(C)c2c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3c(Cl)c(C)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(2-chloro-6-fluoro-3-methylphenyl)ethanone (10 g, 53.6 mmol) and hydrazine (5.05 mL, 161 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide crude 4-chloro-3,5-dimethyl-1H-indazole as a white solid, which was used in the next step directly. MS (ESI+) m/z 180.9 (M+H)+. NaH (60% dispersion in mineral oil, 3.87 g, 97 mmol) was added portion wise to a solution of crude 4-chloro-3,5-dimethyl-1H-indazole (9.7 g, 53.7 mmol) in THF (200 mL) at −20° C. The mixture was allowed to warm to 0° C. and stir for 20 min, then TsCl (14.33 g, 75 mmol) was added. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was cooled to −20° C. and sat. NH4Cl aqueous solution was added to quench excess base. The resulting mixture was extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with EtOAc and filtered to provide 4-chloro-3,5-dimethyl-1-tosyl-1H-indazole. 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J=8.34 Hz, 1 H) 7.84 (m, J=8.34 Hz, 2 H) 7.39 (d, J=8.59 Hz, 1 H) 7.25 (m, J=7.83 Hz, 2 H) 2.73 (s, 3 H) 2.46 (s, 3 H) 2.38 (s, 3 H); MS (ESI+) m/z 334.7 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:16](=[O:18])[CH3:17])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][CH2:17][C:16]([C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([CH:10]([CH3:11])[CH3:12])=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])=[O:18]
Reactant: [Br-]
Reactant: CC(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1-(2,4,6-triisopropylphenyl)ethanone (10.0 g, 65.3 mmol) in acetonitrile (81 mL) was added tetrabutylammoniumtribromide (TBABr3, 19.6 g, 40.6 mmol). The reaction was stirred at room temperature for 3.0 h. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.2 g), which was used directly for the next step without further purification.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(O)c1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 25 g of 2-hydroxy-4-methyl-3-nitropyridine, 12.5 g of phosphorous pentachloride, and 62 ml of phosphorous oxychloride was refluxed for 2 hrs. After cooling, the mixture was poured onto crushed ice and stirred until a precipitate formed. The product was extracted with methylene chloride, dried (sodium sulfate) and concentrated to a brown oil, which was washed with hot hexane. Concentration in vacuo provided 16.2 g of the the title compound, m.p. 45°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH:12]([N-]C(C)C)(C)C.[Li+].CI.Cl>O1CCCC1.CCCCCC.CCCCCCC.C(C1C=CC=CC=1)C>[CH3:1][O:2][C:3](=[O:11])[CH:4]([CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:12]
Reactant: COC(=O)CC1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C(C)C1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.2 %

Procedure:
Into a cooled (−78° C.) solution of 1.00 g (6.32 mmol) of (tetrahydropyran-4-yl)acetic acid methyl ester in tetrahydrofuran (20 mL) was dropped, under an atmosphere of argon, a solution of 4.5 mL (9.00 mmol) of 2 mol/L lithium diisopropylamide in hexane-heptane-ethylbenzene (available from Aldrich) and subsequently 0.47 mL (7.55 mmol) of methyl iodide, and then stirred for 30 minutes at −78° C., followed by stirring for 48 hours at room temperature. After 1N hydrochloric acid was added to the reaction mixture, it was concentrated under a reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by column chromatography (silica gel 30 g, developing solvent: hexane:ethyl acetate=4: 1) to obtain 927 mg (85.1%) of 2-(tetrahydropyran-4-yl)propionic acid methyl ester (IX-166). Its physical property is shown below.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:4][C:5]([NH:7][C:8]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:39])[NH:25][CH:26]([C:35]([O:37]C)=[O:36])[O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:6])[CH3:3].[OH-].[Na+].O.Cl>COCCOC.ClCCl>[CH3:15][C:13]([CH3:16])([O:12][C:10]([NH:9][C:8]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:39])[NH:25][CH:26]([C:35]([OH:37])=[O:36])[O:27][Si:28]([CH3:33])([CH3:34])[C:29]([CH3:31])([CH3:30])[CH3:32])=[N:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:40])=[O:6])=[O:11])[CH3:14]
Reactant: COC(=O)C(NC(=O)CCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NCCCCCCC(=O)NC(O[Si](C)(C)C(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
1.73 g (2.94.10-3 mol) of 3-[[(1,1-dimethylethoxy)carbonyl]amino]-13-(methoxycarbonyl)-15,15,16,16-tetramethyl-11-oxo-14-oxa-2,4,12-triaza-15-silaheptadec-2-enoic acid, 1,1-dimethylethyl ester are dissolved in 4 ml of 1,2-dimethoxyethane, and 4 ml of molar aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 10 minutes at room temperature, 20 ml of water and 20 ml of dichloromethane are then added and the mixture is acidified to pH 2 with 1N hydrochloric acid, with thorough stirring. After separation of the organic phase, the aqueous phase is extracted with 3 times 25 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure to give 1.68 g of the expected product in the form of a colorless oil (quantitative yield).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)N(C)C)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N,N-dimethylacetamide according to the method of Example 2; m.p. 122-124°.
Reaction SMILES: O(C1C=C(C=CC=1)N)C1C=CC([NH2:6])=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.[C:38]1(=[O:48])[O:43][C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>CN1CCCC1=O>[CH:46]1[CH:47]=[C:39]([C:38]([NH2:6])=[O:48])[C:40]([C:41]([OH:43])=[O:42])=[CH:44][CH:45]=1
Reactant: Nc1ccc(Oc2cccc(N)c2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminatedimide polymer with theoretical number average molecular weight of 11,600 g/mole. 3,4'-Oxydianiline (ODA) (25.0 mmole, 5.0062 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (25.0 mmole, 7.3084 g) were dissolvedin N-methylpyrrolidinone (NMP) ( ~ 35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. 3,3',4,4'-Biphenyl tetracarboxylic dianhydride (BPDA) (47.87 mmole, 14.0845 g) and phthalic anhydride (PA) (4.260 mmole, 0.6310 g) were slurried in NMP (~ 35 mL) and were added to the solution. Afterwashing with ~ 38 mL of NMP to provide a 20% solids content reaction, an exotherm of 10°-15° C. was observed. The exotherm quickly subsided and the reaction was stirred at 25° C. for 16 hours to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ninh) of the phthalamide acid-terminated polyamide acid was 0.41 dL/g in NMP at 25° C. To imidize, toluene (30 mL) was added and the reaction was heated at 160° C. for 24 hours. After cooling to 25° C., the polymer was still soluble. The solution was poured into water to precipitate a powder which was washed twice in water and dried at >100° C. to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was soluble in NMP and had a glass transition temperature of 219° C. A film cast from the polyamide acid solution and dried one hour each at 100°, 225°, and 371° C. had a Tg of 223° C. and was tough and creasible.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.ClCCl>CN(C=O)C.[Cu](I)I.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>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:4][N:3]=1
Reactant: Brc1cnc(I)cn1
Reactant: C#CCCn1ccnn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1cnc(C#CCCn2ccnn2)cn1
Reaction time: 5 h

Procedure:
2-Bromo-5-iodo-pyrazine (13.69 g, 48.0 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (7.01 g, 57.9 mmol) and triethyl amine (NEt3) (94 ml) are dissolved in DMF (188 ml) and copper iodide (CuI) (0.984 g, 5.17 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min tetrakis(triphenylphosphine)palladium(0) (2.844 g, 2.46 mmol) is added and stirring is continued for 5 h at r.t. Dichloromethane (300 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 7:3) yielding 2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine as a colorless solid. Yield 9.99 g (75%).
Reaction SMILES: C([O:8][C:9]1C=CC=C[C:10]=1[C:11]([OH:13])=[O:12])C1C=CC=CC=1.C1C([N+:24]([O-])=O)=CC=C(O)C=1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:53]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:54]([CH:58]=[CH:59][CH:60]=2)[C:55]([O-:57])=[O:56])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C(OCC)(=O)C.O1CCCC1.C(N(CC)CC)C>[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:53]([O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[C:54]([CH:58]=[CH:59][CH:60]=2)[C:55]([O-:57])=[O:56])=[CH:48][CH:47]=1)([O-:45])=[O:44].[NH2:24][C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][OH:8]
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])c1cccc(-c2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H](CO)C(=O)O

Procedure:
2-Benzyloxybenzoic acid 4 was then reacted with p-nitrophenol 5 and dicyclohexylcarbodiimide (DCC) in ethyl acetate to produce, after work-up, 4-nitrophenyl-2-(benzyloxy)benzoate 6 in 45% yield. Treatment of the benzoate 6 with L-serine 7 and triethylamine (TEA) in tetrahydrofuran (THF)/water gave the protected E/D fragment 8 of Exochelin 786SM(R) in 79% yield. This segment undergoes subsequent reaction with a protected form of the C/F fragment to generate the largest subunit of the target compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].S1C=CCS1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:41])[C:16]=1[NH:17][C:18](=[O:40])[C:19]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30]C)[CH:28]=2)[N:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:22]=1)=[O:20].Cl>ClCCl>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:41])[C:16]=1[NH:17][C:18](=[O:40])[C:19]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:22]=1)=[O:20]
Reactant: COc1ccc2c(c1)c(C(=O)C(=O)Nc1c(Cl)cncc1Cl)cn2Cc1ccc(F)cc1
Agent: C1=CSSC1
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cncc1Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5 g (38 mmol) anhydrous aluminium chloride is introduced into 50 ml ethane-1,2, -dithiol. A solution of 4.7 g of N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2-oxoacetamide (10 mmol) in 50 ml of dichloromethane is added at 0° C. The mixture is stirred at 0° C. for 4 hours. 50 ml of 10% hydrochloric acid is added dropwise at from 0 to 10° C. with stirring. The crystallizing product is isolated, washed with water and dried at 20° C. A pure product is obtained by recrystallization from ethanol (180 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[N:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
To 2.0 mL of dichloromethane solution containing 70 mg of (7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetaldehyde, 0.11 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 20 μL of acetic acid were added, and stirred at room temperature for 20 min. To the reaction mixture, 0.10 g of sodium triacetoxyborohydride was added, and stirred at the same temperature for 2 hours. Chloroform and water were added, and aqueous saturated sodium hydrogen carbonate solution was added to make the pH 8.0 or more. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2], to give 83 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[S:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].O1CCOCC1>[F:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][C:5]([C:15]2[S:16][CH:17]=[C:13]([CH3:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OCCc1cc(I)cnc1F
Reactant: Cc1csc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1csc(-c2cnc(F)c(CCO)c2)c1
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a microwave tube was added 2-(2-fluoro-5-iodopyridin-3-yl)ethanol (0.09 g, 0.3 mmol), 4-methylthiophen-2-ylboronic acid (0.2 g, 1 mmol), palladium fibrecatalyst (0.010 mg, 10% wt), potassium carbonate (2 M, 0.3 mL, 0.7 mmol), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 150° C., with 80 Watts of power via Powermax. The reaction mixture was partitioned between water/CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography with hexane:acetone (90%:10%) to afford the product as colorless liquid (65 mg). MS (ESI pos. ion) m/z (MH+): 238.3. Calc'd exact mass for C12H12FNOS: 237.1. 1H NMR (300 MHz, Chloroform-d) δ ppm 1.54-1.64 (m, 1 H) 2.30 (s, 3 H) 2.94 (t, J=6.36 Hz, 2 H) 3.95 (q, J=6.24 Hz, 2 H) 6.92 (s, 1 H) 7.11 (s, 1 H) 7.84 (d, J=9.06 Hz, 1 H) 8.27 (s, 1 H).