Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][S:14]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:29][C@@H:30]([CH2:44][C:45]1[CH:46]=[C:47]([F:52])[CH:48]=[C:49]([F:51])[CH:50]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1)=[O:26])[CH2:13][S:14]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])(=[O:15])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 250 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 4.0 g (10 mmole) N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine and 1.2 g (12 mmole) (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride in 50 ml anhydrous methylene chloride. To the reaction mixture was added 5.6 ml (51 mmole) NMM, 1.7 g (13 mmole) hydroxybenzotriazole, and lastly 3.1 g (16 mmole) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring at room temperature for 3 hours, HPLC analysis indicated complete reaction. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, 0.5 M citric acid, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the N2-[(benzyloxy)carbonyl]-N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide. A 50 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with the crude residue in anhydrous methylene chloride. The reaction was cooled to 0° C. and added 2.5 g (12 mmole) di-tert-butyl dicarbonate and 1.2 ml (11 mmole) N-methyl morpholine. The reaction was allowed to warm to room temperature and stirred for 18 hours at which point HPLC analysis indicated complete reaction. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified on silica gel by flash chromatography using a gradient solvent of 5-40% ethyl acetate in hexane to give 3.4 g of N2-[(benzyloxy-)carbonyl]-N1-{(1S,2R)-N-[(t-butyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide. M+Na=824.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH2:27][CH2:26][C:10]3([O:15][CH2:14][CH2:13][N:12]([C:16]([C:18]4[N:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[S:21][CH:22]=4)=[O:17])[CH2:11]3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH2:30][CH2:31][OH:32].FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH2:27][CH2:26][C:10]3([O:15][CH2:14][CH2:13][N:12]([C:16]([C:18]4[N:19]=[C:20]([CH:23]([CH3:24])[CH3:25])[S:21][CH:22]=4)=[O:17])[CH2:11]3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH2:30][CH:31]=[O:32]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(Cl)c(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(Cl)c(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(4-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 75, step d) (0.152 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.049 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.205 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 30 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow gum. Yield 0.197 g.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[C:10]1([C:16]2[O:17][C:18](=[O:21])[CH2:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClCCCl.O.[OH-].[Li+]>C1COCC1.O>[C:10]1([C:16]2[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[C:19]([C:18]([OH:21])=[O:17])[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1=NCCCCC1
Reactant: O=C1CN=C(c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: O=C(O)c1nc(-c2ccccc2)n2c1CCCCC2
Temperature: 150 °C

Procedure:
(E)-7-methoxy-3,4,5,6-tetrahydro-2H-azepine (0.395 g, 3.10 mmol) and 2-phenyloxazol-5(4H)-one (0.5 g, 3.10 mmol) were dissolved together in THF (2 mL) and DCE (2 mL) in a 5 mL microwave vial to give a orange solution. The vial was sealed and the solution was heated to 150° C. for 5 minutes. LCMS showed two peaks of the same mass (tautomers of the condensation product, Rf 0.78 and 0.83 minutes, respectively). The reaction was concentrated and the residue diluted with MeOH (1 mL) and a solution of lithium hydroxide monohydrate (0.391 g, 9.31 mmol) in water (0.5 mL). The reaction was subjected to microwave irradiation and heated at 120° C. for 5 minutes. LCMS showed a single, new peak (Rf0.53 same molecular weight) corresponding to the desired product. The reaction was concentrated to remove MeOH and then diluted with water (1 mL). The solution was acidified to pH 2 with 5M HCl and extracted with of DCM (3×2 mL). The combined organic layers were filter, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide 3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxylic acid (421 mg, 59%) as a brown oil that was used without further purification. LCMS (+ESI) m/z 257.1 [M+H]+.
Reaction SMILES: CN1CCOCC1.Cl.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[NH2:15].[C:20]1(=[O:41])[N:24]([NH:25][C@H:26]([C:33](O)=[O:34])[CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:36])[C:22]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:21]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O>[C:23]1(=[O:36])[N:24]([NH:25][C@H:26]([C:33]([NH:15][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][OH:9])=[O:34])[CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:20](=[O:41])[C:21]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:22]12
Reactant: O=C(O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Methylmorpholine (1.51 ml., 14.5 mmol.) was added to a solution of 6-hydroxy-L-norleucine, methyl ester, hydrochloride (8.53 mmol.) in methylene chloride (34 ml)/dimethylformamide (9 ml.) at room temperature under argon. The resulting mixture was cooled to 0° C. and N-phthalimido-3-(2-thienyl)-L-alanine (2.57 g., 8.54 mmol.), hydroxybenzotriazole (1.19 g., 8.80 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.80 g., 9.4 mmol.) were added sequentially. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 1.5 hours. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with 0.5N hydrochloric acid, water, saturated sodium bicarbonate, and brine, and the organic layer was dried (sodium sulfate), filtered, and concentrated. The residue was flash chromatographed (Merck silica gel) eluting with 2:1 ethyl acetate/hexane to give 3.13 g. of title compound as a white foam. TLC (5% acetic acid in ethyl acetate) Rf =0.68.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 107.4 %

Procedure:
A solution of amine 84 (220 mg, 0.4 mmol) in DCM (10 mL) was cooled to 0° C. and treated with DIPEA (0.21 mL, 1.2 mmol) followed by methanesulfonyl chloride (0.03 mL, 0.42 mmol) and DMAP (5 mg, 0.04 mmol). After 2.5 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 85 (271 mg, 100%) as a yellow-colored foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.08 (q, J=9.3, 18.9 Hz, 1H), 6.86 (br, 1H), 6.76-6.69 (m, 1H), 6.63-6.58 (m, 1H), 4.73-4.65 (m, 1H), 4.60 (d, J=9.6 Hz, 1H), 4.47 (d, J=6.3 Hz, 1H), 4.33-4.29 (m, 1H), 4.16-4.07 (m, 2H), 4.01-3.96 (m, 1H), 3.68-3.53 (m, 3H), 2.93-2.79 (m, 6H), 2.57-2.50 (m, 1H), 2.12-2.06 (m, 1H), 1.61 (s, 1.5H), 1.49 (s, 7.5H), 1.31 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[CH:5][N:6]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([NH:25][C:26]([NH:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[C:7]([C:4]3[O:3][C:2]([CH3:1])=[N:6][CH:5]=3)[N:12]2[N:13]=1)=[O:27])[CH3:24]
Reactant: Cc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)o1
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(C)o3)n2n1
Temperature: 0 °C

Procedure:
A mixture of the product of Step 1 (0.23 g, 0.787 mmol), ethyl isocyanate (0.28 g, 3.93 mmol) and a catalytic quantity of dibutyltin diacetate (3 drops) in THF/toluene (1:1, 10 mL) was heated in a sealed tube at 100° C. for 15 h. This mixture was cooled to 0° C., the solid obtained was filtered and washed with 10% CHCl3/hexanes to provide the target compound, N-ethyl-N′-[5-(2-methyl-1,3-oxazol-5-yl)-7-pyridin-3-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl]urea as a solid. LCMS (APCI+) 364.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(B(O)O)c1O
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c1
Yield: 65 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-3-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 65% yield using method F; δH [2H6]-DMSO 12.35,(1H, s), 8.37,(2H, m), 8.24,(2H, m), 8.17,(1H, d), 8.09,(1H, d), 7.96,(1H, d), 7.65,(1H, s), 7.27,(1H, d), 7.02-6.86,(3H, m), 3.83,(3H, s), 2.26,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.31 minutes.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=4)=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]>ClCCl.FC(F)(F)C([O-])=O>[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=4)=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(c2)c(-c2ccnn2C)cn3COCC[Si](C)(C)C)c1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(O)c1cncc(-c2cnc3[nH]cc(-c4ccnn4C)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
2-Hydroxy-N,N-dimethyl-2-{5-[3-(2-methyl-2H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-acetamide (71 mg, 0.1 mmol) was stirred in dichloromethane/trifluoroacetate acid (1 ml/1 ml) at room temperature for 2 hours. The solvents were removed under vacuum and the crude material was stirred in dichloromethane/ethylenediamine (1 ml/1 ml) for 2 hours at room temperature. The solvents were removed in vacuo and the residue was dissolved in DMSO, filtered and purified by reverse phase HPLC and lyophilized to afford 2-hydroxy-N,N-dimethyl-2-{5-[3-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-acetamide (33 mg, 61% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.87 (s, 3H), 3.00 (s, 3H), 3.93 (s, 3H), 7.53 (m, 1H), 7.94 (s, 1H), 8.12 (m, 1H), 8.25 (m, 1H), 8.56 (m, 1H), 8.65 (m, 1H), 8.92 (m, 1H), 12.38 (s, 1H). MS: m/z 377.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[C:3](=[O:27])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[Pd]>[CH3:1][N:2]([C@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[C:3](=[O:27])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(O)cc1
Yield: 62.3 %

Procedure:
A solution of methyl 2-[N-methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate 48c (3.0 g, 6.59 mmol) in MeOH (75 mL) was hydrogenated under atmospheric pressure using 10% Pd/C (0.6 g) as a catalyst for a period of 4.5 hours. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was purified on a silica gel column using 40% EtOAc/hexane as an eluent to afford the phenol product (1.5 g, 62%) as a solid. MS (CI—NH3): (M+H)+=366.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[C:6](\[CH3:21])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:20])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:19])C.[H-].C([Al+]CC(C)C)C(C)C.CO.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:21]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:20])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:19])=[CH:5]\[CH2:4][OH:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)coc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Product: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid ethyl ester (6 g.) in ether (25 ml.) was added to a solution of diisobutyl aluminum hydride (38 ml.; 25% by volume in hexane) at -40° and stirred for 30 minutes at room temperature. Aqueous methanol (1:1 parts by volume; 1.6 ml.) was added. The mixture was then carefully warmed to room temperature and then treated with anhydrous magnesium sulfate. The solids were filtered off and the solvents were removed to give (E,E,E,E)-3,7-dimethyl-9-(2,4,-dimethyl-3-furyl)-2,4,6,8-nonatetraenol as an oil. The pmr spectrum showed the complete absence of ester or aldehyde functions.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10](OCC)=[O:11])=[CH:8][S:7]/[C:6]/1=[CH:15]\[C:16]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])=[O:17])[CH2:2][CH2:3][CH3:4].[CH3:27][NH2:28]>CO>[CH2:1]([N:5]1[C:9]([C:10]([NH:28][CH3:27])=[O:11])=[CH:8][S:7]/[C:6]/1=[CH:15]\[C:16]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(C(=O)OCC)=CS/C1=C\C(=O)c1cc(Cl)ccc1OC
Reactant: CN
Solvent: CO
Product: CCCCN1C(C(=O)NC)=CS/C1=C\C(=O)c1cc(Cl)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of Example 45 in methanol was added a solution of methylamine in methanol and stirred overnight. The title compound was obtained by concentration of the reaction solution. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.92 (t, J=7.29 Hz, 3 H) 1.23-1.37 (m, 2 H) 1.71 (m, 2 H) 2.74 (d, J=4.75 Hz, 4 H) 3.87 (s, 3 H) 4.15-4.24 (m, 2 H) 6.66 (s, 1 H) 7.14 (d, J=8.81 Hz, 1 H) 7.21 (s, 1 H) 7.44 (dd, J=8.82, 2.71 Hz, 1 H) 7.66 (d, J=2.71 Hz, 1 H) 8.77 (d, J=4.75 Hz, 1 H). MS (DCI) m/z 381 (M+H)+. Anal calcd for C18H21ClN2O3S.1.2H2O.0.3 NH4OH: C, 52.81; H, 6.03; N, 7.87. Found: C, 52.52; H, 5.70; N, 7.81.
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.Cl[Si](C)(C)C.[CH:26]1C=CC=C[CH:27]=1>>[CH3:26][CH2:27][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: c1ccccc1
Agent: C[Si](C)(C)Cl
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Reaction time: 2 h

Procedure:
Another method is reported by Bhakuni et al. (Bhakuni R. S; Jain D. C and Sharma, R P., Indian J. Chemistry, 34B, 529-30 (1995). Arteether was prepared by dissolving dihydroartemisinin in alcohol and benzene mixture and then adding chlorotrimethylsilane as acid catalyst. The reaction was stirred for 2 hrs. at room temperature. The reaction mixture was washed with 10% sodium acetate solution and workup as usual method. The other products formed during the reaction were removed by column chromatography, to obtain pure arteether.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21](=[O:26])[CH:9]([O:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11]
Reactant: CC(C)(C)C(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)C(Oc1ccccc1)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Triethylamine (57.35 g, 566 mmol) was added to a stirred solution of N-[2-chloro-4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline prepared as above (155.9 g, 483 mmol) and phenol (49.9 g, 530 mmol) in dry acetonitrile (1.3 L) under argon. After the addition had been completed, the mixture was heated at reflux for 7 hours. The reaction mixture was then cooled and the solvent was removed under reduced pressure. The residue was dissolved in methanol (300 mL) and allowed to stir at room temperature until crystallization began. After 2 hours, the mixture was cooled in an ice bath for a further 1 hour. The product was removed by filtration, washed with cold methanol, and dried to afford N-[4,4-dimethyl-3-oxo-2-phenoxypentanoyl]-2,4-dichloroaniline (99 g, 54% yield) as a white crystalline solid which melted at 112°-113.5° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:13])[CH3:12])=[C:5]([SH:14])[CH:4]=1>CO>[CH3:10][O:9][C:7]1[C:6]2[C:11](=[O:13])[CH2:12][C:3]3([S:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3
Reactant: COc1cc(S)c(C(C)=O)c(OC)c1
Solvent: CO
Product: COc1cc(OC)c2c(c1)SC1(CCCCC1)CC2=O
Yield: 143.9 %

Procedure:
A solution of (4',6'-dimethoxy-2'-mercaptophenyl) ethanone (prepared in Preparation 77) (0.53 g, 2.5 mmol) and cyclohexanonepyrrolidine enamine (0.57 g, 3.73 mmol) in dry methanol (8 ml) is heated to reflux for 3 hours under nitrogen gas. The solvent is removed by distillation and the residue is dissolved in diethyl ether. The solution is washed with dilute hydrochloric acid and then saturated brine, dried, and the solvent is removed. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:9). The starting material (0.142 g, 26%) and the title compound (crystalline solid, 0.526 g, 71.9%) are obtained, successively. Recrystallization from diethyl ether gives the title compound having a melting point of 104°-105° C.
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:12][NH2:13]>CCOCC.CO>[NH2:13][CH2:12][CH:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:10][CH2:9][OH:8]
Reactant: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 ml of a saturated solution of hydrogen chloride in ether are added to a solution of 149 g of 4-(tetrahydropyran-2-yloxy)-2-(3,4-dichlorophenyl)-1-aminobutane in 700 ml of methanol. The mixture is stirred for 1/2 hour at room temperature and concentrated under vacuum and the residue is taken up in 500 ml of water and washed with ether. The aqueous phase is rendered alkaline with a solution of sodium hydroxide and extracted twice with methylene chloride. The organic phases are dried over MgSO4, filtered and concentrated under vacuum. The residue is taken up in 400 ml of isopropyl ether and the mixture is stirred for one hour at room temperature. The precipitate is filtered off and washed with ether.