Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([OH:39])=[C:34]([CH:38]=1)[C:35](Cl)=[O:36].[OH-].[Na+].Cl>C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([OH:39])=[C:34]([CH:38]=1)[C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:36]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1cc(Cl)ccc1O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.30 g (10.4 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry methylene chloride, add 9.56 g (88.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.34 g (13.30 mmol) of triethylamine and a solution of 1.67 g (8.85 mmol) of 5-chloro-2-hydroxybenzoyl chloride dissolved in 5 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 0.95 g (29%) of 4-[2-(5-chloro-2-hydroxybenzoylamino)benzoylamino]butanoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][N:6]=1.O.NN>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][NH2:9])=[CH:5][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cnc(Cl)s1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.2 %

Procedure:
2-[(2-Chloro-1,3-thiazol-5-yl)methoxy]-1H-isoindole-1,3(2H)-dione (Bionet, 5.0 g), was suspended in ethanol (120 ml) and hydrazine monohydrate (0.83 ml) was added. The mixture was heated to reflux and stirred at this temperature for 4 hours. The mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was evaporated under reduced pressure. The residue was re-suspended in diethyl ether (400 ml) and 4M HCl in dioxane (4.25 ml) was added. The solid material was isolated by filtration and dried under vacuum, and gave the title compound (3.3 g). 13C-NMR (DMSO-d6) δ 152.5, 143.3, 133.5, 66.9.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH:20](C1C=CN=CC=1)=C.BrC1C=C2C(=CC=1)NC=C2.CI>CN(C)C=O.O>[CH3:20][N:3]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: C=Cc1ccncc1
Reactant: C(=C/c1ccc2[nH]ccc2c1)\c1ccncc1
Agent: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cc(/C=C/c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride, 60% dispersion in oil (0.57 g, 14 mmol) was added portionwise to a suspension of (E)-4-(indol-5-yl)ethenylpyridine (2.82 g, 12.8 mmol) [prepared from 4-vinylpyridine and 5-bromoindole by an analogous procedure to Example 16] in dimethylformamide (100 ml). The mixture was stirred at room temperature, under nitrogen, for 1.5 h to give a red solution which was then cooled to 0° C. and treated dropwise with methyl iodide (0.88 ml, 14 mmol). The reaction mixture was stirred at 0° C. under nitrogen for 10 min, allowed to warm to room temperature and stirred for a further 30 min. The resulting suspension was diluted with water (200 ml), the solid collected under suction, washed with 5% aqueous sodium sulfite solution then water and dried in vacuo to afford the title compound as a buff solid (3.07 g); δH (CDCl3) 3.81 (3H, s, N-CH3), 6.51 (1H, dd, J 3.1, 0.7 Hz, 3'-H), 6.98 (1H, d, J 16.3 Hz, CH=CH), 7.07 (1H, d, J 3.1 Hz, 2'-H), 7.31-7.51 (5H, m, CH=CH, ArH), 7.78 (1H, d, J 1.4 Hz, 4'-H), 8.55 (2H, m, 2-H, 6-H-1).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OO)(=O)C.P(Cl)(Cl)([Cl:29])=O>C(O)(=O)C>[Cl:29][C:15]1[CH:14]=[CH:13][C:12]2[C:11]([C:9]([NH:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:10])=[C:20]([CH3:21])[CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2ncccc2c1C(=O)NCC1CCCCC1
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1ccc2nc(Cl)ccc2c1C(=O)NCC1CCCCC1

Procedure:
Prepared according to the method of example 43(a), using N-(cyclohexylmethyl)-6-methyl-5-quinolinecarboxamide (Example 57) (3 g), peracetic acid (3.3 g, 45% in acetic acid), glacial acetic acid (20 mL) and subsequently phosphorous oxychloride (20 mL) to afford the sub-titled compound (1.5 g).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C1OCCOCCOCCOCCOCCOC1>[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1][CH2:2][CH2:3][OH:4])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: OCCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CSCCO)cc1
Temperature: 25 °C
Yield: 119.3 %

Procedure:
β-Mercaptoethanol (3.3 mL, 47.2 mmol) was added to a suspension of 4-nitrobenzyl bromide (10.0 g, 46.3 mmol), K2CO3 (16.1 g, 116.5 mmol), KI (154 mg, 0.9 mmol), and 18-crown-6 (258 mg, 1.0 mmol) in acetone (105 mL). The mixture was refluxed under N2 for 1.5 h, cooled to room temperature, filtered through a pad of celite, and concentrated in vacuo. The filtrate was poured into water (100 mL) and extracted with Et2O (2×100 mL). The extracts were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil (11.78 g), which was used in the following step without purification. MS: M(C9H11NO3S)=213.26, (M−OH)+=196.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C(O)=O.[CH2:32]([NH:34][NH2:35])[CH3:33]>CO>[CH2:17]([C:16]1[N:34]([CH2:32][CH3:33])[N:35]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Cc1ccccc1
Reaction time: 15 h

Procedure:
1-(1-(t-Butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione from Step A, from Method A or Method B, Step B3, (0.851 g, 2.46 mmol) in methanol (25 mL) was added over 10 min to a suspension of ethylhydrazine oxalate (0.444 g, 2.96 mmol) in methanol (5 mL) in a 60° C. oil bath. After 15 h, the reaction was concentrated in vacuo and the residue was purified by repeated FC using a gradient of 50-100% ethyl acetate in hexanes to give first 4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(t-butoxycarbonyl)piperidine (0.148 g total) as the higher Rf product isomer and then the title compound (0.373 g total) as the lower Rf.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:2]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2Br)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (106 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was added 4-pyridinylboronic acid (70 mg, 0.56 mmol), sodium carbonate (0.28 mL, 2 M aqueous, 0.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (10 mg, 0.01 mmol). The resultant solution was heated to 100° C. for 18 hours. The reaction mixture was cooled to room temperature and ether was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ether) provided N-cyclopentyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (48 mg, 46%) as a yellow solid. 1H NMR (CDCl3): δ 8.50 (d, 2H), 7.53 (m, 2H), 7.22–7.18 (m, 3H), 7.06–6.97 (m, 3H), 6.00 (d, 1H), 5.95 (d, 1H), 3.99 (m, 1H), 2.16–2.08 (m, 2H), 1.83–1.66 (m, 6H); 13C NMR (CDCl3) δ 162.99 (d, JCF=246.6 Hz), 150.07, 149.98, 142.77, 141.98, 140.13, 131.02 (d, JCF=8.0 Hz), 129.04, 127.64, 123.98, 115.56 (d, JCF=21.2 Hz), 106.51, 102.22, 89.25, 53.88, 33.36, 24.05; 19F NMR (CDCl3) δ −113.49; MS m/z 373 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[CH:37]1([CH2:40][NH2:41])[CH2:39][CH2:38]1>C1(C)C=CC=CC=1.CO>[CH:37]1([CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:12][CH2:13]5)=[N:15][N:16]=4)[N:19]=3)=[CH:32][CH:31]=2)[CH2:39][CH2:38]1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(NCC1CC1)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (15 mg, 0.036 mmol) in toluene (0.2 mL) was added 2.0 M of trimethylaluminum in toluene (27 μL) at RT followed by addition of cyclopropylmethylamine (5.0 mg, 0.071 mmol). The mixture was stirred at 70° C. overnight. After cooling the mixture was diluted with methanol, and filtered. The filtrate was purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=462.4.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:15][C:14](=[O:16])[C@@H:13]([C:12]1[CH:18]=[CH:19][C:9]([Cl:8])=[CH:10][CH:11]=1)[OH:17]
Reactant: O=C(O)[C@H](O)c1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](O)c1ccc(Cl)cc1

Procedure:
Into toluene (20 ml) were added methanol (3.0 g), (R)-4-chloromandelic acid (5.0 g) and p-toluenesulfonic acid (0.1 g), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled, then washed with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off to obtain a colorless oily compound mentioned above (5.23 g, 97.5%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[C:24]([C:28]#[N:29])=[C:23]([CH3:30])[N:22]=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[N:22]=[C:23]([CH3:30])[C:24]([C:28]#[N:29])=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:18])[N:26]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCOCC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2CCOCC2)c1C#N
Temperature: 90 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (271 mg, 1.05 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (194 mg, 1.149 mmol) and Et3N (0.29 mL, 2.1 mmol) in DMF (5 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the product were combined and lyophilized to give the title compound as a white solid (27 mg, 6.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.53 (m, 3 H), 1.58-1.86 (m, 3 H), 1.91-2.11 (m, 1 H), 2.18-2.29 (m, 3 H), 2.99-3.17 (m, 1 H), 3.37-3.61 (m, 2 H), 3.75-3.90 (m, 3 H), 3.90-4.10 (m, 2 H), 5.63-5.80 (m, 1 H), 6.44-6.57 (m, 1 H), 6.97-7.25 (m, 2 H), 7.32-7.45 (m, 1 H), 7.55-7.65 (m, 1 H), 7.83-7.97 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H25N2O, 392; found 392.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:31]=2)=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:34])=O.O>N1C=CC=CC=1.C(Cl)(Cl)Cl.C1COCC1.C(OCC)(=O)C>[Cl:34][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([C:16]2[CH2:17][CH2:18][O:19][C:13]3[CH:12]=[CH:11][C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[CH:31][C:14]=3[CH:15]=2)=[O:21])=[CH:24][CH:25]=1
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCO3)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reaction time: 20 h

Procedure:
To a suspension of 7-(4-ethoxyphenyl)-N-(4-hydroxymethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (2.55 g) and pyridine (2 drops) in chloroform (50 ml) was added thionyl chloride (0.8 ml) at room temperature, and the mixture was stirred for 20 hours. To the reaction mixture was added water and then THF, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give solid, which was dissolved in THF and ethyl acetate. The mixture was concentrated under reduced pressure to give crystals, which were collected by filtration and washed with diisopropylether to give N-(4-chloromethylphenyl)-7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (2.42 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:16][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:18][CH:19]=2)[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].[CH3:30][S:31]([NH:34][C:35]1[CH:45]=[CH:44][C:38](/[CH:39]=[CH:40]/B(O)O)=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[C:10]([C:6]1[C:7]([O:8][CH3:9])=[C:2]([CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[N:16][C:17]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:18][CH:19]=2)[CH:5]=1)/[CH:40]=[CH:39]/[C:38]1[CH:37]=[CH:36][C:35]([NH:34][S:31]([CH3:30])(=[O:32])=[O:33])=[CH:45][CH:44]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: CS(=O)(=O)Nc1ccc(/C=C/B(O)O)cc1
Reactant: COc1c(Br)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
The product from Example 2 Part A (55.9 mg, 0.12 mmol) and (E)-4-(methylsulfonamido) styrylboronic acid (28.9 mg, 0.120 mmol) were reacted in the same manner as Example 2 Step B. The crude product was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (5% to 25%) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:43]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCN)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCNC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
A solution of 192.4 mg of crude tert-butyl (3RS,4RS)-4-[4-(2-amino-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 3 ml of methylene chloride was treated at 0° C. with 51.7 ml of triethylamine and 64.9 mg (0.462 mmol, 2.0 eq.) of benzoyl chloride and the mixture was stirred at 0° C. for 0.75 hr and at room temperature for 3 hours. The reaction mixture was poured into an ice/water mixture, made basic with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The colourless oil was separated on silica gel using a 95:5 mixture of methylene chloride and acetone as the eluent. There were obtained 44.9 mg (33% of theory) of tert-butyl (3RS,4RS)-4-[4-(2-benzoylamino-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in the form of a light yellow oil; MS: 581 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[OH-].[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO.O.Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])/[CH:11]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)=O)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)/C=C/c2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 1-(2-bromo-4-methoxyphenyl)ethanone (6.2 g, 27.06 mmol) obtained in Step 1 in EtOH (50 mL) at 0° C. was added sequentially aq. NaOH solution (8.12 mL, 81.19 mmol, 3 eq) and benzaldehyde (3.3 mL, 32.48 mmol, 1.2 eq). After being stirred for additional 4 h at room temperature, the mixture was diluted with H2O and neutralized with 3N HCl. The resulting mixture was extracted with EtOAc (20 mL×3). The extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to obtain the desired product (6 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].Cl[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][C:5](=[O:9])[N:6]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:7]=1[CH3:8]
Reactant: CSc1nc(=O)[nH]c(C)c1Cl
Reactant: ClCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(=O)n(Cc2cccs2)c(C)c1Cl
Yield: 13.6 %

Procedure:
A suspension of 5-chloro-6-methyl-4-methylthiopyrimidin-2-one (1.768 g), 2-chloromethylthiophene (1.505 g) and potassium carbonate (2.499 g) in dry N,N-dimethylformamide (20 ml) was stirred and heated at ca 90° C. for 30 min. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate (200 ml) and water (50 ml). The organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated to a brown solid. Preparative layer chromatography on silica developing with chloroform-ethanol (20:1, two runs) gave a solid which was crystallised from acetone to give cream crystals of the title pyrimidinone (362 mg) m.p. 173°-176° C.; λmax (EtOH) 231.5 nm (ε 17030), 276 nm (ε 9360), 320 nm (ε 10010).
Reaction SMILES: [CH:1]1([C:6]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([C:6]([OH:28])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C(O)(c1ccccc1)C1CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H]1CCNC1)C(O)(c1ccccc1)C1CCCC1
Reaction time: 10 h

Procedure:
The compound 2-cyclopentyl-2-hydroxy-N-[(3S)-1-benzyl-pyrrolidin-3-yl]-2-phenyl-acetamide (0.8 g, 2.12 mM) was dissolved in methanol (20.0 ml) and 10% palladium on carbon (0.2 g) is added. After hydrogenating at room temperature for 10 hours at 65-70 psi, the second lot of 10% palladium on carbon (0.2 g) was added and hydrogenation was continued for 10 more hours at 65-70 psi at room temperature. The reaction mixture was diluted with methanol and filtered through a bed of hyflo. The filtrate was concentrated under vacuum and used as such in the next step.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccc3ccc4c(-c5ccc(F)cc5)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixed solution of 2 g of 1,6-dibromopyrene, 2.3 g of 4-fluorophenylboronic acid, 7.0 g of tripotassium phosphate, 1.1 g of tetrabutylammonium bromide, 74 mg of palladium acetate and 50 ml of dimethylformamide was heated with stirring under a nitrogen gas flow at 130° C. for 6 hours. After cooling the solution to room temperature, 50 ml of water was injected, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resultant solid was washed with 30 ml of methanol and then vacuum-dried to obtain 1.8 g of 1,6-bis(4-fluorophenyl)pyrene.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(O)(=[O:30])C>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:30])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Agent: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
βAET was synthesized using 3β,17β- diacetoxyandrost-5-ene as a starting material. Chromic oxide oxidation of 3β,17β-diacetoxyandrost-5-ene in glacial acetic acid by the method of Butenandt (op. cit.) gave 3β,17β-diacetoxyandrost-5-en-7-one, (III), the intermediate for preparation of (I). Aluminum isopropoxide reduction of (III) in isopropanol by the method of Butenandt gave (I).