Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:16]([OH:19])[C:17]#[CH:18]>C(NCC)C.[Cu]I.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>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:18]#[C:17][CH2:16][OH:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 3,5-bistrifluoromethyliodobenzene (which may be prepared as described by S. D. Ross et al, J. Amer. Chem. Soc. (1953), 75, 4967-4969; 340.1 g) in anhydrous diethylamine (665 ml), cooled to 10° C. and under an inert atmosphere, there were added successively copper (I) iodide (1.81 g) and dichlorobis(triphenylphosphine)palladium (3.51 g). 2-Propyn-1-ol (57.8 g) was then added dropwise over 20 minutes and the reaction mixture was then maintained, with stirring, at 25° to 30° C. for 4 hours. The reaction mixture was then maintained overnight, with stirring, at ambient temperature. The solvent was removed by evaporation under reduced pressure (water-pump) and the crystalline residue was partitioned between diethyl ether (670 ml) and water (200 ml). The ether layer was separated, washed with water (2×200 ml), dried over anhydrous sodium sulphate and evaporated under reduced pressure (water-pump). The solid residue thus obtained was distilled to give 1-(3,5-bistrifluoromethylphenyl)-prop-1-yn-3-ol, in the form of a white crystalline solid (231.7 g), m.p. 58°-60° C., b.p. 87°-91° C./1 mm Hg.
Reaction SMILES: I[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34]>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.[Cu]I.C1COCC1>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:34]#[C:33][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1
Reactant: CSc1ncc(C(F)(F)F)c(I)n1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1C#Cc1nc(SC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
4-Iodo-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I14) (2.00 g, 6.24 mmol), PdCl2(PPh3)2 (438 mg, 625 μmol), CuI (119 mg, 625 μmol) and triphenylphosphine (164 mg, 625 μmol) were placed into an oven dried microwave reaction vial under nitrogen. Methyl 2-(2-ethynylphenyl)acetate (I4) (1.31 g, 7.49 mmol), THF (20 mL) and TEA (10 mL) were added and the resulting mixture was stirred at 100° C. under microwave irradiation for 10 minutes. The volatiles were evaporated under reduced pressure then the residue was adsorbed onto silica from DCM. The pre-adsorbed material was chromatographed on silica gel (0-25% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I64) (1.571 g, 69%) as an orange solid; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=0.8 Hz, 1H), 7.68 (dd, J=7.7, 1.1 Hz, 1H), 7.50-7.29 (m, 3H), 3.93 (s, 2H), 3.71 (d, J=3.4 Hz, 3H), 2.62 (d, J=3.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH3:20])=[O:18]>O>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 73.9 %

Procedure:
42 g of Compound [II] and 30 g of sodium bicarbonate were dissolved in 2 l of water, and 34 g of methyl chloroformate was added dropwise to the solution over 1.5 hours at 10° C. The mixture was allowed to react at 10° C. for one hour. After completion of the reaction, the solid product was collected by filtration, washed with water and dried to obtain 44 g of methyl N-(5-t-butyl-3-pyrazolyl)carbamate.
Reaction SMILES: [CH3:1][Li].[C:3]([C:5]1[C:9]([S:10][C:11]([F:14])([F:13])[F:12])=[C:8]([CH:15]=[O:16])[N:7]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:6]=1)#[N:4].Cl>C(OCC)C.[Cu]I>[C:3]([C:5]1[C:9]([S:10][C:11]([F:13])([F:12])[F:14])=[C:8]([CH:15]([OH:16])[CH3:1])[N:7]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[Cl:28])[N:6]=1)#[N:4]
Reactant: [Li]C
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Product: CC(O)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Copper (I) iodide (6.1 g, 0.032 mol) was suspended in anhydrous diethyl ether and cooled to 0° C. Methyllithium (1.6M in diethyl ether, 40 ml, 0.064 mol) was added via cannula and stirred 10 minutes. A solution of the product of Example 3 (10 g, 0.023 mol) in diethyl ether was added via cannula creating a bright yellow suspension. After 15 minutes, 10% aqueous hydrochloric acid (40 ml) was added while venting the reaction vessel. The remaining suspension was filtered through Celite® and washed with diethyl ether several times. The organic phase was washed with saturated sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Trituration from pentane provided crystals that were purified by silica gel chromatography using ethyl acetate:hexanes. The title compound was isolated as a white solid (7.56 g), m.p. about 123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].[CH:14]([NH2:16])=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7]([C:8](=[O:10])[NH:16][CH:14]=[N:13]2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: NC=O
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Product: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Temperature: 165 °C
Yield: 94.9 %

Procedure:
A mixture of 4-nitroanthranilic acid (2.17 g, 11.91 mmol) and formamide (1.5 mL, 38.43 mmol) was heated at 165° C. for 4 hours. The warm reaction mixture was poured into ice/water (30 mL) and the resulting precipitate was collected via filtration, to give an orange solid (2.16 g, 95% yield) which was dried over P2O5. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: Clc1ccccc1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.86 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and chlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87-89/9-13. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.86 to 0.88%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[Cl:14]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2nccc(O)c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(Cl)c(O)c2c1
Temperature: 60 °C
Yield: 96.2 %

Procedure:
6-Methoxy-quinolin-4-ol (18.5 g) in acetic acid (750 mL) was treated with N-chlorosuccinimide (15.52 g) and the mixture was heated at 60° C. for 4.5 hr, cooled, and evaporated. Excess sodium bicarbonate solution was added and the solid collected and washed with water and dried in vacuo at 40° C. overnight, to give a yellow solid (21.3 g).
Reaction SMILES: [OH-].[Na+].S(=O)(=O)(O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:20][CH2:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:20][CH2:21][C@@H:22]([OH:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Reaction time: 24 h
Yield: 67 %

Procedure:
A culture was obtained by the same method as in Example 1 using Geotrichum eriense ATCC 22311 as the microorganism and then adjusted to pH 6 with an aqueous sodium hydroxide solution and an aqueous sulfuric acid solution. A 25-ml portion of this culture, 1 g of glucose and (3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanone were mixed up in a 500-ml Sakaguchi flask and the mixture was shaken for 1 day to thereby allow the reaction to proceed. Then, again, 250 mg of (3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanone was added. The reaction was allowed to proceed for further 2 days with shaking while the glucose concentration was controlled within the range of 0 to 4% by adding glucose portionwise. Thereafter, a further 250 mg portion of (3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanone was added and shaking was continued for further 4 days to allow the reaction to proceed while controlling the glucose concentration in the same manner as mentioned above. The reaction mixture was diluted with 100 ml of water and extracted with 100 ml portion of ethyl acetate for 3 times. The organic extract layers were combined, washed with 100 ml of water and further with 100 ml of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. This solution was concentrated to dryness to give (2S,3S)-1-chloro-3-methoxycarbonylamino-4-phenyl-2-butanol as a white solid (607 mg; yield 67%; purity 83.7 wt %; selectivity 2S,3S/2R,3S=97/3; optical purity 99.7% ee).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([Sn](=O)CCCC)CCC>>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In a reactor fitted with a heating/cooling bath, stirrer, thermocouple, nitrogen inlet, a reflux condenser with a trap to collect distilled off methanol, and a vacuum connection are added 438.6 g (1.5 moles, a 5% excess) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and 386.8 g (1.43 moles) of 1-octadecanol. The mixture is heated to 100° C. under nitrogen with stirring. After drying at 100° C. under vacuum (≤5 mm Hg) for 30 minutes, the mixture is heated to 120° C. under nitrogen and 0.05 g (0.0002 mole) of dibutyltin oxide (Fascat® 4201, Elf-Atochem) is added. The vacuum is lowered to 100 mm Hg and the reaction mixture is heated to 185° C. for one hour. The vacuum is slowly lowered to 2 mm Hg over 1.5 hours and kept at that temperature and pressure for another thirty minutes. The vacuum is broken with nitrogen and the reaction mass is cooled to 100° C. The excess methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate is removed using a wiped-film evaporator to give the title compound as a white solid containing 30 ppm Sn. Essentially a quantitative yield (99.8) of the ester product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([Sn]=O)CCC.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn]=O
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Octadecyl 3-(3,5-di-tertbutyl-4-hydroxyphenyl)-propionate was prepared from 124.8 g (0.427 mole) of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, 88.8 g (0.328 mole) of octadecyl alcohol and 0.13 g (0.0007 mole) of monobutyltin oxide. To the solution (214 g) of it was added 35 g of synthetic magnesium silicate (manufactured by Mizusawa Chemical Co.), and the solution was stirred at 60° C. for 0.5 hour. The organic layer wa separated by filtration. The residual tin content was 3 ppm (removal rate: 99.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and diisopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC=CC=1)C(C)C.C1OC1C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[CH2:12][OH:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CC1CO1
Solvent: CC(C)Cc1ccccc1
Product: CC(C)Cc1ccc(C(C)CO)cc1

Procedure:
preparation of the pharmaceutically-active compound 2-(4-isobutylphenyl) propionic acid, i.e. ibuprofen, by reacting isobutylbenzene with propylene oxide to provide the intermediate 2-(4-isobutylphenyl) propanol followed by oxidation of the alcohol to the corresponding carboxylic acid;
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:10][C:7]1[N:8]=[N:9][C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:11]([CH3:13])[C:5]=2[N:6]=1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2cccc(NS(C)(=O)=O)c2)cc2nnc(N)nc12
Yield: 81.6 %

Procedure:
An oven dried 25 mL round bottom flask was charged with 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.889 g, 3.72 mmol, 1 equiv), 3-(methylsulfonylamino) phenyl boronic acid (1.12 g, 5.21 mmol, 1.4 equiv), sodium carbonate (1.57 g, 14.9 mmol, 4 equiv) and tetrakis(triphenylphosphine) palladium(0) (0.43 g, 0.372 mmol, 0.1 equiv). The reactants were flushed with argon and diluted with ethylene glycol dimethyl ether (20 mL), ethanol (5 mL) and DI water (5 mL). The reaction vessel was outfitted with condenser and refluxed for 4 hours. The reaction was filtered hot and diluted with ethyl acetate. The Organic layer was isolated and concentrated to a dark residue. This was dissolved in DMF (6 mL) and slowly diluted with water so as to precipitate out the product. Solids were filtered off and dried to yield an orange solid (1 g, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:11]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1Cl
Temperature: 64 °C

Procedure:
To a suspension of 5-bromo-2-chlorobenzoic acid (5 g) in MeOH (200 mL) is added concentrated sulfuric acid (2 mL) and the mixture is heated at 64° C. for 16 h. The solution is evaporated in vacuo. The residue is taken up in EtOAc and washed with 10% sodium bicarbonate, brine and dried over sodium sulfate. The solution is filtered and evaporated in vacuo to afford 5-bromo-2-chloro-benzoic acid methyl ester (5.1 g). 1H NMR (300 MHz, CDCl3) □7.3-7.5 (m, 2H); 6.9 (m, 1H); 3.9 (s, 3H).
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]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH2:21](OC(OCC)OCC)[CH3:22].O>C(O)C>[CH3:21][CH2:22][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
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
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dihydroartemisinin (50 mg) was dissolved in 3 ml dry ethanol with stirring the solution for 10 min. at room temperature and add cation exchange resin (Dowex-50, 50 mg) and triethylorthoformate (4 ml) in the solution. The reaction mixture is stirred for 10 hrs at room temperature (30° C.). Water was added in the reaction mixture and filters the cation exchange resin. The reaction product was extracted by dichloromethane. The organic layer was separated, dried over anhydrous sodium sulphate and evaporated under vacuum to yield pure arteether (50 mg).
Reaction SMILES: [CH2:1]=[O:2].[OH-:3].[Na+].[P:5]([OH:9])([OH:8])([OH:7])=[O:6].[NH2:10][C:11]([NH2:13])=[NH:12]>C(O)C>[C:1](=[O:6])([OH:3])[OH:2].[NH2:12][C:11]([NH2:13])=[NH:10].[P:5](=[O:6])([OH:9])([OH:8])[OH:7]
Reactant: C=O
Reactant: [OH-]
Agent: N=C(N)N
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)O

Procedure:
189 grams of 95% paraformaldehyde were dissolved in the heat in 700 grams of ethanol together with 1 gram of sodium hydroxide and heated to reflux. Then in an interval of 3 hours there were added in two equal parts 732 grams of a hot guanidine dihydrogen phosphate solution which had been previously produced from 360 grams of guanidine carbonate (2 moles) and 461 grams of 85% phosphoric acid (4 moles). After the second addition the mixture was heated at reflux for a further 5 hours, then allowed to cool and drawn off. The product corresponds in the molar ratios to those of Examples 5, is dilutable in ethanol and has the composition, solids 49.7%, ethanol 43.2% and water 7.1%.
Reaction SMILES: C(=O)([O-])O.[CH3:5][N:6]([CH3:34])[C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][N+:13]2[CH:17]=[CH:16][N:15]([N:18]=[CH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:14]=2[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1.[BrH:35]>O>[Br-:35].[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[N:18][N+:15]2[CH:16]=[CH:17][N:13]([N:12]=[CH:11][C:10]3[CH:32]=[CH:33][C:7]([N:6]([CH3:5])[CH3:34])=[CH:8][CH:9]=3)[C:14]=2[CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1
Reactant: Br
Agent: CC(C)c1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: O=C([O-])O
Solvent: O
Product: [Br-]

Procedure:
100 mg of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropylimidazolium hydrogen carbonate are suspended in 3 ml of water and 2 ml of 10 percent hydrogen bromide solution are added thereto. After 15 minutes the product is filtered, washed with water and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropylimidazolium bromide of melting point 241° (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[C:19]([Si:16]([CH3:18])([CH3:17])[O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3′-hydroxyacetophenone (0.500 g, 3.67 mmol) and imidazole (0.500 g, 7.34 mmol) in CH2Cl2 (5 mL) was added tert-butyldimethylsilyl chloride (0.609 g, 4.04 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.