Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[F-].[K+].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[C:17]([C:18]1[CH:23]=[CH:22][C:21]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)=[CH:20][CH:19]=1)([O:16][CH3:15])=[O:25]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: COC(=O)c1ccc(-c2cccc(C(C)=O)c2)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 3-acetylphenyl boronic acid (246 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and methyl-4-chlorobenzoate (171 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 229 mg (90%) of the title compound.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)[CH3:2].CN(C(ON1N=[N:25][C:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C1COCC1.CN(C=O)C.C(Cl)Cl>[N:24]1[C:19]2[CH:1]=[CH:2][CH:22]=[CH:21][C:20]=2[NH:25][CH:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
General working instructions 14 (GWI-14): To a solution of (ACI) (1.0 eq.) in THF was added diisopropyl ethylamine (4.0 eq.) at 0° C. followed by HATU (1.5 eq.). The resultant reaction mixture was allowed to stir at room temperature for 15 min. It was again cooled to 0° C. and a solution of the amine (1.3 eq.) in THF-DMF (3:1) was added. The reaction mixture was allowed to stir at room temperature for 16 h. The mixture was then diluted with methylene chloride, washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and finally with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by neutral alumina column chromatography to obtain desired product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:24]/[O:25][CH3:26])/[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].ClP([N:31]=[C:32]=[O:33])(Cl)=O.C([O-])(O)=O.[Na+].Cl>O1CCOCC1.ClCCCl.O>[CH3:26][O:25]/[N:24]=[C:6](\[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][O:18][C:32]([NH2:31])=[O:33])[CH2:15][S:16][C@H:11]12)=[O:8])/[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NP(=O)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in dioxan (20 ml) was added over ca. 1 minute to a stirred solution of dichlorophosphinyl isocyanate (1.46 ml) in 1,2-dichloroethane (30 ml) at 19°, the temperature rising to 28°. The resulting solution was stirred for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (70 ml). This mixture was stirred at ca. 30° for 1 hour, and then heated at 40° to 45° for a total of 4.5 hours, the pH being adjusted to 5.0 with hydrochloric acid after 3 hours. The two-phase mixture was adjusted from pH 5.8 to 7.0 with aqueous NaHCO3 solution and the aqueous phase was washed with 1,2-dichloroethane (20 ml) and ethyl acetate (50 ml), and acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extract washed with 25% aqueous sodium chloride solution and evaporated. The solid residue was slurried with diethyl ether to give the title compound (3.18 g, 75.0%); purity by HPLC 91.6% and by TLC 89.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH3:14]OS(=O)(=O)OC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][CH3:14])=[C:3]([CH:9]=1)[CH2:4][OH:5]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc(C)ccc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNc1ccc(C)cc1CO

Procedure:
Ethyl 2-amino-5-methylbenzoate was treated with dimethylsulfuric acid to give a N-methylated product. The N-methylated product was reduced using lithium aluminum hydride to give 5-methyl-2-methylaminobenzyl alcohol. The obtained alcohol was reacted with thionyl chloride in benzene to give the desired compound, yield 22% (based on the amount of the starting benzoate).
Reaction SMILES: [N:1]1([CH2:6][C:7](=[O:14])[C:8]([CH3:13])([CH3:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[K+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CS(C)=O.O>[CH3:11][CH:9]([C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[CH:6]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:10]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)C(C)(C)C(=O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(C)(C)C(=O)C(Cc1ccc(Cl)cc1)n1cncn1
Temperature: 100 °C
Reaction time: 15 h
Yield: 67.6 %

Procedure:
15.6 g (0.08 mol) of 1-(1,2,4-triazol-1-yl)-3,3,4-trimethylpentan-2-one are dissolved in 100 ml of dimethylsulphoxide, and 4.5 g (0.08 mol) of potassium hydroxide, dissolved in 10 ml of water, are added, while cooling. 16.4 g (0.08 mol) of 4-chlorobenzyl bromide, dissolved in 50 ml of dimethylsulphoxide, are added dropwise to the mixture at a rate such that the temperature does not exceed 40° C. Thereafter, the mixture is slowly warmed to 100° C. and stirred for a further 15 hours at this temperature, and the cooled solution is poured onto 500 ml of water. The mixture is extracted with twice 250 ml of methylene chloride, the methylene chloride phase is then extracted with four times 100 ml of water, and the organic phase is evaporated down. The residue is taken up in 100 ml of acetone, and 14.4 g of naphthalene-1,5-disulphonic acid, dissolved in 50 ml of acetone, are added. The 2,3,3-trimethyl-5-(1,2,4-triazol-1-yl)-6-(4-chlorophenyl)-hexan-3-one salt of naphthalene-1,5-disulphonic acid crystallizes out. The precipitate is filtered off under suction and taken up in 250 ml of saturated sodium bicarbonate solution, the aqueous phase is extracted with four times 100 ml of methylene chloride, the methylene chloride phase is extracted with 100 ml of water, and the solvent is distilled off from the organic phase. 17.3 g (67.6% of theory) of 2,3,3-trimethyl-5-(1,2,4-triazol-1-yl)-6-(4-chlorophenyl)-hexan-4-one are obtained as colorless crystals of melting point 91°-94° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O.C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(COc2cc([N+](=O)[O-])ccc2Cl)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(COc2cc(N)ccc2Cl)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-chloro-5-nitro-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (2.5 g, 7.29 mmol) in 60 mL of MeOH/H2O (1:1) and 3 mL of acetic acid (J. T. Baker) was added Zn powder (2.3 g, 36.47 mmol, Aldrich) at 0° C. The reaction mixture was stirred at 0° C. for 2 h then stirred at 10° C. for 2 h. The resulting mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo. The residue was treated with 60 mL of saturated aqueous NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried with MgSO4. The resulting solution was concentrated in vacuo and the title compound was obtained by column chromatography (silica gel, EtOAc) as a yellow solid.
Reaction SMILES: [C:1]([NH:18][C@H:19]1[CH2:23][CH2:22][C@@H:21]([C:24](O)=[O:25])[CH2:20]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:41]=[CH:40][C:39]([NH:42][CH3:43])=[CH:38][CH:37]=1.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH:19]3[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[N:42]([C:39]4[CH:40]=[CH:41][C:36]([C:28]5[O:27][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=6[N:29]=5)=[CH:37][CH:38]=4)[CH3:43])[CH2:20]3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CNc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)C1)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CN(C(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 2 h

Procedure:
250 mg (0.71 mmol) (−)-(1S,3R)—N-Fmoc-1-Aminocyclopentane-3-carboxylic acid and 0.14 mL (1.07 mmol) 1-chloro-N,N,2-trimethylpropenyldiamine are dissolved in 5 mL DCM and stirred for 2 hours. The resulting product is added to a mixture of 159.6 mg (0.71 mmol) (4-Benzooxazol-2-yl-phenyl)-methyl-amine and 0.14 mL (1.07 mmol) 2,4,6-collidine in 5 mL DCM. The reaction mixture is stirred overnight at RT. The mixture is concentrated under reduced pressure. The residue is taken up in water and extracted with DCM. The organic layer is dried, filtered off and concentrated under reduced pressure. The product is purified by RP-HPLC (water+5-95% acetonitrile (with addition of 0.1% TFA)). The solvent is evaporated.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC1CCCc2cccnc21
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Yield: 86.5 %

Procedure:
A mixture of 3-(5,6,7,8-tetrahydroquinol-8-yl)-propylamine (4.5 g), 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (5 g) and triethylamine (10 ml) was refluxed in ethanol (200 ml) for 7.5 hours. The solvent was removed in vacuo, the residue was dissolved in chloroform and chromatographed on silica in chloroform and later chloroform/methanol 4:1. The fractions containing the product were concentrated to give the title compound as an oil (6.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(OCCN2CCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(OCCN2CCCC2)c1

Procedure:
A mixture of 1-(2-(3-nitrophenoxy)ethyl)pyrrolidine (3.49 g, 14.8 mmol), 10% palladium on carbon (400 mg) and ethyl acetate (20 ml) was reduced under 50 psi hydrogen for 10 h. The reaction mixture was filtered through Celite 545 and the product extracted into 1M HCl (3×20 ml). The acidic layer was washed with ether (2×20 ml) and then the pH adjusted to >10 with 2M NaOH. The aqueous layer was extracted with ether (3×20 ml), dried over MgSO4 and concentrated in vacuo. The product was eluted through a silica gel pad (75% ethyl acetate/hexane/1% Et3N) to yield the product as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[N:6][C:7]#[N:8].[K].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13]>C(#N)C>[O:13]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[N:6][C:7]#[N:8]
Reactant: N#CN=C1CCCN1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [K]
Solvent: CC#N
Product: Cc1ccc(C(=O)CN2CCCC2=NC#N)cc1
Yield: 83.7 %

Procedure:
A suspension of N-(pyrrolidin-2-ylidene)cyanamide (1.09 g; 10 mmol) in acetonitrile (20 mL) was heated gently until dissolution and then potassium hydrogenocarbonate (1.66 g; 12 mmol) and 2-bromo-1-p-tolylethanone (2.98 g; 14 mmol) were added. The well stirred mixture was heated at reflux for 21 h and an extra amount of 2-bromo-1-p-tolylethanone (0.426 g; 2 mmol) was added. The reaction mixture was heated for 6 additional hours. After cooling, the precipitate was filtered, washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (1-20%) in dichloromethane to furnish 2.02 g (84%) of N-(1-(2-oxo-2-p-tolylethyl)pyrrolidin-2-ylidene)cyanamide as an orange solid. ESI/APCI(+): 242 (M+H). 1H NMR (CDI3) δ 7.83 (d, J=8.22 Hz, 2H, Harom.); 7.29 (d, J=8.04 Hz, 2H, Harom.); 4.81 (s, 2H, COCH2); 3.69 (m, 2H, CH2); 3.03 (m, 2H, CH2); 2.43 (s, 3H, CH3); 2.24 (m, 2H, CH2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C(C)=CC=CC=1>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F

Procedure:
2.75 g (0.01 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 30 ml of xylene at room temperature. 6.1 ml (0.012 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 28° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with xylene and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 100°-125° C. bath temperature), 2.31 g (84.7% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)(=[O:3])[CH3:2].BrC[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:24]=2)[CH:19]=1.O>C(O)C>[C:1]([NH:4][CH:5]([CH2:6][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=3[Cl:34])[CH:24]=2)[CH:19]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: Clc1cccc(Cl)c1-c1ccc2cc(CBr)ccc2c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc2cc(-c3c(Cl)cccc3Cl)ccc2c1)NC(C)=O
Reaction time: 1 h

Procedure:
To a solution of Na (0.092 g) in ethanol (5 ml) is added diethyl 2-(acetylamino)malonate (0.870 g). The mixture is stirred for 1 h. A solution of 2-(bromomethyl)-6-(2,6-dichlorophenyl)naphthalene 288 (0.978 g) in ethanol (5 ml) is added, under argon. The mixture is stirred under reflux for 5 h. After addition of water (5 ml), the solution is concentrated under vacuum and then diluted with AcOEt (5 ml). The aqueous phase is extracted with AcOEt (3×15 ml). The organic phases are dried over MgSO4, filtrated and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 20/80 then (40/60) as eluent.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:17]1[CH:22]=[N:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cnc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (60%, 3.0 g, 75 mmol) in 100 mL of DMF was added tert-butyl ethyl propanedioate (14.1 g, 75 mmol) dropwise at 25° C. The mixture was stirred at 40° C. for 30 minutes and 2-bromo-5-nitropyrazine (10.2 g, 50 mmol) in 50 mL of DMF was added dropwise. The resulting suspension was stirred at 50° C. for 2 hours and diluted with 500 mL of EtOAc. The mixture was washed with water (100 mL*3), brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petrol ether: EtOAc=5:1) to afford title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.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.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][C:18]=2[Cl:20])[N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1Cl

Procedure:
6 g (29.12 mmol) of methyl 2,6-dichloropyridine-3-carboxylate, 5.56 g (29.12 mmol) of 2,4-dichlorophenylboronic acid, 12.07 g (87.4 mmol) of potassium carbonate and then 1.68 g (1.46 mmol) of tetrakis(triphenylphosphine)palladium(0) were initially charged in 120 ml of degassed THF, and the mixture was heated under reflux conditions and under an argon atmosphere for 16 h. 300 ml of water and 500 ml of ethyl acetate were added. After separating the phases and removing the solvent, the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 6:1). 2.5 g (27% of theory) of the product were isolated in solid form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([CH2:33][N:31]([CH3:32])[CH3:30])=[CH:35][CH:36]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CN(C)Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (4-((dimethylamino) methyl)phenyl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.065 g, 29% yield). LCMS: 515.40 (M+1)+; HPLC % 96.73 (@254 nm) (Rt; 4.362; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% Bin 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.16 (t, 1H), 7.64 (d, 2H, J=6.8 Hz), 7.45 (d, 2H), 7.30 (s, 1H), 7.16 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 2.75 (t, 1H), 2.65 (s, 3H), 2.32-2.42 (m, 6H), 2.20 (s, 6H), 2.10 (s, 3H), 1.69 (m, 4H), 1.53-1.56 (m, 1H), 1.42-1.45 (m, 2H), 1.10-1.23 (m, 4H). [1H merged in solvent peak].
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7](O)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:20])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1=CO[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of dihydroartemisinin (500 mg, 1.86 mmol) in dichloromethane (28 ml) at 0° C. under nitrogen was added 4-(N,N-dimethylamino)pyridine (37 mg) and trifluoroacetic anhydride (0.79 ml, 5.58 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The solution was then concentrated in vacuo. The residue was purified by flash chromatography (SiO2; ether:hexane from 0.5:9.5 to 1.5:8.5) to give 9,10-anhydro-10-deoxoartemisinin (9,10-anhydroartemisinin) (180 mg, 25%) as a white solid. M.p. 100° C.; [α]D20.5+155.74° (c.0.0101 in CHCl3); νmax (film): 2948, 2922, 2862, 2850, 1684, 1432, 1372, 1334, 1198, 1178, 1158, 1142, 1114, 1078, 1028, 1016, 992, 954, 944, 904, 880, 828, 812; δH: 6.18 (1H, s, H-10), 5.54 (1H, s, H-12), 2.40 (1H, ddd, J=17.1, 13.2, 4.14 Hz, H-9), 2.00-2.09 (2H, m), 1.88-1.95 (1H, m), 1.07-1.73 (8H, m), 1.58 (3H, d, J=1.37 Hz, H-16), 1.42 (3H, s, H-14), 0.98 (3H, d, J=5.98 Hz, H-15); m/z (EI): 380 (M+); Anal. Calc. for C15H22O4: C, 67.67; H, 8.27; Found: C, 67.63; H, 8.51