Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:60](O)(=[O:63])[CH2:61][OH:62]>C(Cl)Cl>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:61](=[O:62])[CH2:60][OH:63])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)CO)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (0.010 g, 0.024 mmol), DIPEA (0.00918 g, 0.071 mmol), TBTU (0.0228 g, 0.071 mmol) in DCM (2 mL) was added Glycolic acid (0.00360 g, 0.0474 mmol) at 0° C. The mixture was stirred for 1 h. The reaction mixture was directly loaded onto Prep TLC for purification (silica gel, eluting with 4% MeOH in DCM) to afford the title compound as a yellow solid. 1H-NMR (CD3OD, 400 MHz): δ=1.88 (d, J=6.8 Hz, 3H), 2.53 (d, J=17.2 Hz, 2H), 3.63 (t, J=5.8 Hz, 1H), 3.83 (t, J=5.8 Hz, 1H), 4.12 (d, J=2.0 Hz, 1H), 4.26 (s, 2H), 4.30 (s, 1H), 6.29 (d, 1H), 6.49 (q, J=6.7 Hz, 1H), 7.15-7.25 (m, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.64 (d, J=10.4 Hz, 1H), 8.20 (s, 1H). MS (ES+): m/z 480.01 (MH+, 35Cl, 37Cl), 481.96 (MH+, 37Cl, 37Cl). HPLC: tR=2.76 min (polar—5 min, ZQ3).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-])=O.CO>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70.9 %

Procedure:
(3aR*,10aS*)-9-(4-Nitrobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (5.06 g, 15 mmol) and 10% palladium-on-carbon (hydrous) (0.5 g) were suspended in THF (15 mL)-methanol (15 mL) and the suspension was stirred under hydrogen at room temperature for 4.5 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to provide 3.27 g (yield 71%) of the title compound. m.p. 149.1°-149.6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=O)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCCCOCCCC>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]2([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[S:28][CH2:25][CH2:26][S:27]2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: SCCS
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccco2)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCCCOCCCC
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccco3)SCCS2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Dissolve 5-(furan-2-carbonyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (290 mg, 0.88 mmol) in dichloromethane (2 mL). Cool to 0° C., add a solution of ethane-1,2-dithiol (0.22 mL, 2.2 mmol) and then add a solution of boron trifluoride dibutyl etherate (0.66 mL, 5.2 mmol) in dichloromethane (5 mL). Warm the mixture to room temperature and stir overnight. Quench with water and dilute with dichloromethane. Wash the organic layer by saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound (38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:11])[CH2:9]C)=[CH:4][CH:3]=1.[C:12]([O-])(O)=[O:13].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:11]=[C:12]=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC[C@H](N)c1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N=C=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)propan-1-amine (5 g, 25 mmol) in CH2Cl2 (10 mL) was added saturated aqueous NaHCO3 (10 mL) and then triphosgene (2.45 g, 8 mmol) at 0□. Then the reaction mixture was stirred for 15 minutes at 0° C. under nitrogen. The reaction mixture was extracted with CH2Cl2 twice. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford (R)-1-bromo-4-(1-isocyanatoethyl)benzene (2.5 g, 44%), which was used for the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>>[NH:19]1[C:18]([NH:17][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[O:12])=[N:22][N:21]=[N:20]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1ccc([N+](=O)[O-])cn1
Yield: 50.6 %

Procedure:
0.72 g of 5-nitro-2-pyridinecarboxylic acid, 13 ml of thionyl chloride and 0.37 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, ethanol and water, whereby 0.51 g of N-(5-tetrazolyl)-5-nitro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C1COCC1>[CH3:9][S:10]([O:1][C@H:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:12])=[O:11]
Reactant: CCOC(=O)[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)OS(C)(=O)=O
Temperature: 12.5 °C
Yield: 60.2 %

Procedure:
(R)-ethyl 2-hydroxypropanoate (15 g, 0.127 mol) and TEA (15.4 g, 0.15 mol) were added to THF and then cooled to 10-15° C. Then MsCl (15 g, 0.13 mol) was added to the solution dropwise with cooling while maintaining the temperature in the range of 10-15° C. at about 2 hours. The mixture was allowed to warm to about 20° C. and the solid was filtered off. The solution was washed with water and dried, concentrated to afford (R)-ethyl 2-(methylsulfonyloxy)propanoate (15 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm, 5.11-5.14 (q, 1H), 4.24-4.29 (m, 2H), 2.81-3.17 (q, 3H, J=7.2 Hz), 1.61-1.43 (d, 3H, J=7.6 Hz), 1.30-1.32 (m, 3H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O=[C:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:3]=[C:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reaction time: 0.67 h
Yield: 108.8 %

Procedure:
Diethyl cyanomethylphosphonate (16 mL, 100 mmol) was dissolved in tetrahydrofuran (360 mL), and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1 M, 100 mL, 100 mmol) and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18 g, 91 mmol) in tetrahydrofuran (36 mL) were added under a nitrogen atmosphere at −70° C., followed by stirring at the same temperature for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and the extract was washed with a saturated aqueous ammonium chloride solution. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.41 (hexane/ethyl acetate=3/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (22 g) as a white solid (quantitative yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH:32]([C:40]([O:42]C)=[O:41])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([CH3:30])[C:22]=3[CH3:31])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:40]([CH:32]([N:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([CH3:30])[C:22]=1[CH3:31])(=[O:20])=[O:19])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([OH:42])=[O:41]
Reactant: COC(=O)c1ccc(-c2ccc(CN(C(Cc3ccccc3)C(=O)OC)S(=O)(=O)c3c(C)cc(OC)c(C)c3C)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc(-c3ccc(C(=O)O)o3)cc2)C(Cc2ccccc2)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(4-{[(1-Methoxycarbonyl-2-phenyl-ethyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-furan-2-carboxylic acid methyl ester (16 mg, 0.026 mmol.) in THF:H2O:MeOH (3:1:2) (1 ml.), was added LiOH in water (1N) (0.2 ml. 0.26 mmol.). The reaction mixture was stirred at room temperature during 1 hr. TLC monitored the progress of the reaction. When the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator. The residue was treated with a solution 20% of KHSO4 and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by silica chromatography using 90% EtOAc, 10% MeOH and 1 drop of AcOH, afforded 5-(4-{[(1-Carboxy-2-phenyl-ethyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-furan-2-carboxylic acid. 1HNMR (Varian 400 MHz, DMSO) δ7.37 (d, 2H, J=8.5 Hz, HPh), 7.27 (d, 2H, J=8.3 Hz, HPh), 7.13 (m, 6H, HPh), 6.69 (d, 1H, J=3.2 Hz, furanH), 6.58 (d, 1H, J=3.2 Hz, furanH), 6.50 (s, 1H, MTRH), 4.81 (d, 1H, J=15.5 Hz, NCH2Ph), 4.41 (d, 1H, J=15.9 Hz, NCH2Ph), 4.06 (dd, 1H, J=3.5 and 9.5 Hz, CHCH2), 3.64 (s, 3H, OCH3), 3.10 (dd, 1H, J=9.5 and 12.6 Hz, CHCH2), 2.65 (dd, 1H, J=3.8 and 12.6 Hz, CHCH2), 2.49 (s, 3H, ArCH3), 2.38 (s, 3H, ArCH3), 1.92 (s, 3H, ArCH3) ppm. MS 576.5 (M−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:19][CH2:20][N:15]([C:12](=[O:14])[CH3:13])[CH2:16][CH2:17]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-chloro-4-fluoronitrobenzene (350 mg), N-acetylpiperazine (0.5 ml) and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 ml) and stirred at 50° C. overnight. The reaction mixture was distilled under reduced pressure to remove dimethylformamide and added with distilled water. Then, the recrystallized yellow solid was filtered and the subsequent reaction was proceeded without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH2:20][C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)Nc2ccc(C#N)c(Cl)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@@H](CN=[N+]=[N-])Nc1ccc(C#N)c(Cl)c1
Yield: 105.4 %

Procedure:
1,1-Dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate (35.0 g, 76 mmol) and sodium azide (9.83 g, 150 mmol) in DMF (150 mL) were stirred at 65° C. for 2.25 h. After cooling, the reaction was diluted with cold H2O (500 mL) and extracted with Et2O (3×). The combined organic extracts were washed with H2O (3×), treated with charcoal and dried (MgSO4), filtered and the solvent evaporated. The residue was dissolved in a small amount of Et2O and filtered through a short plug of silica gel. Evaporation of the filtrate afforded the titled compound (26.9 g, >100%) as an oil. 1H-NMR (CDCl3) δ: 1.46 (9H, s), 2.58 (2H, m), 3.56 (2H, d, J=5.2 Hz), 3.99 (1H, m), 6.54 (1H, d, J=8 Hz), 6.99 (1H, s), 7.43 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 336.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:16]([O:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:12][CH2:13][CH3:14])[C:2]=1[C:22]1[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:17]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnn(C)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Methyl 4-bromo-3,5-diethoxybenzoate (1 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (895 mg) were dissolved in DME in a nitrogen atmosphere, and potassium phosphate (2.1 g) and 1,1′-bis(diphenylphosphino)ferrocene palladium (D) chloride-CH2Cl2 complex (269 mg) were added to it at room temperature, and degassed. The reaction liquid was stirred overnight at 90° C., then cooled to room temperature, and water was added to it, and this was filtered through Celite. The filtrate was extracted with chloroform, washed with saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 50/50 to 35/65) to obtain the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[C:3]=1[C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.II>CS(C)=O>[CH3:26][O:25][C:17]1[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:2]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:1]2
Reactant: COc1cc(O)c(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c(OC)c1OC
Agent: II
Solvent: CS(C)=O
Product: COc1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc(=O)c2c(OC)c1OC
Yield: 92.9 %

Procedure:
A mixture of 7a (0.80 g, 2.2 mmol) and iodine (20 mg) in DMSO (5 ml) was refluxed for 1 h, and then carefully poured onto crushed ice. The precipitate was filtered and washed with 20% Na2SO3. Recrystallization of the precipitate from acetone afforded 8 (0.73 g, 93%). 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 6.74 (s, 1H), 6.82 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 8.34 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:41]([CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C=O)C.O>[C:46]([O:45][C:43](=[O:44])[CH2:42][N:41]([CH2:50][C:51](=[O:52])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)CCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-(benzyloxy)-6-oxohexanoic acid (1.5 g, 6.35 mmol) in DMF (50 mL) at room temperature was added DIPEA (2.218 mL, 12.70 mmol), HOBt (1.945 g, 12.7 mmol), EDC (2.434 g, 12.7 mmol) and di-tert-butyl 2,2′-iminodiacetate (2.34 g, 9.52 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-40% EtOAc in hexane, to give the title compound. LC-MS Method A: m/e=464.04 [M+1]; Rt=2.47 min. 1H NMR (CDCl3) δ 7.32 (m, 5H), 5.07 (s, 2H), 4.02 (s, 2H), 3.96 (s, 2H), 2.35 (s, 2H), 2.26 (s, 2H), 1.66 (s, 4H), 1.42-1.44 (bs, 18H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([C:12](C(=O)C)([CH:16]([OH:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([OH:15])=[O:14])(C)(C)C>>[OH:24][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCCCCC(O)C(C(C)=O)(C(=O)O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC(O)CC(=O)O

Procedure:
Synthesis of analogs 18, 20, 21 proceeded by a shortened piperidine deblock of Fmoc-OBzl-D-Glu.41The reduction of deblock from 20 to 5 minutes was necessary to prevent the cyclization20 of OBzl-D-Glu to pyroglutamic acid. The orthoganol Boc/Fmoc protection scheme allowed the selective removal of the base labile Fmoc group, while maintaining the base insensitive Boc protection on the L-Ile. The synthesis was continued by coupling of Fmoc-L-Leu42 in the usual manner (DCC/HOBT) which was followed by piperidine-catalyzed Fmoc deprotection (20 minutes) and final acylation with either (-)-D-3-hydroxydecanoic acid (-) (23) (for peptides 18 and 20) or decanoic acid (for analog 21). Coupling of D-3-hydroxydecanoic acid was as the Pfp ester (24), with the 3-hydroxyl group unprotected. The acid was obtained by (-)-cinchonidine resolution21 of synthetic (±)-3-hydroxydecanoic acid [(±) 12]. The (±)-3-hydroxydecanoic acid itself (mp 55°-56° C.; 57° C.) was synthesized by the aldol condensation of lithium tert butyl acetate22 with n-octyl aldehyde, followed by TFA hydrolysis of the resulting (±)-tert butyl acetyl-3-hydroxydecanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:28]=[CH:29][C:30]5[N:31]([CH2:40][CH3:41])[C:32]6[C:37]([C:38]=5[CH:39]=4)=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:40]([N:31]1[C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:22]3[N:21]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[N:15][CH:16]=4)[CH:25]=[CH:24][N:23]=3)=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:41]
Reactant: CCn1c2ccccc2c2cc(Nc3nccc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)n3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c2ccccc2c2cc(Nc3nccc(-c4ccc(N5CCNCC5)nc4)n3)ccc21
Yield: 51.9 %

Procedure:
A solution of 4-(2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrid-5-yl)-N-(9-ethylcarbazol-3-yl)-2-pyrimidineamine (65 mg, 0.12 mmol) in dichloromethane (2 ml) was treated with trifluoroacetic acid (2 ml). After 2h the mixture was evaporated and the residue reconcentrated five times from dichloromethane then three times from diethyl ether. The residue was subjected to column chromatography (silica, 0.88 ammonia solution-methanol-dichloromethane 1:5:94) to afford the title compound (28 mg) as a pale yellow solid m.p. 131-137°. δH (d6DMSO) 1.31 (3H, t, J 7.1 Hz), 2.80 (4H, m), 3.56 (4H, m), 4.42 (2H, q, J 7.1 Hz), 6.93 (1H, d, J 9.1 Hz), 7.17 (1H, m), 7.25 (1H, d, J 5.3 Hz), 7.43 (1H, m), 7.55 (2H, m), 7.76 (1H, dd, J 2.9, 8.8 Hz), 8.03 (1H, d, J 7.4 Hz), 8.27 (1H, dd, J 2.1, 9.1 Hz), 8.41 (1H, d, J 5.3 Hz), 8.57 (1H, d, J 1.8 Hz), 8.95 (1H, d, J 2.1 Hz) and 9.45 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[F:20]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[F:20]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(F)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-fluorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(4-chloro-3-fluorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol gave a yellow crystalline solid of melting point >300° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:21]1[CH2:25][CH2:24][C@@H:23]2[CH2:26][N:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][C@H:22]12>ClCCl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:25][CH2:24][C@@H:23]4[CH2:26][N:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][C@H:22]34)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)N1C[C@H]2CCN[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(Br)cc4)cc3)[C@H]2C1
Temperature: 20 °C

Procedure:
The catalyst solution was added to the vessel containing the 4,4′-dibromobiphenyl, cesium carbonate, and the product of Example 41C and the mixture was heated to 98° C. for 12 hours. The mixture was cooled to 20° C. and 80 g of dichloromethane was added. The resulting mixture was stirred and then filtered to remove the catalyst. The resulting solution was concentrated under reduced pressure and the residue was purified by column chromatography to yield 5.65 g of the title compound.