Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Yield: 63.6 %

Procedure:
A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5 g, 0.131 mol), 3-bromopropylamine hydrobromide (42.93 g, 0.196 mol), potassium carbonate (36.14 g, 0.241 mole), and KI (10.8 g, 0.065 mol) in 1,4-dioxane (500 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6N NaOH (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (K2CO3) CH2Cl2 extracts and the residue was purified by column chromatography on silica gel using CHCl3/MeOH/2M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (24.2 g, 83.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([O:21][CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of trans-N-t-butoxycarbonyl-4-(3-methylphenyl)-3 hydroxy piperidine (117 mg, 0.402 mmol), in DMF (2 ml) at 0° C. was added sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.803 mmol). After 10 min, methyl iodide (0.050 ml, 0.803 mmol) was added and the reaction allowed to warm to room temperature over 16 hrs. The reaction was quenched by the addition of saturated NH4Cl solution (5 ml) and extraction with EtOAc. The organic extracts were washed with brine and dried, (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 10-15% EtOAc in hexanes) afforded the title compound as an oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[OH:14]>ClCCl>[F:6][C:7]1[C:8]([OH:14])=[CH:9][C:10]([CH3:13])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(O)c(F)cc1S(=O)(=O)Cl
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
To a solution of chlorosulfonic acid (1.5 g, 13.3 mmol) dissolved in 10 mL of dichloromethane was added 2-fluoro-5-methylphenol (1.1 g, 8.86 mmol) dropwise. After 10 minutes, the reaction was quenched by adding to ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 150 mg (7.5%) of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])[C:17]([O:19][CH2:20]C)=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Br:29])=[N:9][NH:10]2)(=O)C.C[O-].[Mg+2].C[O-]>CO>[Br:29][C:8]1[C:7]2[C:11](=[C:12]([Br:28])[CH:13]=[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]([O:19][CH3:20])=[O:18])[C:6]=2[CH2:5][OH:4])[NH:10][N:9]=1
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1COC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-3,7-dibromo-1H-indazol-5-yl)methyl)succinate(540 mg, 1.011 mmol) was dissolved in methanol (12 mL). 6-10% Magnesium methoxide solution in methanol (2.7 mL, 2.041 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 5 mL 1N hydrochloric acid. Mixture stirred at room temperature for 30 minutes. Methanol was removed from the mixture by roto-vap. Residue was dissolved in water and then made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white foam in 99% yield. 1H NMR, MS (M−H)−=463.1, 461.1, 465.1.
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:21])[N:4]=1.[CH3:22][NH2:23]>CO>[CH3:20][CH:14]1[C:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:3]([NH:23][CH3:22])=[N:4][C:5]([CH3:21])=[N:6]3)=[CH:11][CH:10]=2)=[N:18][NH:17][C:16](=[O:19])[CH2:15]1
Reactant: CN
Reactant: COc1nc(C)nc2cc(C3=NNC(=O)CC3C)ccc12
Solvent: CO
Product: CNc1nc(C)nc2cc(C3=NNC(=O)CC3C)ccc12
Reaction time: 4 h
Yield: 76 %

Procedure:
In 20 ml of 40% methylamine solution in methanol was suspended 0.50 g of Compound 63 obtained in Example 65. The suspension was heated under reflux with stirring for 4 hours and then concentrated. The residue was subjected to partition between water and chloroform, and the organic layer was dried and concentrated. The residue was crystallized from a mixture of dimethylformamide and water to give 0.38 g (76%) of 4,5-dihydro-5-methyl-6-(4-methylamino2-methylquinazolin-7-yl)-3(2H)-pyridazinone (Compound 64).
Reaction SMILES: CO.[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[H][H]>[C].[Pd].O>[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: NC(=O)c1ccc(/C=C/C2CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(CCC2CCNCC2)cc1
Yield: 56 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a methanol (15 ml)/water (5 ml) solution containing 4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (800 mg), followed by stirring in a hydrogen gas atmosphere at room temperature under normal pressure for 4 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from ethanol/acetonitrile to obtain 4-(2-piperidin-4-ylethyl)benzamide hydrochloride (451 mg) (Reference Example 58).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[NH2:28][OH:29]>CO.CCOC(C)=O>[NH2:25]/[C:24](=[N:28]\[OH:29])/[C:22]1[N:21]=[C:20]([Cl:26])[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[CH:23]=1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(/C(N)=N/O)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 80 °C
Yield: 33 %

Procedure:
3,4-Dichloro-N-[1-(2-chloro-6-cyanopyrimidin-4-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 199, 150 mg, 0.36 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol) and TEA (0.05 ml, 0.36 mmol) were combined in MeOH (5 ml), and the reaction was heated at 80° C. for 2 h. The reaction was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried (sodium sulfate), filtered and concentrated to give a pale yellow solid. The crude material was purified by preparatory HPLC, using a gradient of 35-75% acetonitrile/water (0.1% TFA) to give 53 mg of the title compound.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]12([C:22]([NH:24][NH2:25])=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:25]/[NH:24][C:22]([C:12]23[CH2:21][CH:16]4[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]4)[CH2:19]2)[CH2:13]3)=[O:23])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NNC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Yield: 59 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and adamantanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 59%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.27 (m, 6H), 1.60-1.65 (m, 2H), 1.72 (s, 6H), 1.91 (s, 6H), 2.05 (s, 3H), 3.75 (t, J=7.2 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 13.28 (br s, 1H). 13C NMR (DMSO-d6): δ 14.32 (CH3), 22.44 (CH2), 26.38 (CH2), 27.41 (CH2), 27.85 (CH), 31.31 (CH2), 36.32 (CH), 38.80 (CH2), 39.52 (CH2), 110.59 (CH), 119.75 (C), 121.03 (CH), 123.61 (CH), 131.96 (CH), 143.27 (C═N), 161.39 (C═O). HRMS (ES+) calcd for C25H34N3O2 (M+H+), m/e, 408.2660. found, 408.2646.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1>CCOC(C)=O>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH:18]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Brc1cncc(Br)c1
Solvent: CCOC(C)=O
Product: CSc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure Coupling-2 using [3-(methylthio)phenyl]boronic acid and 3,5-dibromopyridine as starting material. Flash chromatography (Hex:EtOAc; 95:5-85:15) afforded the title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (2.0 g) was dissolved in dimethylformamide (20 ml), and benzoyl chloride (0.42 ml) and triethylamine (1.5 ml) were added under ice-cooling. The mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After the solvent was evaporated, the residue was recrystallized from ethyl acetate to give 0.3 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)benzamide.
Reaction SMILES: [Li][CH2:2]CCC.[O:6]([C:13]1[CH:14]=[C:15]([C:19]23[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH2:29][CH:30]=O)([CH2:23][CH2:24]2)[CH2:21][O:20]3)[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:27]([C:22]12[CH2:25][CH2:26][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:14]=3)([CH2:24][CH2:23]1)[O:20][CH2:21]2)[CH2:28][CH2:29][CH:30]=[CH2:2]
Reactant: O=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a 0° C. mixture of methyl triphenylphosphonium bromide (236 mg, 0.66 mmol) in THF (8 mL) was added dropwise n-BuLi (0.27 mL of a 2.5 M solution in hexane, 0.66 mmol). The reaction mixture was stirred at 0° C. for 30 min, and a solution of 4-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanal (116 mg, 0.33 mmol) in THF (2 mL) was added at 0° C. The reaction mixture was warmed to rt and stirred for 2 h, then was quenched with sat′d aq. NH4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2; gradient from 0 to 30% EtOAc:hexanes) to afford the title compound as a colorless oil (94 mg; 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 4H), 7.16-7.05 (m, 2H), 6.98 (dd, J=8.7, 1.0 Hz, 2H), 6.83 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.79 (ddt, J=17.0, 10.3, 6.6 Hz, 1H), 5.03-4.93 (m, 1H), 3.79 (s, 2H), 2.06-1.93 (m, 5H), 1.70-1.52 (m, 6H), 1.48-1.22 (m, 3H), 1.21-1.03 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH3:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[CH2:42]>CCCCCCC>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:41]([CH3:42])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:40])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1
Reactant: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Reactant: C=C(C)c1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCCCCCC
Product: CC(C)(c1ccccc1)c1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Temperature: 160 °C
Reaction time: 26 h
Yield: 65.9 %

Procedure:
To a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, dropping funnel, condenser, thermometer, and a nitrogen atmosphere are charged 5.00 g (14.7 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-phenyl-s-triazine and 300 mg of aluminum isopropoxide. The mixture is heated to 160° C. and 17.3 g of α-methylstyrene are added all at once. After stirring at this temperature for 26 hours the mixture is allowed to cool and a portion of heptane is added. Vacuum filtration affords 4.45 g of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][C:13]([C:15]3[C@@:21]([CH3:22])([C@H:5]1[CH2:4][CH2:3]2)[CH:20]=[CH:19][C:17](=[O:18])[CH:16]=3)=[CH2:14].[BH4-].[Na+]>CO.O>[CH3:1][C@@:2]12[CH:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][C:13]([C:15]3[C@@:21]([CH3:22])([C@H:5]1[CH2:4][CH2:3]2)[CH:20]=[CH:19][C:17](=[O:18])[CH:16]=3)=[CH2:14]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Reaction time: 72 h

Procedure:
17-dihydroexemestane is prepared from exemestane as described in Mareck, U. et al., Rapid Commun Mass Spectrom, 20: 1954-62, 2006 with minor modifications. Briefly, exemestane and NaBH4 are individually dissolved in methanol/water (4:1, v/v). For reduction of the 17-keto functional group of exemestane, NaBH4 is slowly added to the suspended exemestane in a 1:2 molar ratio. The mixture is left at ambient temperature for at least 1 h and then assayed by thin layer chromatography to ensure reaction completeness prior to solvent removal by vacuum. After dissolving the dry residue in 1.5M HCl, 1M KOH (500 μL) is added. The mixture is extracted by ethyl ether, dried by vacuum, and re-dissolved in 30 ml ethyl ether:hexane (1:1) at 50° C. After 3 days, the formed crystals are washed with hexane and dried by vacuum. The synthesized 17-dihydroexemestane structure is characterized by a Bruker 500 MHz nuclear magnetic resonance (NMR) spectrometer and HPLC/MS/MS, with the MS spectrum resulting in a clear peak at m/z 299 [M]+ and a daughter product at m/z 135.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([OH:16])[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].I[CH2:20]C>CN(C=O)C.CCOC(C)=O>[CH3:20][O:16][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[C:10]2[C:5]=1[NH:4][N:3]=[C:2]2[CH3:1]
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(C)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a 0° C. solution of ethyl 3-methyl-7-hydroxy-1H-indazole-5-carboxylate (0.84 g, 3.8 mmol) in DMF (25 mL) was added 60% oil dispersion of NaH (152 mg, 3.81 mmol). After stirring for 1 hour at 0° C., a solution of iodoethane (595 mg, 0.31 mL, 3.81 mmol) in DMF (3 mL) was added. The mixture was kept at 0° C. for several hours before allowing the mixture to warm to room temperature while stirring overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, water, saturated aqueous NaCl and the organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (516 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:11]3[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(OC)cc(-c2ccc3[nH]ccc3c2)c1
Temperature: 85 °C
Reaction time: 13 h

Procedure:
A mixture of methyl 3-methoxy-5-trifluoromethanesulfonyloxybenzoate (314 mg, 1.00 mmol), 5-indoleboronic acid (193 mg, 1.20 mmol), tetrakis(triphenylphosphine)palladium(0) (57.8 mg, 0.050 mmol), potassium phosphate (318 mg, 1.50 mmol) and 1,2-dimethoxyethane (5.0 ml) was stirred in a nitrogen atmosphere at 85° C. for 13 hours. After left cooled, the reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (270 mg, 0.70 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.61 ml, 3.51 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (361 mg, 0.77 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (232 mg, 0.32 mmol, 46% yield) as a clear oil: LCMS (ES) m/e 615, 617 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:20][CH3:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[C:8]([NH2:22])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:23]1([CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:20][CH3:21])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=3[NH2:22])[CH2:26][CH2:25][CH2:24]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCN3CCC3)c2n1
Temperature: 50 °C
Yield: 7.2 %

Procedure:
2-(Butyloxy)-9-(4-chlorobutyl)-8-(methyloxy)-9H-purin-6-amine (100 mg, 0.305 mmol), azetidine (0.021 ml, 0.305 mmol) and N,N-diisopropylethylamine (0.107 ml, 0.610 mmol) were dissolved in DMF (2 ml) and heated at 50° C. for 48 hours. LCMS indicated the reaction to be incomplete and additional azetidine (0.021 ml, 0.305 mmol) and N,N-diisopropylethylamine (0.107 ml, 0.610 mmol) were added and the reaction mixture heated at 50° C. for a further 48 hours. The mixture was then partitioned between DCM (4 ml) and water (4 ml) and the layers separated using a hydrophobic frit. The aqueous phase was re-extracted with DCM (4 ml) and the combined organic extracts were concentrated and the residue purified by MDAP (Method A). The product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (7.6 mg).
Reaction SMILES: CCC(OOC(OO)(CC)C)([O:5]O)C.[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:18]([OH:19])[C:17]=1O>>[CH3:15][C:16]1[CH:17]=[C:18]([OH:19])[CH:20]=[C:21]([CH3:23])[C:22]=1[OH:5]
Reactant: CCC(C)(OO)OOC(C)(CC)OO
Reactant: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 56 except that 11.2 g. (P=67.7) of methyl ethyl ketone peroxide was used instead of 4-methyl-2-pentanone peroxide, 4.68 g. (33.9 m.moles) of 3,5-dimethylcatechol and 2.17 g. (15.7 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 73.3%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[CH2:12]1[O:14][CH2:13]1>C(O)C>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][OH:14])[CH3:2]
Reactant: CCCCCCCCNCC
Reactant: C1CO1
Solvent: CCO
Product: CCCCCCCCN(CC)CCO
Yield: 80.6 %

Procedure:
A mixture of 15.7 g of ethyl-n-octylamine, 5 g of ethyleneoxide and 100 ml of 96% ethanol was held at 100° C. for one hour in a steel autoclave. The reaction mixture was distilled and gave 16.2 g of N-ethyl-N-n-octyl-ethanolamine, b.p. 85°-87° C./0.2 mm Hg, nD22 = 1.4490.