Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]([O:16]CC)=[O:15])[CH:5]=1)([CH3:3])[CH3:2].CC(C)([O-:22])C.[K+].O=O.S([O-])([O-])=O.[Na+].[Na+].O.[OH-].[Li+].Cl>O1CCCC1.O>[OH:22][C:1]([C:4]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)C)nc(C(F)(F)F)n1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: O=O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: -35 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 6-isopropyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (2.00 g, 7.63 mmol, from Step A) in tetrahydrofuran (40 mL) was added to 1.0M potassium tert-butoxide in THF (22.9 mL, 22.9 mmol) held at −40° C. After stirring for 45 minutes at this temperature, oxygen was introduced below the surface of the reaction solution via a syringe attached to a balloon containing oxygen. The oxygen was bubbled subsurface periodically (by addition and removal of an outlet) for 20 minutes, while maintaining the reaction temperature between −40 to −30° C. The reaction was then allowed to slowly reach room temperature with periodic bubbling of oxygen through the solution. Near a temperature of −30 deg C., the reaction turned from purple to orange in color. The reaction was kept under atmosphere of oxygen overnight, at which time the reaction was quenched with water and sodium sulfite (2 g, 20 mmol) was added. Lithium hydroxide, monohydrate (0.928 g, 22.1 mmol) was also added and the reaction was stirred overnight. Concentrated HCl was added drop wise into the reaction to achieve pH between 3 and 4. The layers were separated and the THF layer was reserved for addition to the subsequent two ethyl acetate extractions. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated, then azeotroped twice with MeOH to afford a yellow syrup which was used without further purification (1.7 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 1.57 (s, 6H); LCMS (M+H)+: 251.0
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([CH2:6][CH2:7]1)[C@@H:4]([C:9](O)=[O:10])[NH:3]2.[AlH4-].[Li+]>O1CCCC1>[C@H:2]12[CH2:8][C@H:5]([CH2:6][CH2:7]1)[C@@H:4]([CH2:9][OH:10])[NH:3]2
Reactant: O=C(O)[C@H]1N[C@@H]2CC[C@H]1C2
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1N[C@@H]2CC[C@H]1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid hydrogen chloride (500 mg, 3 mmol) in tetrahydrofuran (4.6 mL) was added lithium tetrahydroaluminate (1N solution in tetrahydrofuran, 5.7 mL, 6 mmol) dropwise over 10 minutes. The reaction mixture was stirred overnight at ambient temperature under an atmosphere of nitrogen. The reaction was quenched with a few drops of water, diluted with diethyl ether (50 mL) and tetrahydrofuran (25 mL). The reaction mixture was basified to a pH of ˜11 by the addition of potassium hydroxide pellets and then stirred vigorously for 30 minutes. The reaction mixture was filtered over sodium sulfate, concentrated in vacuo, redissolved in methylene chloride (10 mL), dried once more over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow crystalline solid, which was used in the next step without any further purification (400 mg, 100%).
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[C:37]4[CH2:39][NH:40][CH2:41][CH2:42][C:36]4=[N:35][C:34]=3[NH:43][CH:44]([CH3:46])[CH3:45])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.C=O>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[C:37]4[CH2:39][N:40]([CH3:2])[CH2:41][CH2:42][C:36]4=[N:35][C:34]=3[NH:43][CH:44]([CH3:45])[CH3:46])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (6.9 mg, 0.033 mmol) was added to a solution of DIPEA (6 μL, 0.033 mmol), (5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone TFA salt (8.9 mg, 0.016 mmol) and formaldehyde (1.5 μL, 0.016 mmol) in MeOH (160 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (2.2 mg, 24.1%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.81-1.94 (m, 2H), 1.96-2.05 (m, 2H), 2.85 (t, J=11.5 Hz, 2H), 3.00 (d, J=6.3 Hz, 2H), 3.07 (s, 3H), 3.44-3.53 (m, 4H), 3.71-3.82 (m, 1H), 4.14-4.23 (m, 2H), 4.28-4.37 (m, 1H), 7.28 (dd, J=10.6, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.1, 2.8 Hz, 1H), 7.75 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]2[CH2:13][CH:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH2:11]2)[CH:4]=1)[NH2:2].[CH3:24][C:25]([OH:27])=O>CC(N(C)C)=O.CC(N(C)C)=O>[CH3:4][C:5]1[N:6]=[C:7]([C@@H:25]([OH:27])[CH3:24])[N:1]([C:3]2[CH:4]=[C:5]([N:10]3[CH2:11][CH:12]([C:14]4[N:18]([CH3:19])[C:17]5[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=5[N:15]=4)[CH2:13]3)[N:6]=[C:7]([CH3:9])[N:8]=2)[N:2]=1
Reactant: CC(=O)O
Reactant: Cc1nc(NN)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Solvent: CC(=O)N(C)C
Product: Cc1nc(N2CC(c3nc4ccccc4n3C)C2)cc(-n2nc(C)nc2[C@H](C)O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Intermediate 2 (11.0 g, 35.6 mmol) in AcOH (100 mL) was added to crude Intermediate 13 (24.2 g, 89 mmol, prepared by heating the corresponding primary amide in neat DMA-DMA at 50° C. overnight followed by removal of excess DMA-DMA by rotary evaporation). The reaction mixture was allowed to stir for 10 min at room temperature and then heated at 80° C. for 1 h. Sampling of the reaction by LCMS suggested cyclization to the silyl-protected hydroxy triazole had occurred. The reaction was allowed to stir at 80° C. for an additional 16 h at which point complete de-silylation of the hydroxy group had occurred. The reaction was cooled to room temperature, poured carefully over saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% 2-propanol/DCM) to give Example 1 as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.76-7.74 (m, 1H), 7.35-7.28 (m, 3H), 6.96 (m, 1H), 6.62 (s, 1H), 5.12-5.07 (m, 1H), 4.71-4.58 (br s, 4H), 4.34-4.24 (m, 1H), 3.75 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H) 1.71 (d, J=6.6 Hz, 3H); MS: m/z=405.5 (M+H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:15]([NH:17][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14]>C(O)=O>[NH2:1][C@@H:2]([C:15]([NH:17][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14]
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1c(C#N)[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=CO
Product: CCCC[C@@H](NC(=O)[C@H](N)Cc1c(C#N)[nH]c2ccccc12)C(=O)OC
Yield: 98.5 %

Procedure:
A solution of Boc-DTrp(2-CN)-DNle-OMe (52 mg, prepared in Example (2-b)) in formic acid (5 mL) was stirred at room temperature for 1 h, and then evaporated. The residue was dissolved in ethyl acetate (60 mL) and the solution was washed with sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4 and evaporated under reduced pressure to give the product (40 mg).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.CN(C)C.[H][H]>[Pd].CO>[CH3:2][C:3]1[CH:4]=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:6]=[C:7]([NH2:9])[CH:8]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(Cl)Cl)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CN(C)C
Solvent: CO
Product: Cc1cc(N)cc(C(F)(F)F)c1
Yield: 83 %

Procedure:
At room temperature, 32.3 gms of crude nitrated product from Example V was added to a mixture of 150 ml MeOH and 30 gms (2.5 eq) of trimethylamine. The dark solution was charged with 1.6 gms of 50% wet 5% Pd/C catalyst and hydrogenated for 48 hours at 60° C. with hydrogen at 4 atms. The final solution was concentrated by distilling about half of the MeOH, diluted with 250 ml H2O and washed 3 times with 100 ml CH2Cl2. All of the organic extractions were combined, dried (Na2SO4), filtered and concentrated to 24 gms of a dark liquid which was Kugelrohr distilled at 95°-110° C./32 mm to 17.6 gms of light yellow colored crystals of 3-methyl-5-amino benzotrifluoride; mp 27°-28° C. (83% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:16]([N:15]([CH3:14])[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCCCNC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)C(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
2-Naphthoyl chloride (3.81 g 0.020 moles) dissolved in dichloromethane (10 ml) was added dropwise to an ice cold solution of N-methylbutylamine (1.74 g, 0.020 moles) and diisopropylethylamine (4.5 ml, 0.025 moles) in dichloromethane (40 ml). The mixture was stirred at room temperature for 18 hours and evaporated in vacuo. The residue was taken up into dichloromethane (50 ml), washed with 2M HCl (2×25 ml), dried (MgSO4) then evaporated in vacuo to give N-butyl-N-methyl-naphthalene-2-carboxamide (4.6 g, 0.019 moles) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].[H-].[Na+].Br[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O>CN(C)C=O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CCBr
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)c(NCCC(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
1.03 g (2.54mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1) was dissolved in 20 mL of dimethylformamide under argon atmosphere, 308 mg (7.62 mmol) of sodium hydride (60% oil dispersion) and 0.77 mL (6.4 mmol) of 1-bromo-3-methylbutane were added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, the mixture was extracted once with ethyl acetate, the organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:n-hexane=3:1) to give 708 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-5-(3-methylbutylamino)-4H-1-benzopyran-4-one (yield: 59%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=O)[CH2:8][CH2:7]1.S(Cl)(Cl)=O.[CH3:37][N:38]([CH:40]=O)[CH3:39]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([NH:6][C:12]2[CH:13]=[CH:14][C:15]([CH2:40][N:38]([CH3:37])[CH:39]3[CH2:25][CH2:24][O:23][CH2:20][CH2:19]3)=[CH:16][CH:11]=2)=[O:32])[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCCOC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.083 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (15 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (138 mg) and triethylamine (0.48 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 3 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:4→1:3→1:2), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 1-(3-methoxypropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 103) (264 mg) as yellow crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH2:17][CH2:18][CH2:19][OH:20]>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:17][CH2:18][CH2:19][OH:20])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: NCCO
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCO)OC2

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), 2-aminoethanol (0.5 ml, 24.9 mmol) and EtOH (1.0 ml). 1H-NMR (400 MHz, MeOH): δ 7.51 (1H, dd, J1 8.0 Hz, J2 1.6 Hz), δ 7.41 (1H, d, J 1.2 Hz), δ 7.32 (1H, d, J 8.0 Hz), δ 5.27 (1H, t, J 4.8 Hz), δ 5.09 (2H, dd, J1 50.0 Hz, J2 15.6 Hz), δ 3.68 (2H, t, J 5.6 Hz), δ 3.11 (3H, s), δ 3.02 (2H, t, J 4.0 Hz), δ 2.82 (2H, t, J 5.6 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].CO>C(Cl)Cl.CCN(CC)CC>[N:19]1([CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[CH:9]2[CH2:10][C:11]3[CH:12]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=3[CH2:7][CH2:8]2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(OC)cc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Compound 38a (3.21 g, 9.70 mmol) was dissolved in 120 ml of CH2Cl2 and cooled to −78° C. 1M boron tribromide (30 ml) was added dropwise and the mixture was allowed to warm to ambient temperature and was stirred overnight. Sat. NaHCO3 was added and the product extracted with dichloromethane, dried (Na2SO4), filtered, and concentrated to yield the crude product. Column chromatography (7:3:1 CH2Cl2:MeOH:Et3N) afforded 2.41 g (84%) of 39a. 1H NMR (400 MHz, CDCl3) 0.98-1.02 (t, 3H, 7.6 Hz), 1.27-1.31 (m, 2H), 1.70-1.82 (m, 3H), 2.25-2.28 (m, 1H), 2.58-2.06 (m, 1H), 2.73-2.78 (m, 4H), 2.97-3.09 (m, 5H), 3.16-3.20 (m, 9H), 6.45 (s, 1H), 6.53-6.55 (d, 1H, J=9.2 Hz), 6.84-6.85 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:34]C(OC)=O)[CH2:20][C@@H:21]3[O:29]C(OC)=O)=[CH:16][CH:15]4[O:39]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C[O-].[Na+]>CO.O>[CH3:44][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:34])[CH2:20][C@@H:21]3[OH:29])=[CH:16][C@H:15]4[OH:39])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COC(=O)OC1C=C2C[C@@H](OC(=O)OC)C[C@H](OC(=O)OC)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
In 5 ml of methanol was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7-tris(methoxycarbonyloxy)pregn-5-ene, followed by addition of 30 mg of sodium methoxide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured in water and extracted with methylene chloride. The extracts were pooled, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The concentrate was recrystallized from ethyl acetate to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-5-ene-1α,3β,7α-triol showing the following physical properties.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][O:16][CH3:17]>CCN(CC)CC.CS(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:15][O:16][CH3:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(I)cc2)on1
Reactant: COCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCOc1cc(-c2ccc(I)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of 5-(4-iodophenyl)isoxazol-3-ol (128 mg, 0.43 mmol) in Et3N/DMSO (10:1 v/v, 5.5 mL) at 0° C., chloro(methoxy)methane (45 mg, 0.64 mmol) was added dropwise. After stirring at 0° C. for 0.5 h, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as white solid (55 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 7.79 (d, 2H), 7.46 (d, 2H), 6.23 (s, 1H), 5.36 (s, 2H), 3.57 (s, 3H). LCMS: 332 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:49])[C:31]([CH3:48])([C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[CH3:32].N1C=CC=CC=1>C(Cl)Cl.Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:28][O:29][C:30](=[O:49])[C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[C:11]4[C:24]([F:27])([F:25])[F:26])[CH:18]=2)[CH:38]=1)([CH3:48])[CH3:32]
Reactant: COC(=O)C(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)c1cccc(Oc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenol (96 mg, 0.26 mmol), 2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (80 mg, 0.26 mmol), Cu(OAc)2 (47 mg, 0.26 mmol) and pyridine (42 μL, 0.52 mmol) were dissolved in 3 ml anhydrous CH2Cl2 and stirred at room temperature with crushed molsieves (4 Å) overnight. The reaction mixture was diluted with 1 M HCl (aq.) and the product was extracted three times with CH2Cl2. The combined organic phases were dried, evaporated and the crude material was purified by preparative HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 8.4 mg of analytically pure product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(N(CC)CC)C.[F:16][C:17]([F:34])([F:33])[C:18]1[CH:22]=[C:21]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[O:20][N:19]=1>C(Cl)(Cl)Cl>[Br:1][C:22]1[C:18]([C:17]([F:16])([F:33])[F:34])=[N:19][O:20][C:21]=1[NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Nc1cc(C(F)(F)F)no1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1onc(C(F)(F)F)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
N-Bromosuccinimide (64 mg, 0.35 mmol) and triethylamine (0.072 ml, 0.51 mmol) were added to a solution of N-(3-trifluoromethyl-5isoxazolyl)benzenesulfonamide(100 mg, 0.34 mmol)in chloroform (20 ml) at room temperature. The reaction was stirred at room temperature for 2 h. Chloroform (30 ml) was added and the solution was washed with 1N hydrochloric acid (40 ml), dried over magnesium sulfate and concentrated. The crude product was purified by HPLC to afford 114 mg (90%) N-(4-bromo-3-trifiuoromethyl-5-isoxazolyl)benzenesulfonamide as an off-white solid, m.p. 104°-105° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([OH:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[C:26]([CH2:28]O)[CH:25]=[CH:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([O:20][CH2:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([F:21])[CH:27]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCc2ccnc(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3′-hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (304 mg, 1.08 mmol), 2-Fluoro-4-pyridinemethanol (138 mg, 1.08 mmol), and triphenylphosphine (286 mg, 1.09 mmol) in THF (5 mL) was added diethyl azidocarboxylate (210 mg, 1.21 mmol) dropwise. The resulting clear brown solution was stirred at room temperature for 16 h, then concentrated in vacuo. The crude solids were purified by flash chromatography (silica gel, 1:2 EtOAc:Hexanes). Product 3′-(2-fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was obtained as white solid (113 mg, 26.9% yield).