Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[O:26])[CH3:25])[N:23]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:24]([C:22]1[N:23]=[C:19]([NH:18][C:17](=[O:27])[C@@H:8]([NH2:7])[C@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:20][CH:21]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)c1csc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
[(1S,2S)-1-(4-Acetyl-thiazol-2-ylcarbamoyl)-2-phenyl-propyl]-carbamic acid tert-butyl ester (2.8 g, 6.25 mmol) was dissolved in dichloromethane (42 mL) in an ice bath. Trifluoroacetic acid (35 mL) was added. After 30 minutes, the reaction mixture was evaporated and the residue was precipitated with hexanes/ether. The mixture was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave (2S,3S)-N-(4-acetyl-thiazol-2-yl)-2-amino-3-phenyl-butyramide (1.9 g, 95%) as a white solid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([C:41]3[CH:45]=[C:44]([CH2:46][N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[O:43][CH:42]=3)=[N:9]2)=CC=1.COC1C=CC(CN2C3=NC=CC(OC4C=CC(N(C5C=CC(F)=CC=5)C(C5(C(N)=O)CC5)=O)=CC=4F)=C3C(C3OC(CN4CCN(C)CC4)=CC=3Br)=N2)=CC=1.C(O)(C(F)(F)F)=O>>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:41]3[CH:45]=[C:44]([CH2:46][N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[O:43][CH:42]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(-c3coc(CN4CCN(C)CC4)c3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Agent: COc1ccc(Cn2nc(-c3oc(CN4CCN(C)CC4)cc3Br)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2cc(-c3n[nH]c4nccc(Oc5ccc(N(C(=O)C6(C(N)=O)CC6)c6ccc(F)cc6)cc5F)c34)co2)CC1
Temperature: 25 °C

Procedure:
A 17:83 mixture of N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (26 mg, 0.035 mmol) were heated with TFA (0.5 mL) at 80° C. for 2 hours in a sealed vessel. After cooling to ambient temperature, the mixture was concentrated in vacuo, using toluene to azeotrope. The resulting solid was portioned between EtOAc (5 mL) and 1:1 saturated aqueous NaHCO3/water (5 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The crude products were separated by preparative TLC (0.5 mm thickness; N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.33; N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.25), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product, N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, was obtained as a white powder (1 mg, 5%). HPLC: 98% purity (254 nm); LRMS (ESI+): 100% purity, 220 nm, 628 m/z (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.32 (d, J=5 Hz, 1H), 8.18 (m, 2H), 7.77 (m, 1H), 7.45 (m, 2H), 7.24 (m, 1H), 7.07 (t, J=9 Hz, 2H), 6.92 (s, 1H), 6.32 (d, J=5 Hz, 1H), 3.62 (s, 2H), 2.64 (br s, 8H), 2.37 (s, 3H), 1.83 (m, 2H), 1.63 (m, 2H).
Reaction SMILES: [C:1](=[C:4]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5]1)([CH3:3])[CH3:2].O=C[C:12](=[CH2:14])[CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:21]([O:23]CC)C>>[C:1](=[C:4]1[CH:5]2[C:12]([CH3:14])=[CH:13][CH:8]1[C:7]([CH2:21][OH:23])([CH3:9])[CH2:6]2)([CH3:3])[CH3:2]
Reactant: CC1=CC(=C(C)C)C=C1
Reactant: C=C(C)C=O
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1=CC2C(=C(C)C)C1CC2(C)CO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-isopropylidene-2-methyl-cyclopenta-1,3-diene (26.4 g, 0.22 mol) and methacroleine (29.4 g, 0.42 mol) were stirred for 2 days at room temperature. The mixture was diluted with diethyl ether (50 ml) and added dropwise at 0° C. to a suspension of LiAlH4 (6.25 g, 0.16 mol) in ether (100 ml). After having been stirred for 1 h at room temperature, the mixture was dropwise quenched successively with water (6 ml), NaOH (15%, 6 ml) and water (6 ml). The mixture was filtered, concentrated in vacuo and the residue was purified by chromatography on silica gel (hexane:MTBE=9:1) to yield 21.6 g of a colorless oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=O.Cl>CO>[N+:19]([C:16]1[CH:17]=[CH:18][C:11]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:13][C:12]=2[CH:15]=1)([O-:21])=[O:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A 2000 ml 3-necked round-bottomed flask, 250 ml pressure equalized dropping funnel, Teflon stirrer, and gas inlet were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, and allowed to cool to room temperature. The cooled flask was charged with methanol (600 ml) and methyl thioglycolate (28.6 g, 0.27 mole). Sodium methoxide (19,98 g, 0.37 mole) in methanol (125 ml) was added to the reaction mixture over 10 minutes while stirring. The reaction mixture was then warmed to 40° C. and a solution of 2-chloro-5-nitrobenzaldehyde (28.6 g, 0.27 mole) in methanol (300 ml) was added over a period of about 20 minutes. The resulting slurry was stirred at 40° C. for 1 hour, cooled to room temperature, and acidified with 2M hydrochloric acid. The resulting white solid was filtered, washed with water (2×300 ml) and air-dried to give 61 g (95%) of methyl 5-nitrobenzothiophene-2-carboxylate. See, R. A. Zambias, M. L. Hammond, Synthetic Communications, 21:959 (1991).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9](=O)[NH:10][C:11](=O)[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:16].C(N(CC)CC)C.P(Cl)(Cl)([Cl:26])=O>>[Cl:16][C:11]1[N:10]=[C:9]([Cl:26])[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][N:12]=1
Reactant: Cl
Reactant: O=c1[nH]cc(Nc2ccccc2)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ncc(Nc2ccccc2)c(Cl)n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
A mixture of 5-phenylamino-1H-pyrimidine-2,4-dione (0.25 g, 1.23 mmol) in phosphorous oxychloride (5 mL) was heated at 80° C. for 4 h, and room temperature for 20 h. Triethylamine hydrochloride (0.50 g, 3.69 mmol) was added and the reaction was stirred 6 d at 80° C. and 6 d at room temperature. Phosphorous oxychloride was evaporated (azeotroping with toluene), then the residue was cooled to 0° C. and diluted with ethyl acetate. Excess reagent was carefully quenched with ice-chips, then the mixture was washed with sodium bicarbonate and brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:9 ethyl acetate:hexanes provided (2,4-dichloro-pyrimidin-5-yl)-phenyl-amine (0.20 g, 67% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) 8.33 (s, 1H), 7.36 (t, 2H), 7.12 (m, 3H), 5.93 (s, 1H) ppm; MS (FIA) 335.9/337.9 (M+H); HPLC (method A) 3.554 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=C2)([O-:3])=[O:2].[OH2:13].Cl[CH2:15][CH2:16]Cl>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:15]2[CH:16]=[O:13])([O-:3])=[O:2]
Reactant: ClCCCl
Reactant: O
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Product: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Yield: 80 %

Procedure:
Then a solution of 5-nitroindole (1.62 g, 0.01 mol) in 1,2-dichloroethane (50 ml) was added and the mixture heated to reflux for 3 h. After cooling the mixture was poured onto iced water, the precipitate filtered off and washed with water. Thereupon the residue was chromatographed over silica gel using benzene/ethylacetate as eluant. Thus pure title compound was obtained in 80% yield (1.52 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:19]=[N:20][CH:21]=2)=[N:10]S(CC(C)C)=O)=[CH:5][C:4]=1[F:29])#[N:2].[ClH:30].[CH3:31]O>O1CCOCC1>[ClH:30].[ClH:30].[NH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:29])[CH:5]=1)([C:17]1[N:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:19]=[N:20][CH:21]=1)[CH3:31]
Reactant: CO
Reactant: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1-c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)(c1ccc(C#N)c(F)c1)c1cncn1-c1ccc(F)cc1

Procedure:
N-[(4-Cyano-3-fluoro-phenyl)-(3-(4-fluorophenyl)-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (2.217 g, 5.17 mmol) was dissolved in MeOH (20 mL) and 4M HCl in dioxane (10 mL) with stirring at ambient temperature. After 1 h the reaction mixture was concentrated in vacuo, made basic with NaHCO3 solution, extracted with CH2Cl2 (3×20 mL), the organics combined, dried (Na2SO4), filtered, and concentrated to give the title compound as a mixture of enantiomers.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])#[N:2].[CH3:14][O-:15].[Na+].[ClH:17]>CO>[Cl:17][C:6]1[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=[C:1]([O:15][CH3:14])[N:2]=1.[CH3:14][O:15][C:1]1[NH:2][C:6](=[O:7])[C:5]2[C:4]([CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)c1ccccc1CC#N
Reactant: Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2ccccc2c(=O)[nH]1
Product: COc1cc2ccccc2c(Cl)n1
Yield: 80 %

Procedure:
A mixture of methyl 2-(cyanomethyl)benzoate (3.50 g, 20 mmol) and sodium methoxide (10 mL, 25% wt in methanol) in 35 mL MeOH was heated to reflux under nitrogen for 3 h. While still hot, the solution was acidified with 1N HCl solution until the green solution turned to yellow color and a lot of white solid precipitated out. After cooling, the precipitated product was collected by filtration, washed with water and dried to yield the desired product 3-methoxyisoquinolin-1(2H)-one as a white solid (2.8 g, 80%). MS: MS m/z 176.1 (M++1).
Reaction SMILES: F[B-](F)(F)F.B(F)(F)[F:7].CCOCC.N[C:16]1[CH:17]=[CH:18][C:19]2[CH2:20][CH2:21][C@@H:22]3[C@@H:31]([C:32]=2[CH:33]=1)[CH2:30][CH2:29][C@@:27]1([CH3:28])[C@H:23]3[CH2:24][CH2:25][CH2:26]1.C(ON=O)(C)(C)C>C(Cl)Cl.CCCCC>[F:7][C:17]1[CH:16]=[CH:33][C:32]2[C@@H:31]3[C@H:22]([C@H:23]4[C@@:27]([CH2:29][CH2:30]3)([CH3:28])[CH2:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][C:19]=2[CH:18]=1
Reactant: FB(F)F
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCc3ccc(N)cc3[C@H]1CC2
Agent: CC(C)(C)ON=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCC
Solvent: CCOCC
Product: C[C@@]12CCC[C@H]1[C@@H]1CCc3cc(F)ccc3[C@H]1CC2
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
3-Fluoroestrone was synthesized from 2-aminoestrone by adapting the procedure reported by Doyle and Bryker (J. Org. Chem. 44, 1572-1574, 1979) for the synthesis of arenediaxonium tetrafluoroborate salts from aromatic amines. The procedure is as followed: To neat stirred boron trifluoride etherate (642 μL, 719 mg, 5.07 mmol) at −15° C. under Ar (g) was added a solution of 3-aminoestrone (101) (910 mg, 3.38 mmol) in dry CH2Cl2 (10 mL). After 15 min, a solution of t-butylnitrite (482 μL, 418 mg, 4.05 mmol) in dry CH2Cl2 (5 mL) was dropwise added. The now dark brown solution was stirred at −15° C. for 15 min, then at 0° C. for 30 min. Pentane was added to the solution and a gummy solid precipitated. The solvent was decanted and the residue was dried under vacuum to give a crude light brown solid. The neat solid was heated under vacuum at 70-80° C. in an oil bath for 15 min to give a crude orange solid. Purification by flash chromatography on SiO2 using 1:9 EtOAc/Hexanes gave 3-fluoroestrone (102) as a white solid (437 mg, 47%). M.p. 178° C.; [α]25D +152.0° (c 1.03, CDCl3); IR (ν) 3044, 3039, 2928, 1740 (CO), 1611, 1585, 1495, 1474, 1458, 1428, 1405, 1377, 1340, 1272, 1245, 1230, 1212, 1148, 1094, 1084, 1053, 1008, 908, 889, 817, 784, 718, 704, 642, 620, 580, 564, 467 cm−1; 1H NMR (CDCl3) δ 0.92 (3H, s), 1.37-1.70 (6H, m), 1.93-2.44 (6H, m), 2.52 (1H, dd, J=18.8 Hz, J′=9.0 Hz), 2.91 (2H, dd, J=8.4 Hz, J′=3.8 Hz), 6.82 (2H, dq, J=8.3 Hz, J′=2.8 Hz), 7.23 (1H, dd, J=8.5 Hz, J′=5.8 Hz); 13C NMR (CDCl3) δ 13.8, 21.6, 25.9, 26.3, 29.5, 31.5, 35.9, 38.1, 44.0, 47.9, 50.4, 112.5 (d, J=21.6 Hz), 115.1 (d, J=19.7 Hz), 126.8 (d, J=7.5 Hz), 135.3, 138.7, 161.0 (d, J=244.3 Hz), 220.7.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:43])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:27]=[CH:26][N:25]=2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[N:44]1([C:50](=[O:52])[CH3:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:50]([N:44]1[CH2:49][CH2:48][N:47]([CH2:2][C:3]2[N:8]=[C:7]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[C:24]3[CH:29]=[C:28]([C:30](=[O:43])[NH:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[CH:27]=[CH:26][N:25]=3)=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:46][CH2:45]1)(=[O:52])[CH3:51]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)n2)c1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Into a 8-mL sealed tube, was placed a solution of 6-(chloromethyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (120 mg, 0.20 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 1-(piperazin-1-yl)ethanone (37.9 mg, 0.30 mmol, 1.50 equiv), potassium carbonate (82 mg, 0.59 mmol, 3.00 equiv), and potassium iodide (7 mg, 0.04 mmol, 0.20 equiv). The resulting solution was stirred for 3 h at 65° C. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 89.2 mg (56%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.56 (s, 1H), 9.54 (t, J=6.0 Hz, 1H), 9.08 (d, J=5.1 Hz, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.25-8.17 (m, 3H), 7.84 (d, J=3.9 Hz, 2H), 7.71-7.58 (m, 5H), 7.51 (s, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.49 (s, 2H), 3.31-3.21 (m, 10H), 2.01 (s, 3H), 1.72-1.59 (m, 6H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:18])=[C:5]2C(O)=O.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:18][C:23]1[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=1)=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccc(F)cc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cc(F)ccc4nc3-c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 11 h
Yield: 18 %

Procedure:
6-Fluoro-3-hydroxy-2-phenyl-quinoline-4-carboxylic acid (118 mg), 4-chloro-6,7-dimethoxyquinoline (330 mg), and 4-dimethylaminopyridine (310 mg) were suspended in o-dichlorobenzene (8 ml), and the mixture was stirred at 160° C. for 11 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (32 mg, yield 18%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClC(Cl)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:17](=[O:19])[CH3:18])=[C:4]([OH:12])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Oc1cc(Br)c2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1c(O)cc(Br)c2ccccc12
Temperature: 0 °C
Yield: 83.4 %

Procedure:
To a solution of 0.625 g (2.80 mmol) 4-bromonapthalen-2-ol in dichloroethane (2.5 mL) was added aluminum chloride (0.561 g, 4.20 mmol), followed by acetyl chloride (0.20 mL, 2.8 mmol). The solution was refluxed for 2 h, then poured into 50 mL ice-cold 1M hydrochloric acid. This solution was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 3:1 hexanes/ethyl acetate) gave 0.619 g (83%) of 1-(4-bromo-2-hydroxynapthalen-1-yl)ethanone as a pale pink solid. 1H NMR (400 MHz, d6-DMSO): 13.22 (s, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.61 (dt, 1H), 7.51 (s, 1H), 7.49 (t, 1H), 2.83 (s, 3H); MS (EI) for C12H9O2Br: 265 (MH+), 267 (M+2).
Reaction SMILES: [Li].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].[Br:18][C:19]1[C:28]([CH2:29]Br)=[C:27]([O:31][CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[O:33][CH3:34]>C1COCC1.O.C(Cl)Cl>[Br:18][C:19]1[C:28]([CH2:29][CH2:13][C:12]([O:15][CH2:16][CH3:17])=[O:14])=[C:27]([O:31][CH3:32])[C:26]2[C:21]([C:20]=1[O:33][CH3:34])=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1c(Br)c(OC)c2ccccc2c1OC
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
Following a modified procedure of Clegg et al.,28 lithium hexamethyldisilizade (LiHMDS, 1 M in THF, 1.5 ml, 1.5 mmol) was added to a flame-dried round bottom flask containing THF (20.0 mL) at 78° C. Ethyl acetate (0.15 ml, 1.5 mmol) was then added slowly at 78° C. and stirred at 78° C. for 30 minutes. 36 (0.415 g, 1.15 mmol) was then dissolved in THF (10.0 mL) and added at 78° C., at which point the reaction was allowed to warm to room temperature, and was stirred at room temperature for 4 h. The reaction was monitored by TLC (CH2Cl2) for disappearance of the less polar starting material. More LiHMDS (2.0 mL, 2.0 mmol) and EtOAc (0.70 mL, 0.70 mmol) were added and the reaction was monitored for the disappearance of starting material. When no starting material was present, 10 hours, the reaction was then poured into water, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and condensed. The product was the purified by column chromatography (CH2Cl2 to 1:19 EtOAc:CH2Cl2) to provide 67a (0.361 g, 0.983 mmol, 86%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH:40]4[CH2:41][CH2:42][CH2:43][O:39]4)[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COC(CN2CCNCC2)C1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC2CCCO2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(tetrahydro-furan-2-ylmethyl)-piperazine (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C40H51N4O3Cl2 [(M+H)+] 705.3333, observed 705.3332.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[O:29][C:21]1=[N:22][CH:23]=[C:24]([C:26]([OH:28])=O)[CH:25]=[C:20]1[CH2:19]2.[NH2:30][C@H:31]1[CH2:36][C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:34]([CH3:43])[N:33]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:32]1=[O:49].Cl.N[C@H]1C[C@@H](C2C=CC=CC=2)[C@@H](C)N(CC(F)(F)F)C1=O.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:43][C@H:34]1[N:33]([CH2:44][C:45]([F:48])([F:46])[F:47])[C:32](=[O:49])[C@@H:31]([NH:30][C:26]([C:24]2[CH:25]=[C:20]3[CH2:19][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:2]4=[O:1])[O:29][C:21]3=[N:22][CH:23]=2)=[O:28])[CH2:36][C@H:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(C(=O)O)cnc3O2)c2cccnc21
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)CC2(O3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2′-oxo-1′-((2-(trimethylsilyl)ethoxy)methyl)-1′,2′-dihydro-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid, (described in Intermediate 5) (0.095 g, 0.23 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one, (described in Intermediate 1) (0.098 g, 0.35 mmol), N,N-diisopropylethylamine (0.12 mL, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.065 g, 0.35 mmol) and HOBT (0.015 g, 0.12 mmol) in DMF (3 mL) was stirred initially at 0° C. for 15 min, then gradually warmed to 23° C. and stirred for 3 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to give the title compounds as a 1:1 mixture of isomers. MS: m/z=682.5 (M+1).