Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH:9]12[O:14][CH:13]1[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:10]2>C1COCC1>[OH:14][CH:13]1[CH:9]([CH3:4])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1
Reactant: CCOCC
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
3M methylmagnesium bromide in ether (99 ml, 296 mmol) was added dropwise over 1 hour to a suspension of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (26 g, 119 mmol) and copper bromide-dimethyl sulfide complex (24.38 g, 119 mmol) in anhydrous THF (250 ml) at −40° C. under a nitrogen atmosphere. The reaction was allowed to stir at this temperature for an additional 1 hour before cautiously quenching of the reaction using 125 mL sat. ammonium chloride. The reaction was then allowed to warm to rt and diluted with water (125 mL), then extracted with ethyl acetate (3×150 mL). Ethyl acetate phases were combined, washed with brine, then dried with Na2SO4. After concentration, the crude material was purified by flash chromatography. (+/−)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (24.5 g, 104 mmol, 88% yield) was obtained as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.46 (5 H, m), 5.14 (2 H, s), 3.93-4.05 (1 H, m), 3.63-3.78 (2 H, m), 3.25-3.43 (1 H, m), 3.12 (1 H, ddd, J=13.26, 10. This material was resolved using the following chiral SFC conditions: column. Chiralpak AD-H 5×25 cm, 5 μm, Column Temp. 40° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=82/18, Injection Volume: 2.5 mL (Conc. 118 mg/mL), detector wavelength: 212 nm. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk2 were concentrated to afford 10 g of (3R,4S)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate as a yellow oil. 84, 5.17 Hz), 2.06-2.26 (1 H, m), 1.90 (1 H, d, J=8.36 Hz), 1.03 (3 H, dd, J=6.71, 5.39 Hz); LCMS (Chromolith RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 2.56 min; MS (ES+) m/z: 236.0 (M+H+); HPLC retention time: 3.028 min (analytical HPLC Method H). Chiral purity: 99.9% ee (chiral HPLC conditions: column. Chiralpak AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2, 3 mL/min, 40° C., 200-400 nm, 100 bars).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][CH:22]=[CH:23][C:17]=3[CH2:16]2)(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:22]1[O:21][C:18]2[CH2:19][CH2:20][N:15]([S:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:14])=[O:13])[CH2:16][C:17]=2[CH:23]=1)[CH3:26]
Reactant: CNC
Reactant: C=O
Reactant: O=S(=O)(CCCCCc1ccccc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)CCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.329 g (0.967 mmol) of 5-(5-phenylpentylsulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.11 g (1.2 mmol) of 50% aqueous dimethylamine and 96 mg (1.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].C[O-:10].[K+].[C:12](#[N:22])[CH2:13][CH2:14][CH2:15]CCCCCC.Cl>O.C(OCC)(=O)C>[C:14]([CH:13]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:12]#[N:22])(=[O:10])[CH3:15]
Reactant: CCCCCCCCCC#N
Reactant: C[O-]
Reactant: Cc1ccccc1C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCC(C#N)C(C)=O
Temperature: 105 °C
Reaction time: 4 h

Procedure:
In a stirred vessel fitted with reflux condenser and dropping funnel, 317 g of o-xylene were initially charged, 198.96 g of solid potassium methoxide were added and the mixture was heated at reflux. A mixture of 170 g of decanonitrile and 133.9 g of ethyl acetate was then added via the dropping funnel over a period of 10 min. After the addition had ended, stirring was continued for 4 h, and the mixture was then cooled to 105° C. 372 g of water were then added, and the mixture was adjusted to pH 4.3 by addition of about 470 g of 20% strength hydrochloric acid. The temperature was set to 65° C., and the (lower) aqueous phase was removed. The organic phase was washed with another 186 g of water. After removal of the aqueous phase, the organic phase was concentrated to about half of its original volume to remove the water. This gave 211.7 g of a light-yellow solution having a content of product of value of 66.8% a/a (GC), which solution can be reacted further as such. For purification, the compound was distilled under high vacuum, with the product passing over at 106 to 121° C./1 mbar.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[OH:24][CH2:25][C:26](O)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:27][CH2:26][C:25]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]3[C:8]=2[NH:7][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]3)[CH2:17][CH2:16]1)=[O:24]
Reactant: Cc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)CO)CC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(5-Methyl-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine (305 mg, 1 mmol) prepared in Example 90 was dissolved in DMF (5 mL). Hydroxyacetic acid (76 mg, 1 mmol), EDC (232 mg, 1.3 mmol), HOBT (229 mg, 1.5 mmol) and Et3N (280 uL, 2 mmol) were added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, saturated aqueous NaHCO3 solution was added to the reaction mixture, which was then extracted with EtOAc, washed with saturated aqueous NaCl solution and 1N HCl, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>ClCCCl>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 92.5 %

Procedure:
4.9 g (0.12 mole) of sodium borohydride was suspended at room temperature in a solution of 24.9 g (0.10 mole) of isobutyl (R)-(+)-2-(1-isobutoxyethoxy)propionate dissolved in 100 ml of 1,2-dichloroethane. Thereto was dropwise added slowly 24.0 ml (0.60 mole) of methanol with stirring so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature with the disappearance of the raw material being monitored by GC, to give rise to a reaction. 20 hours were necessary. Then, 50 ml of water was added, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 50 ml of toluene. The two organic layers were combined and washed with 30 ml of water and 30 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 16.3 g (yield: 92.6%) of an oily title compound (diastereomixture).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=O>>[N:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[S:10][CH:11]=[CH:12][N:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: Nc1n[nH]cc1C(=O)c1nccs1
Product: O=C(c1nccs1)c1cnn2c(-c3ccncc3)ccnc12

Procedure:
As described for Example 1, (3-amino-1H-pyrazol-4-yl)-2-thiazolyl-methanone was reacted with 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one to give the product as crystals, mp 323°-325° C.
Reaction SMILES: [C:1]1([O:7]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([OH:16])=[O:15].[S:17]([O:22][CH3:23])([O:20][CH3:21])(=[O:19])=[O:18].[C:24](=[O:27])([O-:26])[O-:25].[K+].[K+]>[Na].[OH-].[K+].CC(C)=O>[OH:7][C:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]=1[C:24]([OH:26])=[O:25].[S:17]([O:22][CH3:23])([O:20][CH3:21])(=[O:19])=[O:18].[CH3:21][O:16][C:14]([C:10]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[O:27][CH3:24])=[O:15]
Reactant: COc1ccccc1
Reactant: O=C(O)c1ccco1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1c(OC)ccc2ccccc12
Product: O=C(O)c1c(O)ccc2ccccc12

Procedure:
This methyl ester was previously made by fusion of anisole and 2-furoic acid followed by esterification of the acid intermediate, J. Amer. Chem. Soc., Vol. 69, 2261 (1947). Methyl esters of methoxy carboxylic acids were prepared by methylation of aromatic hydroxy carboxylic acids with dimethyl sulfate in the presence of potassium carbonate as base, using acetone as the solvent, Houben-Weyl, Methoden der Organischen Chemie., Vol. 8, 542-3 (1952). Methylation of 2-hydroxy-1-naphthoic acid with dimethyl sulfate in aqueous sodium or potassium hydroxide produced mainly methyl-2-methoxy-1-naphthalenecarboxylate, Chemische Berichte, Vol. 37, 3658-61 (1904). In aqueous solutions, at pH 4-6.5, methylation of hydroxy napthoic acids with dimethyl sulfate produced the methyl esters of the hydroxy naphthoic acids.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](O)(=[O:22])=[O:21])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O=P(Cl)(Cl)[Cl:27].N1C=CC=CC=1.O>CN1CCN(C)C1=O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20]([Cl:27])(=[O:22])=[O:21])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)O)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-methoxy-3-sulfo-phenyl)-3-phenyl-propionic acid methyl ester (850 mg, 2.43 mmol) in 1,3-dimethyl-2-imidazolidinone (25 mL) is added POCl3 (0.57 ml, 6.06 mmol) and pyridine (0.33 mL, 4.13 mmol). The reaction mixture is stirred at RT for 1 h. After this time, water (50 mL) is added and the reaction mixture is extracted with DCM (3×50 mL). The combined organic phases are washed with brine (30 mL) then dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:31]([O-])=O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:31]1
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCc3ccccn3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4ccccn4)c(C(F)(F)F)c3)cc21
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To 3-amino-4-(methylamino)-6-(4-(pyridin-2-ylmethoxy)-3-(trifluoromethyl)-phenyl)picolinonitrile (1.7 g) in NMP (20 ml) was added 1M hydrochloric acid (22 ml) and cooled to 5-10° C. with an ice bath. To above solution was then added dropwise a solution of sodium nitrite (0.59 g) in water (5 ml) during 5 minutes. The mixture was stirred at room temperature for another 1 hour. After adding ethyl acetate (200 ml), the mixture washed with water (4×100 ml), brine (50 ml), solvent removed under reduced pressure. Upon addition of methanol (20 ml) to the residue, the desired product precipitated and collected by filtration to give 1-methyl-6-(4-(pyridin-2-yl-methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (480 mg) as a white solid. 1H NMR (CDCl3) δ: 8.61 (d, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 7.98 (s, 1H), 7.78 (t, 1H), 7.60 (d, 1H), 7.27 (t, 1H), 7.22 (d, 1H), 5.40 (s, 2H), 4.44 (s, 3H). MS m/z 411 (M+H).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14](OC)=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][NH2:20].Cl>O>[CH:1]1([C:5]2[C:13]([C:14](=[O:15])[NH:20][CH3:19])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Into a 20-mL sealed tube, was placed 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 62.2, 1.0 g, 4.0 mmol) and methylamine (30% in ethanol) (8 mL). The resulting solution was stirred overnight at 120° C. behind a blast shield, then cooled and diluted with H2O (20 mL). The pH of the solution was adjusted to 4-5 with hydrogen chloride (1 M) and the solids were collected by filtration. The crude product was re-crystallized from ethyl acetate/petroleum ether in the ratio of 1:10 to yield the title compound as an off-white solid (500 mg, 50%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2([C:30]3[N:13]4[CH2:14][CH2:15][S:16][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:19])[CH2:11][C:12]4=[N:33][N:32]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Br)cc2)CC1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A solution of 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (34.4 g, 108 mmol) and the compound (27.5 g, 108 mmol) obtained in Example 16-3) in 1-butanol (800 mL) was stirred at 140° C. for 6 h. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1 to 1:0) to obtain the title compound (36.3 g, 66%) as a white solid.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:15]=[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[N:11][C:12]=3[CH:13]=[CH:14][N:5]2[N:4]=1.[OH2:17]>CNC>[N:15]1[C:3]([CH:2]=[O:17])=[N:4][N:5]2[CH:14]=[CH:13][C:12]3[N:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=12
Reactant: O
Reactant: ClC(Cl)c1nc2c3cccnc3ccn2n1
Agent: CNC
Product: O=Cc1nc2c3cccnc3ccn2n1
Temperature: 70 °C
Yield: 60 %

Procedure:
A microwave tube was charged with a mixture of 2-(dichloromethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine (180 mg, 0.71 mmol) in dimethylamine in water (5 mL, 33% wt in water) and heated at 70° C. in oil bath for 5 h, and then cooled to room temperature. The mixture was extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 100/1 and 50/1) to yield [1,2,4]triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde as a white solid (85 mg, yield 60%). ESI MS: m/z 199 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 9.06 (m, 1H), 8.97 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 7.65 (m, 2H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:22]([C@@:23]([OH:33])([C@H:25]([OH:32])[CH2:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[CH3:24])[CH2:21][CH2:20][C@@:19]1([OH:34])[C:6]1=[CH:7][C:8]([C@@H:10]3[CH2:15][C@@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12][C@:11]3([CH3:18])[C@H:5]1[CH2:4][CH2:3]2)=[O:9].[CH3:35][C@@:36]12[C@@H:56]([C@@:57]([OH:67])([C@H:59]([OH:66])[CH2:60][CH2:61][C:62](O)([CH3:64])[CH3:63])[CH3:58])[CH2:55][CH2:54][C@@:53]1([OH:68])[C:40]1=[CH:41][C:42]([C@@H:44]3[CH2:49][C@@H:48]([OH:50])[C@@H:47]([OH:51])[CH2:46][C@:45]3([CH3:52])[C@H:39]1[C@H:38](O)[CH2:37]2)=[O:43]>>[CH3:1][C@@:2]12[C@@H:22]([C@@:23]([OH:33])([C@H:25]([OH:32])[CH2:26][CH2:27][C:28]([OH:31])([CH3:29])[CH3:30])[CH3:24])[CH2:21][CH2:20][C@@:19]1([OH:34])[C:6]1=[CH:7][C:8]([C@@H:10]3[CH2:15][C@@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12][C@:11]3([CH3:18])[C@H:5]1[CH2:4][CH2:3]2)=[O:9].[CH3:64][CH:62]([CH2:61][CH2:60][C@@H:59]([OH:66])[C@:57]([OH:67])([C@@H:56]1[C@@:36]2([CH3:35])[CH2:37][CH2:38][C@@H:39]3[C@@:45]4([CH3:52])[CH2:46][C@H:47]([OH:51])[C@H:48]([OH:50])[CH2:49][C@H:44]4[C:42](=[O:43])[CH:41]=[C:40]3[C@:53]2([OH:68])[CH2:54][CH2:55]1)[CH3:58])[CH3:63]
Reactant: CC(C)(O)CC[C@@H](O)[C@](C)(O)[C@H]1CC[C@@]2(O)C3=CC(=O)[C@@H]4C[C@@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Agent: CC(C)(O)CC[C@@H](O)[C@](C)(O)[C@H]1CC[C@@]2(O)C3=CC(=O)[C@@H]4C[C@@H](O)[C@@H](O)C[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CC[C@@H](O)[C@](C)(O)[C@H]1CC[C@@]2(O)C3=CC(=O)[C@@H]4C[C@@H](O)[C@@H](O)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Semi-synthetic steroids 20E 2-methyl ether, 20E 3-methyl ether, 20E 22-methyl ether, 20E 2,22-dimethyl ether, 20E 3,33-dimethyl ether, 20E 2,3,14,22-tetramethyl ether, 20-hydroxyecdysone 22-O-pyrrole carboxylate, and turkesterone-11 alpha propionate, turkesterone-11 alpha hexanoate, turkesterone-11 alpha decanoate were prepared from 20E or turkesterone. The remaining steroids were isolated from plant materials, except for ponasterone A which was also synthesised from 20-hydroxyecdysone. Muristerone A which was purchased by AG Scientific Inc (San Diego, Calif.). The following compounds were generously supplied by other researchers: 2-deoxyecdysone, ecdysone, 2-deoxy-20-hydroxyecdysone, and cyasterone (Prof. René Lafont), taxisterone, polypodine B, ajugasterone C, (25S)-inokosterone, (25R)-inokosterone, makisterone A, makisterone C, carthamosterone, intergristerone A (Dr. Juraj Harmatha), 20-hydroxyecdysone (Dr. Vladimir Volodin), turkesterone (Prof. Zyadilla Saatov) and canescensterone (Prof. Apichart Suksamram). Reagents and solvents used for the synthesis/purification were purchased from Fisher Scientific and Sigma-Aldrich. Water for HPLC was deionized to a degree of purity of 17 W.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][N:9]([CH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][CH:13]=1)[CH3:10].CN(C)[CH:21]=[O:22]>C(O)C>[CH3:8][N:9]([CH2:11][C:12]1[N:17]=[C:16]([O:5][CH2:4][CH2:3][CH2:2][NH:1][CH:21]=[O:22])[CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: NCCCO
Reactant: CN(C)Cc1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)Cc1cccc(OCCCNC=O)n1
Temperature: 80 °C

Procedure:
3-Aminopropanol (2.55 g, 0.034 mol) is added to a suspension of 60% sodium hydride in mineral oil (1.29 g, 0.033 mol) in dry dimethylformamide (30 ml) and the mixture is warmed to 80° C. before adding dropwise a solution of 6-dimethylaminomethyl-2-chloropyridine (5.45 g, 0.032 mol) in 30 ml of dry dimethylformamide. The reaction temperature is increased to 125° C. for 3 hours. Then the reaction is cooled, diluted with ethanol and the precipitated salts filtered. The solvents are removed under vacuum. The residue is dissolved in chloroform, washed with water, extracted into dilute hydrochloric acid and the acidic extract neutralized with sodium carbonate. The crude product is extracted into chloroform dried and evaporated (7.6 g). This residue is chromatorgrphed on silica gel (200 g) eluting with 3-8% methanol/chloroform to give 3.2 g of pure product as an oil.
Reaction SMILES: [CH2:1]([Cl:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])O.CS(O)(=O)=O>>[C:13]([NH:12][CH2:10][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][Cl:9])=[CH:4][CH:5]=1)(=[O:16])[CH:14]=[CH2:15]
Reactant: ClCCc1ccccc1
Reactant: C=CC(=O)NCO
Agent: CS(=O)(=O)O
Product: C=CC(=O)NCc1ccc(CCCl)cc1
Temperature: 15 °C
Yield: 75 %

Procedure:
70 parts (0.5 mole) of phenethyl chloride and 51.5 parts (0.51 mole) of N-methylolacrylamide are stirred, in succession, into 300 parts by volume of methanesulfonic acid which has been cooled to 15° C. Stirring is continued for 6 hours at from 15° to 20° C., and hydrolysis is effected by adding 1,500 parts of crushed ice. After the ice has thawed, the product is filtered off and dried in the air to give 84 parts (yield: 75%) of crude p-acrylamidomethylphenethyl chloride, which is recrystallized from methyl alcohol to give a pure product of melting point 145°-147° C.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1C([O-])=O.[BH4-]>CO>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])C1CCCO1
Agent: [BH4-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in amixture of 807 mL of methanol and 807 mL of tetrahydrofuranat -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solidsodium borohydride over one hundred minutes. The solventswere removed under reduced pressure at 40° C. and the residuedissolved in ethyl acetate (approx. 1 L). The solution waswashed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodiumchloride solution. After drying over anhydrous magnesiumsulfate and filtering, the solution was removed underreduced pressure. To the resulting oil was added hexane(approx. 1 L) and the mixture warmed to 60° C. with swirling.After cooling to room temperature, the solids werecollected and washed with 2 L of hexane. The resultingsolid was recrystallized from hot ethyl acetate and hexaneto afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. andM+Li+ =340.