Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ccccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 2-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 2-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 2-(2-chloro-phenyl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:14])[CH3:13])[S:9][CH:10]=1.[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1OC>>[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:13])[CH3:14])[S:9][CH:10]=1
Reactant: CN(C)Cc1cc(OCCCN)cs1
Reactant: COc1c(N)c(=O)c1=O
Product: CN(C)Cc1cc(OCCCNc2c(N)c(=O)c2=O)cs1

Procedure:
An equimolar mixture of 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine [prepared according to the procedure described in published European Patent Application 27,744] and 1-amino-2-methoxycyclobutene-3,4-dione is reacted according to the general procedure of Example 19 to yield the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:4][CH:3]=1.[Br:17][C:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B(O)O)=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[CH:23]2.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.COCCOC>[Br:17][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]4[CH:16]=3)=[CH:4][CH:3]=2)=[C:26]2[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]2
Reactant: OB(O)c1c2ccccc2c(Br)c2ccccc12
Reactant: Ic1ccc(-c2cn3ccccc3n2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1c2ccccc2c(-c2ccc(-c3cn4ccccc4n3)cc2)c2ccccc12
Yield: 78.9 %

Procedure:
Ten point six grams (33 mmol) of 2-(4-iodophenyl)-imidazo [1,2-a] pyridine, 10 g (33 mmol) of 10-bromoanthracene-9-boronic acid and 0.77 g of tetrakis (triphenylphosphine) palladium were dissolved into 100 milliliter of 1,2-dimethoxyethane, and adding 50 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 11.7 g of 2-[4-(10-bromo-anthracene-9-yl)-phenyl]-imidazo [1,2-a] pyridine (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][S:22]([C:21]([F:27])([F:26])[F:20])(=[O:24])=[O:23])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(O)cc(Cl)cc1Cl
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cc(Cl)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of the above ester (4.64 g, 20.99 mmol) and pyridine (1.87 mL, 23.09 mmol) in 100 mL CH2Cl2 was cooled to 0° C. Trifluoromethanesulfonic acid (4.94 mL, 29.39 mmol) was added, and the solution was stirred for 2 h. The reaction mixture was washed with aqueous sodium bicarbonate, aqueous copper sulfate and brine, dried over Na2SO4, filtered and concentrated to provide methyl 2,4-dichloro-6-{[(trifluoromethyl)sulfonyl]oxy}benzoate that gave proton NMR spectra consistent with theory.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH:14](OCC)(OCC)OCC.C(=O)(O)[O-].[Na+]>>[F:11][C:9]([S:8][C:6]1[CH:5]=[CH:4][C:3]2[O:13][CH:14]=[N:1][C:2]=2[CH:7]=1)([F:12])[F:10]
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)Sc1ccc2ocnc2c1

Procedure:
A mixture of 0.50 g of 2-amino-4-trifluoromethylsulfanylphenol and 3 ml of triethyl orthoformate was stirred under heating and refluxing for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.50 g of 5-trifluoromethylsulfanylbenzoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C(OC([N:43]1[CH2:48][CH2:47][O:46][CH:45]([C:49](O)=[O:50])[CH2:44]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[OH-].[Li+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:49]([CH:45]5[O:46][CH2:47][CH2:48][NH:43][CH2:44]5)=[O:50])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine (0.06 g, 0.12 mmol) in CH2Cl2 (3 mL) was added 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and iPr2NEt (0.06 g, 0.47 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) and allowed to stir at room temperature for 2 hours. The resulting solution was concentrated in vacuo, dissolved in THF (4 mL) and treated with 1N aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130° C. for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MeOH/H2O with 6 mM HCl over 15 minutes. The purified fractions were concentrated to provide the bis-hydrochloride of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1)[CH3:26]
Reactant: CNC
Reactant: CC(C)Cn1nc(-c2ccccc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccccc2)cc(CN(C)C)c1=O
Yield: 81.1 %

Procedure:
Following the procedure of Example 7, 2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 81.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH3:22])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH2:15]([C:11]1[C:12]([OH:14])=[N:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:3][CH:4]=2)=[N:9][C:10]=1[CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 54 (0.050 g, 0.17 mmol) in THF (3 mL), was added triethylamine (0.025 g, 0.25 mmol) and chloroacetylchloride (0.029 g, 0.25 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](O)[CH3:11])=[CH:4][C:3]=2[O:2]1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(O)c1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g, 10 mmol) in dry pyridine was added acetic anhydride and the resultant reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was poured into ice-water and was extracted with ether (2×75 ml). The combined ether extract was washed with water (2×50 ml), 5% Hcl (2×50 ml) and then with 5% NaHCO3 (2×50 ml). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane as a solid (1.7 g, 81% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[CH2:21][N:22](CC)CC>CN1C(=O)CCC1>[CH3:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(Cl)nc12
Reactant: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CNc1ccc2cccc(OC(C)CC(C)(C)C)c2n1

Procedure:
A 7.5 mL conical microwave vessel (Personal Chemistry) equipped with a septum cap and a magnetic stirring bar was charged with 0.25 g (0.90 mmol) of 2-Chloro-8-(1,3,3-trimethylbutoxy)quinoline, NEt3 (1.26 mL) and NMP (1.26 mL). The resulting suspension was irradiated in Personal Chemistry Smith Synthesizer (220° C. for 25 min; 300 W). Upon cooling, the residue was dissolved in a 3:1 hexanes/CH2Cl2 mixture (10 mL) and washed with H2O. The organic layer was evaporated in vacuo and the residue was purified by silica gel column chromatography (5–15% MeOH/CH2Cl2) to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 6.67–7.79 (m, 5H), 4.87 (m, 1H), 3.11 (m, 3H), 2.03 (m, 1H), 1.56 (m, 1H), 1.30 (m, 3H), 0.89 (m, 9H); MS (DCI/NH3) m/z 273 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: Cc1cc(SCC#Cc2cccc(C(F)(F)F)c2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-iodo-3-trifluoromethyl-benzene gave the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[C:7]([CH2:9][C:10]1([C:15]#[N:16])CC(=C)[CH2:11]1)#[N:8].I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[C:7]([CH2:9][C:10]1([C:15]#[N:16])[CH2:5][C:6](=[O:1])[CH2:11]1)#[N:8]
Reactant: C=C1CC(C#N)(CC#N)C1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: N#CCC1(C#N)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of water (2 mL, 0.1 mol) and 1,4-dioxane (6 mL, 0.08 mol), 1-(cyanomethyl)-3-methylenecyclobutanecarbonitrile (0.270 g, 0.00204 mol), and 0.2 M of osmium tetraoxide in water (0.04 mL) was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (0.919 g, 0.00430 mol) was added in portions over a period of 30 min. The mixture was stirred overnight. The mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4. After removal of the solvents, the crude product was used directly in next step.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([OH:45])=[C:40]([C:43]#[N:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:30][C:29]=1[F:48]>C(OCC)(=O)C.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][O:45][C:39]2[CH:38]=[C:37]3[C:42]([C:33]([O:32][C:31]4[CH:46]=[CH:47][C:28]([NH2:27])=[C:29]([F:48])[CH:30]=4)=[CH:34][CH:35]=[N:36]3)=[CH:41][C:40]=2[C:43]#[N:44])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)c(F)c4)c3cc2C#N)CC1
Temperature: 50 °C
Yield: 47.7 %

Procedure:
After adding dimethylformamide (4 ml), tert-butyl 4-(bromomethyl)-1-piperidine carboxylate (708 mg) and potassium carbonate (467 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (500 mg), the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate and the organic layer was washed with water and saturated saline in that order and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate) to obtain the title compound (398 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)ncn2Cc1ccccc1
Reactant: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(ncn2Cc2ccccc2)c1Br
Yield: 60 %

Procedure:
To a solution of 1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitate. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 0.90 g (2.5 mmol, 60%) of the product.
Reaction SMILES: C([O:8][C:9]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: COc1ccc(C#N)c(OCc2ccccc2)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C#N)c(O)c1OC
Reaction time: 4 h
Yield: 96.9 %

Procedure:
10% palladium on charcoal (2.0 g) was added to a solution of 2-benzyloxy-3,4-dimethoxybenzonitrile (20.8 g, 0.077 mol) in ethanol (250 ml) and the reaction stirred under a hydrogen atmosphere of 414 kPa (60 p.s.i.) for 4 hours. On cooling, the mixture was filtered through Arbocel™, washing with further ethanol. The filtrate was evaporated under reduced pressure to give the subtitle compound as a yellow solid (13.37 g, 97%). Rf 0.19 (dichloromethane). MS m/z 197 (MNH4)+.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:31][OH:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]([C:22]2[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=2)=[O:21])=[NH:18])=[CH:8][CH:7]=1.CO.O.[C:36]1(C)[CH:41]=CC(S(O)(=O)=O)=C[CH:37]=1>CC(C)=O>[CH3:37][C:36]1([CH3:41])[O:2][CH:3]([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]([C:22]3[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=3)=[O:21])=[NH:18])=[CH:10][CH:11]=2)[CH2:31][O:32]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N=C(NCCCCc1ccc(OCC(O)CO)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC1(C)OCC(COc2ccc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)cc2)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 185.6 %

Procedure:
Compound 33 (150 mg, 0.3 mmol) was suspended in dry acetone (50 mL) then methanol was added until a clear solution was formed (approx. 15 mL). p-Toluenesulfonic acid monohydrate (25 mg) was added along with molecular sieves (5 A) and the reaction mixture was stirred for 48 h at room temperature. After this time, the reaction mixture was filtered, silica gel (20 mL) was added and the solvent was removed under reduced pressure. This silica gel with the reaction mixture adsorbed was added to the top of a silica gel flash chromatography column. Compound 37 (120 mg, 81%) was isolated by flash chromatography (silica gel, 10:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) d 1.30 (s, 3H), 1.34 (s, 3H), 1.52 (br s, 4H), 2.56 (br s, 2H), 3.13 (br s, 2H), 3.71 (m, 1H), 3.92 (m, 2H), 4.08 (m, 1H), 4.45 (m, 1H), 6.64 (br s, 2H), 6.82 (m, 2H), 7.12 (m, 2H). APCI MS m/z=492 [C22H30ClN7O4+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:17][C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:50][C:51]([O:58][CH2:59][C:60]#[CH:61])([CH3:57])[C:52]([O:54][CH2:55]I)=[O:53]>C1COCC1>[CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([N:17]([CH2:55][O:54][C:52](=[O:53])[C:51]([CH3:50])([O:58][CH2:59][C:60]#[CH:61])[CH3:57])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Reactant: C#CCOC(C)(C)C(=O)OCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCOC(C)(C)C(=O)OCN(C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)[C@@H](CC(C)C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a light yellow solution of (S)-4-methoxybenzyl 4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanoate (2.16 g. 4.0 mmol) in THF (15 mL) at −50° C. was added KHMDS solution (1 M in THF. 5.0 mL, 5.0 mmol) dropwise maintaining the internal reaction temperature below −50° C. The mixture was stirred for 10 min and a solution of iodomethyl 2-methyl-2-(prop-2-ynyloxy)propanoate (1.58 g, 5.6 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with methanol (3 mL) and then diluted with ethyl acetate. The resulting mixture was washed with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel (hexanes/ethyl acetate=9:1 to 7:3) to afford compound (major spot, 1.9 g, 68.5% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@@H:12]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]2[CH3:19])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.N>C1COCC1.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@@H:12]3[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]3[CH3:19])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1CC(C)(C)C[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CC(C)(C)C[C@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
To a solution of Intermediate 87b (950 mg, 3.57 mmol), Ph3P (1.87 g, 7.14 mmol) and Et3N (1.44 g, 14.28 mmol) in THF (40 mL) was added hexachloroethane (1.65 g, 7.14 mmol) and the mixture stirred at RT for 20 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM gave the title compound as a clear oil (750 mg, 84%). 1H NMR (400 MHz, CDCl3): 1.22 (3H, s), 1.24 (3H, s), 1.84 (1H, dd, J 12.7, 10.8), 2.04 (1H, dd, J 12.4, 7.4), 2.16 (3H, s), 2.25 (1H, d J, 9.1), 3.04 (1H, d, J 9.3), 4.22 (1H, dd, J 10.0, 7.6), 7.14-7.23 (1H, m), 7.69-7.77 (1H, m), 8.75-8.80 (1H, m).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][C:13]([CH3:28])=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH:29]O.[OH-]>CO>[O:29]1[C@:14]2([C@:18]3([CH3:27])[C@@H:11]([CH2:12][C@@:13]12[CH3:28])[C@H:10]1[C@@H:21]([C@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9]1)[CH2:6][C@H:5]([OH:4])[CH2:24][CH2:23]2)[C:20](=[O:26])[CH2:19]3)[C:15](=[O:17])[CH3:16]
Reactant: OO
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=C(C)C[C@@H]32)C1
Agent: [OH-]
Solvent: CO
Product: CC(=O)[C@@]12O[C@]1(C)C[C@H]1[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]12C
Reaction time: 0.67 h

Procedure:
A solution of 20.0 g. of 3α-acetoxy-16-methyl-16-pregnene-11,20-dione dissolved in 600 ml. of methanol, is cooled to 18°C., and 80 ml. of 30% hydrogen peroxide followed by 80 ml. of 2.5 N sodiim hydroxide are added. Considerable material precipitates from solution, but all redissolves on stirring the reaction mixture at 25°-30°C. for 40 minutes. The solution is kept at 15°-20°C. for 18 hours at which time the ultraviolet maximum at 249 has completely disappeared. Then 600 ml. of saturated salt water is slowly added, the crystalline precipitate is filtered, washed with water, and dried in air and in vacuum. The 16α,17α-epoxy-3α-hydroxy-16β-methyl-pregnane-11,20-dione thus formed weighs about 17 g.