Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]#[CH:11])[CH:9]=1
Reactant: C[Si](C)(C)C#Cc1cncc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Add a 1 M aqueous solution of potassium hydroxide (369.7 mmol, 370 mL) to a stirred solution of 3-bromo-5-trimethylsilanylethynyl-pyridine (85.4 g, 336.1 mmol), (prepared essentially as described in PREPARATION 22), in 850 mL of methanol at 15° C. Stir at room temperature for 2 h and concentrate. Dissolve the residue in 800 mL of dichloromethane, sequentially wash with water (160 mL) and an aqueous saturated solution of sodium chloride (160 mL), dry (magnesium sulfate) and concentrate with only slight heating to give the title compound as a pale volatile brown solid (53.84 g, 88%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:7]1[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccnc1-n1cccn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and powdered potassium carbonate (2 g) in DM[(10 mL) was stirred vigorously at room temperature for 4 days. The mixture was diluted with water, causing precipitation of a solid, which was filtered and dried, affording 670 mg (63%) of 3-nitro-2-(pyrazol-1-yl)pyridine. 1H NMR (CDCl3) δ6.51 (m, 1), 7.37 (dd, 1 J=5, 8), 7.76 (m, 1) 8.03 (dd, 1, J=2, 8), 8.40 (m, 1), 8.60 (dd, 1, J=2, 5).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:20]([O-:22])=[O:21])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOc1ccc(N)cc1
Solvent: CC(=O)OC(C)=O
Product: COCCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
4-(2-Methoxyethoxy)aniline (500 mg) was added to acetic anhydride (2.38 g) and the mixture was cooled down to 10° C. HNO3 (65% in water, 0.62 mL) was added slowly in order to keep the temperature of the reaction mixture below 15° C. After the end of the addition, the reaction mixture was allowed to warm to RT over 1 h, was quenched with ice-cold water and stirred for 10 min. The resulting suspension was filtered off and dried in high vacuo. The resulting yellow powder was dissolved in dioxane (1.4 mL), treated with 6N HCl (1.4 mL) and the reaction mixture was stirred at 70° C. for 3 h. After cooling down to RT, water was added and the pH was adjusted to 10 with 1M NaOH. The layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 303 mg of yellow solid. LC-MS (B): tR=0.99 min; [M+H]+: 213.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(C)cc1

Procedure:
The method described in Referential Example 242 was performed by use of p-toluidine and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24]OS(C)(=O)=O)[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.CS(O)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24][N:1]=[N+:2]=[N-:3])[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Temperature: 90 °C
Yield: 45 %

Procedure:
Sodium azide (1.10 g, 16.90 mmol) was added to the mixture of methanesulfonic acid 1-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-ylmethyl ester and methanesulfonic acid 3-(3,5-(difluoro-4-thiomorpholin-4-yl-phenyl)-3H-[1,2,3]triazol-5-ylmethyl ester, obtained in Example 9, in DMF (10 mL) and heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The solution was washed with water (100 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Removal of volatiles and purification of the residual material by silica gel column chromatography (eluent, 1:9-3:7 ethyl acetate/hexane) yielded compounds 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-4-ylmethyl azide (13A) (800 mg, 45%) followed by 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-5-ylmethyl azide (13B) (850 mg, 50%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[NH:6][S:5]1(=[O:17])=[O:16])[CH3:3].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[N:6]([CH2:22][CH:21]=[CH2:20])[S:5]1(=[O:17])=[O:16])[CH3:1]
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1c2ccc(SC)cc2CN(C(C)C)S1(=O)=O

Procedure:
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10 g, 0.0367 mol) was added to a suspension of sodium hydride (1.61 g, 60% dispersion) in dry dimethylformamide (200 ml) at room temperature under a nitrogen atmosphere. The pale grey suspension was stirred for ten mins, and then allyl bromide (3.49 ml, 0.0404 mol) was added in one portion. The reaction mixture was stirred at 80° C. for 3 hr. The mixture was then concentrated in vacuo to yield a brown residue. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. δ(1H NMR, DMSO, ppm): 1.1 (6H, d), 2.5 (3H, s), 4.1 (1H, m), 4.5 (2H, d), 4.7 (2H, s), 5.3 (1H, dd), 5.4 (1H, dd), 6.0 (1H, m), 7.0 (1H, d), 7.3 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:16][CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].O>CN(C)C=O>[N:27]([CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12](=[NH:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15][CH2:16]1)=[N+:28]=[N-:29]
Reactant: CS(=O)(=O)OCCC1CCN(C(=N)NC(=O)OCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCC1CCN(C(=N)NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
In 100 ml of dimethylformamide was dissolved 4.4 g (0.0115 mol) of crude 1-benzyloxycarbonylamidino-4-mesyloxyethyl piperidine and 4.5 g (0.069 Mol) of sodium azide was added. The mixture was heated at 100° C. for 2.5 h. It was then poured into water and extracted with ethyl acetate three times. The combined organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was flash chromatographed on silica gel using ethyl acetate/heptane 1/1 as eluent. Yield: 3.0 g (79%).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:10][Si:9]([Cl:11])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: C=CCCCC
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC[Si](Cl)(Cl)CC(C)c1ccccc1
Yield: 60.6 %

Procedure:
in the same apparatus and procedures as EXAMPLE 1, 5.0 g (0.023 mole) of 3-phenyl-1,1-dichloro-1-silabutane, 5.8 g (0.07 mole) of 1-hexene, and 100 μl of 1% chloroplatinic acid in isopropanol were placed and reacted under the dry nitrogen atmosphere. Vacuum distillation of the reaction products gave 4.23 g (bp, 115°-8° C./0.6 mmHg) of 4,4-dichloro-2-phenyl-4-siladecane.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:5]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc(F)c1O
Solvent: O
Product: O=C(O)c1cc2cccc(F)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
3-Fluorosalicylaldehyde (97.2 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 99.6 mg of 8-fluoro-3-carboxy-coumarin in a 68% yield.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]([Br:16])=[CH:8][N:7]=1>S(=O)(=O)(O)O>[CH3:15][O:14][C:12]([C:11]1[C:6](=[O:2])[NH:7][CH:8]=[C:9]([Br:16])[N:10]=1)=[O:13]
Reactant: O=N[O-]
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1nc(Br)c[nH]c1=O
Temperature: 3.5 °C

Procedure:
Concentrated sulphuric acid (5 ml) was stirred and cooled to 2-5° C. and sodium nitrite (0.7 g) added batchwise such that the reaction exotherm did not exceed 10° C. The reaction mixture was allowed to reach room temperature and then warmed to 40° for 2-3 minutes to give a homogeneous solution. The stirred reaction mixture was then cooled to 2°-5° C. and a cooled (2°-5° C.) solution of 2-amino-3-methoxycarbonyl-5-bromopyrazine (JACS, 1949, 71, 2798; 2.32 g) in concentrated sulphuric acid added dropwise so that the reaction temperature did not exceed 5° C. After the addition was complete, the reaction mixture was allowed to warm to 15° C. over three hours and then added dropwise to crushed ice (200 g). The resulting mixture was extracted with ethyl acetate. The organic phase washed with brine, dried with sodium sulphate and evaporated under reduced pressure to give the crude product as a yellow solid. The crude product was used in further experiments without further purification. A portion of the crude product was recrystallised from acetonepetroleum ether (boiling range 60°-80° C.) to give 3-methoxycarbonyl-5-bromopyrazine-2-one as a yellow solid:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:8][C:7]1[C:2]([C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][C:11]=2[CH3:10])[NH2:15])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1cnc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1-c1ncc(F)cc1F

Procedure:
To a round bottom flask is added 2-chloro-3,5-difluoropyridine (1.5 g, 10 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.2 g, 10 mmol), Pd(PPh3)4 (300 mg, 0.26 mmol), toluene (60 mL), ethanol (20 mL) and 2M Na2CO3 (20 mL, 40 mmol). The reaction is stirred under reflux condition for 15 hours. After cooling, the reaction mixture is diluted with ethyl acetate, washed with brine and dried over Na2SO4. The organic phase is then dried by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 3-(3,5-difluoropyridin-2-yl)-4-methylaniline as a light brown solid. MS m/z 221.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:13]CCC[CH2:9]2)=[CH:4][CH:3]=1.[N-]=C=O.ClC1C=C(C(C2C=C(Cl)C(O)=C(Cl)C=2)(C)C)C=C(Cl)C=1O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:9])=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Agent: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(O)c(Cl)c1
Agent: [N-]=C=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
1,1-bis(4-hydroxyphenyl)-cyclohexane, at a molar ratio of (1):(2) of from 100 mol %:0 mol % to 10 mol %:90 mol %,
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22](OC(C)(C)C)(=[O:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:25][C:23](=[O:24])[C:22](=[O:30])/[CH:2]=[C:1](/[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)\[OH:3])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(=O)/C=C(\O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
A solution of 4-acetylbenzonitrile (13.2 g, 90.9 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to −70° C. under nitrogen and sodium bis(trimethylsilyl)amide solution (1.0 M in THF, 100 mL, 100 mmol) added dropwise over 30 minutes. The solution was stirred at −70° C. for 1 hour before di-tert-butyl oxalate (22.1 g, 109 mmol) was added. The resulting suspension allowed to warm to room temperature and stir for 16 hours. The suspension was poured onto water (250 mL) containing ammonium chloride (53.5 g, 1.0 mol) and extracted with ethyl acetate (100 mL+50 mL). The organic layer was washed with water (100 mL) and concentrated under reduced pressure to afford a dark solid residue. The residue was triturated with diethyl ether (130 mL) and the residue filtered and dried under reduced pressure to give the title compound as a brown solid (7.13 g, 29%). 1H NMR (400 MHz, CDCl3): δ 1.40 (9 H, s), 7.01 (1 H, br), 8.01-8.23 (4 H, m).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)=[C:15]([Cl:28])[CH:14]=4)=[N:10][CH:9]=[N:8][C:7]=3[S:29][C:4]=2[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[H-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:28][C:15]1[CH:14]=[C:13]([NH:12][C:11]2[C:6]3[C:5]4[CH:30]=[CH:31][C:2]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:3][C:4]=4[S:29][C:7]=3[N:8]=[CH:9][N:10]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: C1COCCN1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(Br)ccc5c34)cc2Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(N6CCOCC6)ccc5c34)cc2Cl)c1
Temperature: 137.5 °C
Reaction time: 0.33 h
Yield: 57.4 %

Procedure:
To a stirring suspension of (7-bromo-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine (50 mg, 0.097 mmol) in morpholine (500 mg, 5.74 mmol) was added sodium hydride (60%, 15.5 mg, 0.388 mmol). The resulting mixture was bubbled with N2 for 2 min, followed by addition of 2-dicyclohexyphino-2′-(N,N-dimethylamino)biphenyl (1.91 mg, 4.86 μmol), and tris(dibenzylideneacetone)dipalladium (4.45 mg, 4.86 μmol). The mixture was further bubbled with N2 for 2 min, and stirred at 135-140° C. for 20 min. It was cooled to rt, and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2/CH3OH=8/1) to give the target product (29.0 mg, 57%). 1H-NMR (DMSO-d6) δ 8.83 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H), 7.73 (d, 1H), 7.61 (d, 1H), 7.51 (q, 1H), 7.43-7.48 (m, 1H), 7.28-7.32 (m, 2H), 7.21-7.25 (m, 2H), 7.16 (m, 1H), 5.25 (s, 1H), 3.78 (t, 4H), 3.26 (t, 4H). LCMS RT=3.90 min; [M+H]+=521.1.
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[CH:42]=[CH:41][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:28]=3)[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=3)=[O:17])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[N:2]1([C:6]([C:8]2[CH:42]=[CH:41][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][OH:32])[CH:28]=3)[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=3)=[O:17])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)nn1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO)c2)nn1C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
3.5M Hydrochloric acid (1.0 mL) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(1,5-dimethyl-1H-pyrazol-3-yl)benzamide (232 mg, 0.4 mmol) in methanol (10 mL). The reaction mixture was stirred for 45 minutes then saturated sodium bicarbonate added until the pH was adjusted to 7. The mixture was reduced in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed water (25 mL) and brine (25 mL). Dried (MgSO4) and reduced to a white foam. The crude product was purified by chromatography on silica, eluting with 0-10% methanol in ethyl acetate, to obtain the required product as a white foam (123 mg).
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[CH3:49][Mg]Br>O1CCCC1.S([O-])(O)(=O)=O.[K+]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:6]([CH2:5][C:4](=[O:47])[CH3:49])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: C[Mg]Br
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 1 h

Procedure:
To a stirred solution of 0.79 g of N-methoxy-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide in 10 ml of tetrahydrofuran are added 1.3 ml of a 3M solution of methyl magnesium bromide in tetrahydrofuran at 0° C. The reaction mixture is stirred for 1 hour, diluted with an aqueous solution of 1N potassium hydrogen sulfate, extracted with tert-butyl methyl ether. The organic phases are combined and dried over sodium sulfate. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.20 (EtOAc-heptane 1:1); Rt=5.14.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[CH:4][CH:3]=1.[Si]([C:17]#[N:18])(C)(C)C.CN(C)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:17]#[N:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc[n+]([O-])c2c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2ccc(C#N)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 7-methylquinoline N-oxide (1-2, 246 g, 1.54 mol, 1.0 equiv) in methylene chloride (5 L, 0.31 M) was added TMS-CN (414 ml, 3.1 mol., 2 equiv.) followed by dimethylcarbamoyl chloride (284 ml, 3.1 mol. 2 equiv), and the resulting mixture was stirred at room temperature overnight. The solution was quenched with saturated sodium bicarbonate, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent removed to give 260 g of crude material which was recrystallized from methanol to give 186 g of 7-methylquinoline-2-carbonitrile (1-3) in two crops. LRMS m/z (M+H)+ 169.1 found, 169.2 required.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.BrN1C(=O)CCC1=O.[CH:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:24]1([NH:31][CH2:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][C:4]=3[CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCCC1
Reactant: Cc1ccc2c(ccc3ccccc32)c1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)ccc1cc(CNC3CCCCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
2-Methylphenanthrene (2.00 g, 10.4 mmol) was brominated with N-bromosuccinimide (2.05 g, 11.5 mmol) and the product compound was added gradually to a suspension of cycloheptylamine (2.38 g, 21.0 mmol) and potassium carbonate (2.90 g, 21.0 mmol) in dimethylformamide (20 ml) with ice-cooling. The mixture was then stirred at room temperature for 16 hrs and, then, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2.11 g of a viscous liquid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH:5]=[CH:6][C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C:8]=3[CH2:9][CH2:10][C@@H:11]2[OH:22])=[CH:3]1.C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[C:2]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][O:21][C:20](=[O:21])[CH3:17])[C:4]([CH:5]=[CH:6][C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C:8]=3[CH2:9][CH2:10][C@@H:11]2[O:22][C:27](=[O:29])[CH3:28])=[CH:3]1)(=[O:1])[CH3:3]
Reactant: C[C@]12CC[C@H]3C(=C1CC[C@@H]2O)C=CC1=C[C@@H](O)CC[C@@]13CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C=C1C=CC1=C3CC[C@H](OC(C)=O)[C@@]3(C)CC[C@@H]12
Reaction time: 16 h

Procedure:
A mixture of 500 mg of 3β,17β,19-trihydroxyandrosta-4,6,8(14)-triene, 1.0 ml of pyridine and 0.5 ml of acetic anhydride was left to stand at room temperature for 16 hours in an atmosphere of nitrogen. Dilution with water, followed by extraction with ether and concentration at reduced pressure gave 3β,17β,19-triacetoxyandrosta-4,6,8(14)-triene as a white crystalline product.