Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH2:4][NH:3]1.[H][H].CO>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[N:14]=2)[CH2:4][NH:3]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc5c4C(=O)NC5)n3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc5c4C(=O)NC5)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
tert-Butyl 4-(4-((4-((3-oxoisoindolin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I62) (0.149 g, 0.258 mmol) was dissolved in dry DMF (6 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.090 g) in EtOAc (6 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a yellow solid which was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I63) (0.084 g, 56% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.98 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 7.62-7.55 (m, 2H), 7.44 (t, J=7.4 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.17 (brd, J=6.0 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 3.56 (t, J=7.6 Hz, 2H), 3.51-3.41 (m, 4H), 3.12 (t, J=7.5 Hz, 2H), 3.08-2.98 (m, 4H), 1.42 (s, 9H). LCMS Method A: rt 5.86 min; m/z 583.5 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)(=O)C>[CH2:13]([O:12][C:10]([C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2])=[O:11])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)ccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of hydroquinone in 500 ml of acetic acid, 108.5 g(1 mol) of ethyl chloroformate was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of methylene chloride was added to the reaction mixture, and the unreacted excess hydroquinone was filtered and collected (recoverd amount: 110 g, recycled without any purification process). A desired mono ethoxycarbonyl hydroquinone was obtained by evaporating the residue under vacuum. (Yield: 164.6 g(98%). mp: 81-82° C., 1H-NMR(200 MHz, CDCl3, ppm) 1.38 (t, 3H), 4.31 (q, 2H), 5.57 (br, 1H) 6.72 (d, 2H), 6.98 (d, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])C.C(Cl)(Cl)Cl>O1CCOC1>[O:31]1[CH2:34][CH2:33][O:32][CH:29]1[C@@H:10]1[C@@H:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[O:13][C:12](=[O:14])[CH2:11]1
Reactant: CCOC(C)=O
Reactant: O=C1C=C[C@@H](COC2CCCCO2)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: O=C1C[C@H](C2OCCO2)[C@@H](COC2CCCCO2)O1

Procedure:
A solution containing 136 mg (0.686 mmol) compound (2f) and 18.7 mg (0.103 mmol) benzophenone in 100 mL [1,3]-dioxolane was irradiated at 20° C. for 5.75 hours according to the general procedure. Column chromatography (silica gel 40 g, ethyl acetate in hexanes 60%) gave compound (3f) as two diastereomers (170 mg, 91%) as a colorless oil, Rf=0.25, [α]25D −129°, c 0.8, CHCl3. 1H-NMR (300 MHz, CDCl3) δ: 1.38-1.82 (m, 6H), 2.40-2.46 (m, 1H), 2.60-2.75 (m, 2H), 3.39-3.48 (m, 1H), 3.61-3.70 (m, 1H), 3.75-3.81 (m, 2H), 3.84-3.87 (m, 2H), 3.93-3.98 (m, 2H), 4.53-4.63 (m, 2H), 4.86-4.89 (m, 1H). 13C-NMR (75.4 MHz, CDCl3, Dept) diastereomer A: δ: 18.72 (−), 25.20 (−), 29.98 (−), 30.02 (−), 40.08 (+), 61.52 (−), 64.68 (−), 65.33 (−), 68.33 (−), 78.98 (+), 98.21 (+), 103.64 (+), 176.51 (quat); B: δ: 19.23 (−), 25.20 (−), 30.21 (−), 30.24 (−), 40.08 (+), 62.20 (−), 65.05 (−), 65.45 (−), 68.81 (−), 79.08 (+), 99.09 (+), 103.71 (+), 176.72 (quat). C13H20O6; Exact Mass: 272.13; Mol. Wt.: 272.29; C, 57.34; H, 7.40; O, 35.25.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](O)=[O:40].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:33])[CH:7]([NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccco1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (350 mg, 0.77 mmol) and 2-Furoic acid (87 mg, 0.77 mmol, 1 equiv.) in DMF (6 mL) was added BOP reagent (409 mg, 0.92 mmol, 1.2 equiv.) and Hunig base (0.16 mL, 0.92 mmol, 1.2 equiv.) under N2. The mixture was stirred at room temperature overnight. Reaction was complete was determined by LC-MS. The reaction mixture was then poured onto cold water. Solid precipitated from the mixture was collected by filtration. The solid was then dissolved in EtOAc, washed with 1N HCl, saturated NaHCO3, and brine, and then dried over MgSO4. After removing the solvent, the solid was dried under vacuum overnight to provide 2-({4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester in 87% yield (369 mg). MS (ESI) m/z 549.
Reaction SMILES: [C:1]1(C(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]O.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O:22]C(OC(OC)=O)=O>CC(C)=O>[C:1]1([OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:19]
Reactant: CC(C)c1ccccc1
Reactant: COC(=O)OC(=O)OC
Agent: [O-]O
Solvent: CC(C)=O
Product: C=C(C)c1ccccc1
Product: Oc1ccccc1

Procedure:
It has been discovered that when a cumene oxidation product mixture containing cumene hydroperoxide (CHP) and DMPC is decomposed to produce phenol, acetone and alpha-methyl styrene, by passing the cumene oxidation product mixture into a vessel having a liquid hourly space velocity (LHSV) from about 10 hr−1 to about 30 hr−1 and then passing the cumene oxidation product mixture into a circulating loop comprising cumene hydroperoxide, an acid catalyst, phenol and acetone thereby producing an exothermic heat of reaction, an improved yield of alpha-methyl styrene is realized. The cumene oxidation product mixture is the result of cumene oxidation with oxygen and preferably comprises a cumene hydroperoxide concentration from about 60 to about 95 weight percent. The ratio of the flow rate of the cumene oxidation product mixture to the flow rate of the circulating loop is preferably from about 1:10 to about 1:100. In accordance with the present invention, a suitable and preferred acid catalyst is sulfuric acid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:20]=2)[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:10])([CH3:9])[CH3:11])=[O:4]
Reactant: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1)C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate (0.68 g, 2.2 mmol) and methyl thiosalicylate (0.60 g, 3.6 mmol) were dissolved in toluene (2.5 ml), and triethylamine (0.56 ml, 4.0 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 53%) as white crystals.
Reaction SMILES: [CH2:1]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])CCC(OC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:32]O>C(O)(C)C>[CH2:1]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[OH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OO
Reactant: CCCCCCCCCCCCN(CCCCCCCCCCCC)CCC(=O)OC
Solvent: CC(C)O
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 43.4 %

Procedure:
Using the general procedure of Example 2, 87.6 grams (0.2 mol) of the product of Example 5 in 800 ml of isopropanol is oxidized using 9.7 ml (0.25 mol) of 70% aqueous hydrogen peroxide solution to give 32.1 grams (44% yield) of the above-named product as a white solid melting at 85°-86° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32]([O-:35])([O-:34])=O.[Na+].[Na+].CN([CH:41]=[O:42])C>>[C:22]1([CH:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)[C:32]([O:35][CH2:16][C:14]([O:42][CH3:41])=[O:15])=[O:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: COC(=O)COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of intermediate (2) (0.0117 mol) and Na2CO3 (0.0141 mol) in DMF (100 ml) was stirred at room temperature. A solution of intermediate (43) (0.0141 mol) in DMF (80 ml) was added dropwise. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated. The residue was stirred in DCM (150 ml). The organic layer was washed with water, washed with a saturated NaHCO3 solution and washed with water. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The desired fractions were collected and the solvent was evaporated. The residue was stirred in DIPE (150 ml). The mixture was warmed up to reflux and 2-propanol (30 ml) and DCM (5 ml) was added. The mixture was stirred and refluxed until complete dissolution, then brought to room temperature. The mixture was stirred at room temperature for 60 hours. The precipitate was filtered off and dried in vacuo at 50° C., yielding 3.32 g of 2-methoxy-2-oxoethyl α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazineacetate (compound 14, mp. 106° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc(-c2nsnc2Cl)c(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nsnc1Cl

Procedure:
A solution of 3-[2-(bromomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole (0.193 g, 0.60 mmol) and sodium azide (38.7 mg, 0.60 mmol) in DMF (0.6 mL) was stirred at 60° C. for 16 h. The solution was partitioned between water and ether. The organic phase was separated, washed with brine, dried (Na2SO4) and reduced in vacuo. 3-[2-(Azidomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole was isolated as an oil. MS m/z=258.5.
Reaction SMILES: N1CCC(CO)CC1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(#N)C>[Br:40][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: OCC1CCNCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reaction time: 8 h

Procedure:
To a solution of 5.792 g (50.287 mM) of 4-piperidylmethanol in 150 ml of dichloromethane was added 12.1 g (55.3 mM) of di-tert-butyl dicarbonate dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. The solvent was then distilled off under reduced pressure to recover crude tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. This crude product was not purified but used as it was in the next reaction. To a solution of the above crude tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 18.3 g (55.3 mM) of carbon tetrabromide in 100 ml of acetonitrile was added 14.5 g (55.3 mM) of triphenylphosphine at room temperature and the mixture was stirred at the prevailing temperature for 3 hours. The solvent was then distilled off under reduced pressure. To the residue was added diethyl ether, and after stirring, the resulting precipitate (triphenylphosphine oxide) was filtered off and washed with diethyl ether. The filtrate and washes were combined and concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 15/1 to 9/1) to provide the title compound.
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH-:23].[Na+].Cl.[CH3:26]N(C)C=O>O>[OH:23][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH2:21][CH3:26])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3
Reactant: CN(C)C=O
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Br)C[C@@H]32)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
16α-Bromo-3β-methylandrost-5-en-17-one (1.00 g, 2.74 mmol) was dissolved in dimethylformamide (90 mL). Sodium hydroxide (165 mg, 4.1 mmol) in water (10 mL) was added and the solution stirred for 2 h. at room temperature. The solution was poured into 1% HCl (200 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with 5% sodium biocarbonate, water, then dried over magnesium sulfate and filtered. Evaporation gave a pale yellow solid which was chromatographed on flash silica gel and eluted with ether/hexane (10/90). Recrystallization from ether gave 0.54 g (65%) 16α-hydroxy-3β-ethylandrost-5-en-17-one mp 166°-168° C.; NMR (DMSO-d6) δ5.30 (br s, 1H, H-3), 4.38 (t, 1H, 16β-H), 2.0-1.05 (m, complex), 0.98 (s, 3H, C-19 Me), 0.95 (d, J=8 Hz, 3H, C-3 Me), 0.87 Cs, 3H, C-18 Me); IR (KBr) 3440, 2900, 1735, 1445, 1365, 1010; MS 302 (M+, 100), 287(24), 274(7), 259(7), 241(7), 230(72), 215(41), 159(31); Anal. Calcd for C20 H30O2 : C, 79.42; H, 9.99. Found: C, 79.24; H, 10.04.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([N:25]([CH3:33])[CH3:24])=[CH:27][CH:28]=3)=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 60 °C
Yield: 12.7 %

Procedure:
Under a nitrogen atmosphere, oxlyl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and cooled (0°-10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 50 ml of dimethylformamide. After the addition was complete, the reaction solution was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (<10° C.) suspension of N,N-dimethyl-1,4-phenylenediamine dihydrochloride (3.64 g, 0.0174 mole),triethylamine (5.27 g, 0.052 mole), and 75 ml of dimethylformamide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 1800 ml of water and refrigerated overnight. The solid was collected by filtration and dried. The solid was recrystallized twice from isopropyl alcohol, collected by filtration, washed with water, and dried under high vacuum at 98° C. overnight to give 0.9 g (12.7%) of crystals, mp 245°-246.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH2:12]Cl)[C:4]=1[OH:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[OH2:23]>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Cl-].[Zn+2]>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:17]=1)[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH2:12][C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[OH:23])[C:4]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(CCl)c(O)c(CCl)c1
Reactant: O
Reactant: Oc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cc(Cc2cc(Cl)ccc2O)c(O)c(Cc2cc(Cl)ccc2O)c1
Reaction time: 30 h

Procedure:
The 2,6-bis(chloromethyl)-4-nitrophenol (8 g) and p-chlorophenol (8.7 g) were dissolved in nitrobenzene (125 ml) at 25°. After cooling to 10° ZnCl2 (28 g) was added over 1 hr. The stirred mixture was held at room temperature for 30 hrs and poured into 200 mls of water. The organic layer was washed with water and the nitrobenzene removed by vacuum distillation. Column chromatography gave 1.5 g of 2,6-bis(5-chloro-2-hydroxybenzyl)-4-nitrophenol (mp 220°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][N:30]2[CH2:31][CH2:32][CH:27]([C:23]3[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=3)[CH2:28][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccsc1Sc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccsc3Sc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-[(4- chlorophenyl)sulfanyl]-3-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.0 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture at 0° C. under N2 of sodium azide (1.47 g, 22.6 mmol) in anhydrous DMF (30 mL) was added a solution of 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (6.00 g, 18.8 mmol), prepared as in Example 1178A-D, in anhydrous DMF (10 mL). Reaction stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[O:20]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:19]2([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[O:20]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc21
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)OC(=O)c3ccccc32)C1=O)OCc1ccccc1
Yield: 64.1 %

Procedure:
In 5 ml of dichloromethane were dissolved 236 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 347 mg of Compound (98). To the solution was added, under ice-cooling, 0.14 ml of triethylamine, and the mixture was stirred for 30 minutes. The solvent was evaporated off. To the residue was added ethyl acetate, which was washed with water and an aqueous saline solution. The organic layer was dried, then the solvent was evaporated off. The residue was subjected to a column chromatography using Florisil, followed by elution with hexane--ethyl acetate (2:1→1:1) to give 350 mg of the subject Compound (99) as a pale yellow oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>CCCCCC.C1COCC1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(C2CC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C2CC2)cc1
Temperature: -20 °C

Procedure:
2.5 M solution of nButyllithium in hexane (14.5 mL) is added dropwise to 1-bromo-4-cyclopropyl-benzene (5.92 g) dissolved in THF (14 mL) and toluene (50 mL) and chilled to −70° C. The resultant solution is stirred at −70° C. for 30 min before triisopropyl borate (8.5 mL) is added. The solution is warmed to −20° C. and then treated with 4 M aqueous hydrochloric acid (15.5 mL). The reaction mixture is further warmed to room temperature and then the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (sodium sulfate). The solvent is evaporated and the residue is washed with a mixture of ether and cyclohexane to give the product as a colorless solid.