Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)C1OC[C@H](C(C)(C)C)N=1.[Cl:20][C:21]([F:23])=[CH2:22].[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>C1CCCCC1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:20][C:21]1([F:23])[CH2:22][CH:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)Cl
Agent: [Cu+2]
Agent: CC(C)(C)[C@H]1COC(CC2=N[C@@H](C(C)(C)C)CO2)=N1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline] (293 mg, 1.1 mmol), and copper (II) trifluoromethanesulfonate (361 mg, 1.0 mmol) were added in an autoclave, and then 1-chloro-1-fluoroethylene (80 g, 1.0 mol) was charged under elevated pressure. After the mixture was warmed to 30° C., a mixed solution containing 95% of ethyl diazoacetate (12.01 g, 100 mmol) and cyclohexane (50 g) was charged under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to obtain a solution of ethyl 2-chloro-2-fluorocyclopropane-carboxylate in cyclohexane (183.86 g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 4.92% (yield based on ethyl diazoacetate: 54.3%), and the ratio of cis-isomer/trans-isomer was 59.5/40.5. The optical purity of the cis-isomer was 71% e.e. (1S,2R), and the optical purity of the trans-isomer was 19% e.e. (1S,2S).
Reaction SMILES: C(OCCC1CC(CO[Si](C(C)(C)C)(C)C)=CCC1)C1C=CC=CC=1.N.CS(C)=O.C(OCCC1CC(CO)=CCC1)C1C=CC=CC=1.[C:49]([SiH2:53][O:54][C:55]([CH3:66])([CH3:65])[C:56]1[CH2:57][CH:58]([CH2:62][CH2:63][OH:64])[CH2:59][CH2:60][CH:61]=1)([CH3:52])([CH3:51])[CH3:50]>C1COCC1.C(Cl)Cl.CCN(CC)CC>[C:49]([SiH2:53][O:54][C:55]([CH3:66])([CH3:65])[C:56]1[CH2:57][CH:58]([CH2:62][CH:63]=[O:64])[CH2:59][CH2:60][CH:61]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1=CCCC(CCO)C1
Agent: CC(C)(C)[Si](C)(C)OCC1=CCCC(CCOCc2ccccc2)C1
Agent: N
Agent: OCC1=CCCC(CCOCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)C1=CCCC(CC=O)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The benzyl protected alcohol (Intermediate A4) (2.0 g, 5.55 mmol) in THF (20 mL) was cooled to −70° C. and NH3 was condensed in this flask (˜20 mL). Na chunks were added and the mixture was allowed to stir at −70° C. for 15 m. The mixture was warmed to −30° C. for 20 m. The mixture was quenched with NH4Cl and the product was isolated by extraction. The residue was purified by chromatography on SiO2 with 25% EtOAc:Hx (99%). The alcohol was oxidized by the standard “Swern-type” protocol. A solution of oxalyl chloride (33 mL, 2M in CH2Cl2) (available from Aldrich) in CH2Cl2 was cooled to −78° C. DMSO (5.4 mL, 76 mmol) in CH2Cl2 (80 mL) was added via addition funnel over 45 m, and the mixture stirred for an addition 45 m. A solution of the alcohol, 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-ethanol (13.7 g, 50.8 mmol) in CH2Cl2 (45 mL) was added over 30 m to this solution at −78° C. After 1 h, NEt3 (14.5 mL) in CH2Cl2 (10 mL) was added over 15 m and the mixture was warmed to rt for 3 h. After standard aqueous work-up and flash chromatographic purification, [3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-acetaldehyde (Intermediate A5) was isolated 10 g (˜75%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]#[N:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.C(O)(=O)C.O1CCOCC1>O>[C:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][CH2:6][CH:2]=[O:1])[CH2:9][CH2:10]2)[CH2:19][CH2:18]1)#[N:21]
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3.0 g of crude trans-4-[trans-4-[2-(I.3-dioxolan-2-yl)ethyl]cyclohexyl)cyclohexanecarbonitrile were suspended in 50 ml of water, 25 ml of glacial acetic acid and 10 ml of dioxan while gassing with argon and stirred at 100° C. for 1 hour. Thereafter, the reaction solution was treated with 100 ml of water. The aqueous phase was separated and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of dilute sodium hydrogen carbonate solution and with 100 ml of water, dried over magnesium sulfate, filtered and concentrated. Recrystallization of the yellow crystals obtained (2.25 g) from 60 ml of hexane gave 1.98 g of 3-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]-propionaldehyde as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]([C@@H:9]([CH2:11][O:12][S:13]([CH3:16])(=[O:15])=[O:14])[OH:10])[OH:8])(=[O:4])=[O:3].[CH2:17]=O.S(=O)(=O)(O)O>>[CH3:16][S:13]([O:12][CH2:11][C@@:9]1([CH2:17][O:8][C@@H:7]1[CH2:6][O:5][S:2]([CH3:1])(=[O:3])=[O:4])[OH:10])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)OC[C@@H](O)[C@H](O)COS(C)(=O)=O
Reactant: C=O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)OC[C@H]1OC[C@@]1(O)COS(C)(=O)=O
Yield: 61 %

Procedure:
D-threitol 1,4-bis(methanesulfonate) was reacted with formaldehyde and concentrated sulfuric acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3-O-methylene-D-threitol 1,4-bis(methanesulfonate) in 61% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4cc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
6-Hydroxy-7-methylquinoline (180 mg), 4-chloro-6,7-dimethoxyquinoline (126 mg), and 4-dimethylaminopyridine (69 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (36 mg, yield 60%).
Reaction SMILES: [N+:1]([C:4]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O>C(O)C.[Pd]>[CH3:12][O:11][C:10]1[C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(N)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
To a solution of 2-nitro-3-methoxyaniline (90 mg; 0.54 mmol) in ethanol (3 ml) was added 5% palladium on carbon (18 mg; 20 wt %). The resulting suspension was stirred at room temperature under an atmosphere of hydrogen for 18 hours. The suspension was then filtered through celite and the filtrate evaporated to give 3-methoxy-1,2-phenylenediamine (73 mg, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:14])=[C:9]([CH:12]=[O:13])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[CH3:11][C:10]1[C:9]([CH:12]=[O:13])=[C:8]([CH3:14])[NH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(C(=O)O)c(C)c1C=O
Temperature: 0 °C
Yield: 96.8 %

Procedure:
3,5-Dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (19.52 g, 100 mmol) reported in the references was suspended in ethanol (100 ml) and a 2 N sodium hydroxide aqueous solution (100 ml, 200 mmol), and then stirred for 4 hours under reflux condition. After the completion of the reaction, 200 ml of water and 100 ml of a 2 N hydrochloric acid aqueous solution were added under the ice cooled. The precipitate was collected by filtration, washed with water and diethylether, and dried at reduced pressure to afford 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid (16.18 g, 97%) as a light brown solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(F)c2)cc1
Yield: 79.5 %

Procedure:
The title compound (D31) (55 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3-fluoro benzyl bromide (0.044 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[C:6]([NH2:11])[CH:5]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN(C=O)C>[F:13][C:3]([F:2])([F:12])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: N#Cc1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Sc1ccc(C(F)(F)F)cc1N

Procedure:
Using a procedure analagous to that of Example 3, 4-trifluoromethyl-2-aminothiophenol hydrochloride (11.48 g, 50 mmol) was combined with 2-fluorobenzonitrile in DMF as solvent (100 ml) to give crude 2-(4-trifluoromethyl-2-aminophenylthio) benzonitrile (6.84 g). Hydrolysis and subsequent condensation gave the title compound as off-white crystals from ethanol (1.1 g, m.p. 233°-235° C., Rf 0.21, CH2Cl2 /MeOH 50:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:8][C:7]=1[C:13]([F:16])([F:14])[F:15]
Reactant: CCO[C@@H](Cc1ccc(O)cc1C(F)(F)F)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C(F)(F)F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C@H:35]1([C:43]([OH:45])=[O:44])[CH2:39][CH2:38][CH2:37][C@@H:36]1[C:40]([OH:42])=O>>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:40]([C@H:36]4[CH2:37][CH2:38][CH2:39][C@@H:35]4[C:43]([OH:45])=[O:44])=[O:42])[CH2:13][CH2:12]3)=[CH:19][CH:18]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: O=C(O)[C@H]1CCC[C@@H]1C(=O)O
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)[C@H]5CCC[C@@H]5C(=O)O)CC4)cc3)[nH]c12

Procedure:
With a procedure similar to example above, (1S,2S)-2-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid was prepared from 4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester and (1S,2S)-cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C28H32N4O5 (m/e) 504, obsd 505 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH:4]=[CH:5][CH2:6][OH:7].[C:9]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]>O1CCCC1>[C:9]([Si:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:7][CH2:6][CH:5]=[CH:4][CH2:3][OH:8])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC=CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
NaH (3 g, 75 mmol, 60% in oil) was added portion-wise to a stirred and cooled (0° C.) solution of but-2-ene-1,4-diol (6 g, 68.09 mmol) in dry tetrahydrofuran (250 mL). After the addition, the mixture was allowed to warm to room temperature and stirred for another two hours. The resulting white mixture was then cooled (0° C.) and tert-butyl-chlorodiphenylsilane (15.7 mL, 61.28 mmol) was added drop wise. After twenty minutes, the cooling bath was removed and the mixture was allowed to stir overnight at room temperature. Saturated NH4Cl was poured into the reaction mixture and the reaction was partitioned with diethyl ether (200 mL). The organic layer was washed with brine, dried (MgSO4), and filtered. The resulting oil was used in the following step without further purification.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][Si:10]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.CI>O1CCCC1>[CH3:26][Si:10]([CH3:9])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:1])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Into dry tetrahydrofuran (20 ml) at 0° C. under anhydrous conditions was added slowly with stirring lithium diisopropylamide (2.67 g, 25 mmol) and then a solution of 4-(dimethyl-tert-butylsilyloxy)phenylacetic acid (2.66 g, 10 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The resultant brown solution was stirred at 20°-25° C. for one hour and at 50° C. for 30 minutes. The solution was then cooled to 0° C. and methyl iodide (3.54 g, 25 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for about 16 hours and then quenched with saturated aqueous ammonium chloride (20 ml) and acidified with 3N hydrochloric acid. The reaction mixture was extracted with diethyl ether (3×100 ml) and the combined extracts washed with saturated aqueous sodium chloride (2×50 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford a tan oil. The oil was chromatographed on a 5×15 cm column of silica gel eluted with 10 percent isopropanol/hexane to yield the desired product as a solid. m.p. 52°-4° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:17](Br)=[C:18]([Br:20])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:17]=[C:18]([Br:20])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1nc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of 12.3 (1 g, 2.04 mmol) in THF (11 ml) at −78° C. was added 1.6 M BuLi in hexanes (1.59 ml, 2.55 mmol). The mixture was stirred at −78° C. for 0.5 h, quenched with H2O, warmed to rt, and partitioned between EtOAc and H2O. The organic phase was washed with brine, dried (Na2SO4), concentrated, and the crude product purified by SiO2 chromatography (stepwise gradient: 10 to 15 to 25% EtOAc/hexanes) to afford 723 mg (86%) of 12.4. MS (ESI) 411.3 (MH+).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([O-])=O>O1CCCC1>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:21]=[CH:22][C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][CH:8]=2)=[N:12][CH:13]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: C1CCOC1
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. To a stirred suspension of LiA1H4 (3.062 mmol, 2.5 eq) in dry tetrahydrofurane (20 ml) was added 2-[4-(2-nitro-vinyl)-phenoxy]-5-trifluoromethyl-pyridine (1.225 mmol, 1 eq) dissolved in dry tetrahydrofurane (10 ml) dropwise. Reaction mixture was stirred at rt for 2 h. Reaction mixture was quenched with 0.5 ml water. Celite and NaOH (3 ml, 5 N) were added and the mixture was filtered through Celite, rinsing the filter cake well with ether and DCM. Solvents were evaporated till dry. Crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-5% for 3CV then from 5-40% for 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-[4-[5-trifluoromethyl-pyridin-2yloxy)phenyl]-ethylamine s yellow oil (0.443 mmol, yield=36%, purity=91%). [M+H]+=283.30 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.68 (d, 2H), 2.79 (d, J=7.5 Hz, 2H), 7.06-7.13 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.23-7.29 (m, 2H), 8.17-8.20 (m, 1H), 8.20-8.23 (m, 1H), 8.51-8.57 (m, 2H)
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][OH:6].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>CN(C)C=O>[Cl:3][CH2:4][CH2:5][O:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: OCCCl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCl
Reaction time: 1 h
Yield: 75 %

Procedure:
A suspension of 25.0 g of sodium hydride (as a 60% w/w suspension in mineral oil ) in 100 ml of dimethylformamide was added dropwise to a solution of 50 g of 2-chloroethanol and 104 g of ethyl bromoacetate in 350 ml of dimethylformamide at between -45° C. and -40 C., and the mixture was stirred at the same temperature for 1 hour, at between -30° C. and -25° C. for 2 hours, at -5° C.-5° C. for 1 hour and then at room temperature for 2 hours. At the end of this time, it was concentrated by evaporation under reduced pressure, and 1000 ml of toluene were added to the residue. The solution was then washed with water, and the solvent was removed by evaporation under reduced pressure. Distillation gave 77.6 g (yield 75%) of the title compound, boiling at 57°-58° C./2.5 mmHg (333 Pa).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:17][C:13]4([CH2:16][O:15][CH2:14]4)[CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[C:20]1([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:16]1[C:13]2([CH2:12][N:11]([CH2:10][C:9]3[CH:18]=[CH:19][C:6]([O:5][CH:3]4[CH2:4][N:1]([C:31]([C:29]5[O:30][C:26]([C:20]6[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=6)=[N:27][N:28]=5)=[O:32])[CH2:2]4)=[CH:7][CH:8]=3)[CH2:17]2)[CH2:14][O:15]1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: c1cc(OC2CNC2)ccc1CN1CC2(COC2)C1
Solvent: CS(C)=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
3B (0.30 g, 1.15 mmol) was mixed with ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.30 g, 1.38 mmol) in a microwave vial and sealed. The solid mixture was melted in a preheated oil bath and stirred at 120° C. for 4 h. DMSO (2 mL) was added and the mixture was filtered, and then purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 25 min, 0.2% ammonia buffer). The pure fractions were combined and then evaporated. Dichloromethane was added and the solution was dried (phase separator) and concentrated in vacuo. There was obtained 0.30 g (61%) of 3 as a colorless oil. The oil gradually solidified on standing in room temperature. 1H NMR (500 MHz, CDCl3): δ 3.38 (s, 4H), 3.49 (s, 2H), 4.31 (d, 1H), 4.65 (m, 1H), 4.73 (s, 5H), 5.06 (m, 1H), 5.11 (m, 1H), 6.72 (d, 2H), 7.19 (d, 2H), 7.47-7.63 (m, 3H), 8.14 (d, 2H), MS (APCI+) m/z 433 [M+H]+, LC purity: 97%.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([C:15](O)=[O:16])=[CH2:14])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([CH2:15][OH:16])=[CH2:14])[CH2:4][CH2:3]1
Reactant: C=C(C(=O)O)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(CO)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
Artemisinic acid (100.0 mg, 0.43 mmol) was dissolved in THF (10.0 mL) and LiAlH4 (17.0 mg, 0.45 mmol) was added. The heterogeneous mixture was held at reflux (70° C.) for 15 h. After cooling, the reaction was quenched with water (3.0 mL) and 15% aqueous NaOH (3.0 mL), stirred for 10 min and filtered through celite. The organic phase was separated, dried over MgSO4, and concentrated using a rotary evaporator. The product was purified by column chromatography (2:1 hexanes/EtOAc) to give 61.0 mg (65% yield) of the alcohol as a colorless oil. A minor amount of artemisinic acid contaminant was further removed by column chromatography over neutral alumina (Brockman activity 1). Characterization data was consistent with literature values.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[Cl:11][CH:12](OC(Cl)Cl)Cl>ClC(Cl)CCl>[Cl:11][CH2:12][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: CCCCCCCCO
Agent: Cl
Solvent: ClCC(Cl)Cl
Product: CCCCCCCCOCCl

Procedure:
33 g (1.1 mole) of (CH2O)n were stirred in 100 ml 1,1,2-trichloroethane with 130 g (1.0 mole) 1-octanol at 0°-5° C. HCl gas was passed for one hour. The product was analysed by MS-GC, as described in example 7 and was found to contain 2.3% bis-chloromethylether.