Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Temperature: 30 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of tert-butyl N-(3′-bezyloxy-biphenyl-4-ylmethyl)carbamate (1.16 g) in ethanol/tetrahydrofuran (4/1, 30 mL) was added 10% palladium-on carbon (55.4 wt % H2O, 0.520 g), and the resulting mixture was stirred at 30° C. for 5 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/2) to give the title compound (0.731 g).
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]3[CH3:29])=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:8]3[CH2:9][CH2:10][CH:6]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:7]3)=[CH:13][CH:14]=2)[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: C1CCNC1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(OS(C)(=O)=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(N3CCCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
3-[4-({3-[(methylsulfonyl)oxy]cyclopentyl}oxy)phenyl]-2-methyl -4(3H)-quinazolinone (550 mg, 1.33 mmol), pyrrolidine (474 mg, 6.7 mmol) and potassium carbonate (277 mg, 2.0 mmol) were mixed in dimethylformamide (10 mL) and stirred at 80° C. overnight. Distilled water was added, and the mixture extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain the title compound (143 mg) as a colorless solid. 2-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone (trans isomer)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[NH2:13][C@H:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:15][OH:16]>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:13][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:15][OH:16])=[N:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)nc1N[C@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
A solution of 2,3,6-trifluoro-5-nitropyridine (1.2 g, 6.7 mmol) in THF (40 ml) was cooled to 0° C. (R)-2-amino-2-(4-fluorophenyl)ethanol (1.0 g, 6.7 mmol) was then added and the reaction was stirred at 0° C. for 30 minutes. The reaction was quenched with water (50 ml) and then extracted with DCM (2×75 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (1.2 g, 57%). The product was carried over to the next step without characterization.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.O1CCOCC1.[Na]>O>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[N:20][CH:21]=1
Reactant: COCCN1CC2CC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(CCOC)C2)ncc1Cl
Temperature: 120 °C
Yield: 52.3 %

Procedure:
10-(2-Methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (45 mg, 0.19 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (65 mg, 0.19 mmol) and 4N HCl in dioxane (53 μl, 0.21 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-15% methanol in methylene chloride as the eluent to yield 2-[5-chloro-2-(10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (52.57 mg, 43%) as a white foam. MP: 92-94° C., 1H-NMR (CDCl3) δ 9.10 (s, 1H), 8.50 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.58 (m, 1H), 7.35 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.95 (s, 1H), 4.61-4.53 (m, 1H), 3.36 (t, J=5.9 Hz, 2H), 3.29 (s, 3H), 3.08 (br s, 1H), 3.02 (br s, 1H), 2.85 (m, 2H), 2.64 (d, J=5.3 Hz, 3H), 2.57-2.45 (m, 4H), 2.27 (m, 1H), 1.71 (d, J=10.1 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([N:19]2[CH2:20][CH2:22][CH2:25][CH2:23]2)=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 3-methylpyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (348 mg, 1.52 mmol) in DMF (10 mL) were added DIPEA (0.53 mL, 3.04 mmol), pyrrolidine (0.25 mL, 3.04 mmol) and HATU (693 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (334 mg, 78%). 1H NMR (400 MHz, CHCl3-d): δ 3.61-3.38 (m, 8 H); 2.00-1.79 (m, 6 H); 1.47-1.44 (m, 9 H); 1.33 (s, 3 H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[C:8](Br)[C:7]([C:16]#[N:17])=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)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>[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:8]1[C:7]([C:16]#[N:17])=[N:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]=1[CH2:10][C:11]([OH:14])([CH3:13])[CH3:12]
Reactant: CCCCn1nc(C#N)c(Br)c1CC(C)(C)O
Reactant: Nc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CCCCn1nc(C#N)c(-c2ccccc2N)c1CC(C)(C)O

Procedure:
A modification of the method described in Part H of Example 1255 was used to treat 1-butyl-4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (2.7 g, 9.2 mmol). Two equivalents of 2-aminophenylboronic acid hydrochloride (3.2 g, 18.4 mmol) and 2 mol % dichlorobis(triphenylphosphine)palladium(II) (0.126 g, 0.18 mmol) were added at the beginning of the reaction, and the reaction was heated at reflux for five hours. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 4-(2-aminophenyl)-1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([Sn](=O)CCCC)CCC>>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In a reactor fitted with a heating/cooling bath, stirrer, thermocouple, nitrogen inlet, a reflux condenser with a trap to collect distilled off methanol, and a vacuum connection are added 438.6 g (1.5 moles, a 5% excess) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and 386.8 g (1.43 moles) of 1-octadecanol. The mixture is heated to 100° C. under nitrogen with stirring. After drying at 100° C. under vacuum (≤5 mm Hg) for 30 minutes, the mixture is heated to 120° C. under nitrogen and 0.05 g (0.0002 mole) of dibutyltin oxide (Fascat® 4201, Elf-Atochem) is added. The vacuum is lowered to 100 mm Hg and the reaction mixture is heated to 185° C. for one hour. The vacuum is slowly lowered to 2 mm Hg over 1.5 hours and kept at that temperature and pressure for another thirty minutes. The vacuum is broken with nitrogen and the reaction mass is cooled to 100° C. The excess methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate is removed using a wiped-film evaporator to give the title compound as a white solid containing 30 ppm Sn. Essentially a quantitative yield (99.8) of the ester product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:13])[S:27]([C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)(=[O:29])=[O:28])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1cc(C(=O)OC)cc(Cl)n1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(N(C)S(=O)(=O)c2cccnc2)c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 91.6 %

Procedure:
To a solution of methyl 2-chloro-6-(methylamino)isonicotinate (2.00 g, 9.97 mmol) in 3:1 CH2Cl2:pyridine (100 mL total) was added 3-pyridine sulfonyl chloride hydrochloride (6.40 g, 29.9 mmol) and dimethylaminopyridine (0.609 g, 4.98 mmol). Reaction heated to reflux at 50° C. After 36 h, reaction cooled to rt. Reaction diluted with CH2Cl2 (200 mL) and washed with 1N HCl (150 mL) solution. The aqueous solution was extracted with CH2Cl2 (100 mL×2). The combined organics were washed with brine (100 mL), dried over Mg2SO4, filtered, and concentrated in vacuo. Purification by normal-phase chromatography (20->40% EtOAc/hexanes) yielded 3.12 g (92%) of methyl 2-chloro-6-[methyl(pyridin-3-ylsulfonyl)amino]isonicotinate as a yellow residue. 1H NMR (CDCl3, 400 MHz) 8.95 (d, J=0.64 Hz, 1H); 8.82 (m, 1H); 8.03 (m, 2H); 7.67 (m, 1H); 7.45 (m, 1H); 3.99 (s, 3H); 3.39 (s, 3H); LC/MS [M+H]+=341.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]1)=[O:20])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 55 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 55%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 3.16-3.21 (m, 4H), 3.75-3.79 (m, 4H), 4.15 (s, 3H), 6.52-6.59 (m, 3H), 7.31 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].[F:26][C:27]([F:38])([F:37])[O:28]OCCOS(C)(=O)=O.[I-].[Na+].[C:41](OCC)(=O)[CH3:42]>CN(C)C=O.C(OCC)(=O)C.CCCCCC.CCCCCC>[F:38][C:27]([F:26])([F:37])[O:28][CH2:41][CH2:42][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)OCCOOC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2CCOC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.158 g, 0.5 mmol) and dimethylformamide (4 mL). Cool in an ice-bath. Add sodium hydride (0.013 g, 60% in oil, 55 mmol). Warm to ambient temperature. After 30 minutes, add a solution of 2-(methanesulfonyloxy)ethyl trifluoromethoxy ether (0.15 g, 0.75 mmol) in dimethylformamide (1 mL). Add sodium iodide (0.11 g, 075 mmol). After 2 hours, heat to 80° C. After 4 hours, cool to ambient temperature. After 18 hours dilute the reaction mixture with ethyl acetate and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with hexane, 30% ethyl acetate/hexane and then 50% ethyl acetate/hexane to give (1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine: Rf=0.26 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[NH:15][CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(NC(=O)C2)CC1)(=O)C1C=CC=CC=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[C:42]=1[CH3:50]>C1COCC1.CN(C=O)C>[C:1]([O:9][CH:10]1[CH:17]2[CH:16]([N:15]([CH2:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[C:42]=3[CH3:50])[C:14](=[O:18])[CH2:13]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCC2C(=O)NCC12)c1ccccc1
Reactant: Cc1c(CBr)ccc(C#N)c1Cl
Agent: O=C1CC2C(CCC2OC(=O)c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(CN2C(=O)CC3C(OC(=O)c4ccccc4)CCC32)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution containing mixtures of compound 1I and 1J (170 mg, 0.69 mmol, different batch than previous lot in example 1) in anhydrous THF (4 mL) and anhydrous DMF (4 mL) was added sodium hydride (27.7 mg, 0.69 mmol) at 0° C., and stirred at 0° C. for 45 min. Compound 7C (169 mg, 0.69 mmol) was added at 0° C., the ice-water bath was removed, and the stirring was continued between 0° C. to RT for 2 hr before it was quenched with saturated NH4Cl solution. The mixture was diluted with EtOAc, organic layer was separated, washed with water, dried over MgSO4, and concentrated. Purification by silica gel chromatography (30-100% EtOAc in hexanes) provide the title compound 7D (90 mg) and 7E (151 mg). Compound 7D: (ES) m/z 409 [M+H]+. Compound 7E: (ES) m/z 409 [M+H]+.
Reaction SMILES: CO.Cl.CON.[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C@@H:14]2[C@@H:18]([CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[O:17][CH:16]([OH:29])[C@H:15]2[F:30])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C@H:14]([C@H:18]([OH:17])[CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C@@H:15]([F:30])[CH:16]=[O:29])=[CH:10][CH:9]=1
Reactant: OC1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccc(Cl)cc2)[C@@H]1F
Agent: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C[C@H](F)[C@H](OCc1ccc(Cl)cc1)[C@H](O)COCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.9 %

Procedure:
In a nitrogen atmosphere, 14 mL of methanol and 0.72 g of O-methylhydroxylamine hydrochloride were added to 2.89 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolan-2-ol, and thereafter, 1.21 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 12 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 3.09 g of (2R,3R,4R)-3,5-bis((4-chlorobenzyl)oxy)-2-fluoro-4-hydroxypentanal=O-methyl=oxime in the form of a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH2:2][CH3:3].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:11]1[CH:10]=[C:7]2[C:8](=[O:9])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCCN1C(=O)c2ccccc2C1=O
Product: CCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
N-propylphthalimide (50 g) was nitrated in 500 g 99% nitric acid to produce 4-nitro-N-propylphthalimide under conditions described in Example 2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[CH:12]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:12]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 541.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH2:31](O)C.C(NC(C)C)(C)C>[Pd].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH2:29][CH3:31])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCC(C(=O)OC(C)(C)C)N1CCC(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 18 h

Procedure:
A mixture of Intermediate 112 [Mixture 1] (0.051 g), 10% palladium on carbon (0.01 g) and ethanol (5 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give a yellow gum. The gum (0.034 g) in DCM (2 ml) was treated with 6-chloronaphthylsulphonyl chloride1 (0.04 g) and N,N-diisopropylamine (0.073 ml) and stirred at room temperature for 24 h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was partially purified using SPE (silica, eluting with cyclohexane:ethyl acetate 1:1) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C1CNC(=O)C1.[Br:22][Br-]Br.N1CCCC1=O>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[C:8]1[CH:14]=[CH:15][C:5]([C:1](=[O:4])[CH:2]([Br:22])[CH3:3])=[CH:6][CH:7]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(C(=O)CC)cc1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)Br)cc1

Procedure:
Ethyl 4-propionylbenzoate (2.0 mmol), pyrrolidinone hydrotribromide (2.1 mmol) and 2-pyrrolidinone (2.2 mmol) were heated in THF (20 mL) at 50 C for 2.5 h. The mixture was cooled, filtered, concentrated under vacuum and the residual oil partitioned between H2O and MTBE. The aqueous layer was extracted with MTBE, and the combined organic layers were washed with saturated aqueous sodium metabisulfite solution, H2O, brine, dried over MgSO4 and the solvent removed under vacuum. The residue was purified by flash column chromatography (9:1 IHexane: MTBE) to afford ethyl-4(2′-bromopropionyl)benzoate as a clear oil.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C1COCC1>[C:1]([C:3]1([NH:9][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2]
Reactant: O=S1(=O)CCCO1
Reactant: C#CC1(N)CCCCC1
Solvent: C1CCOC1
Product: C#CC1(NCCCS(=O)(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 1-ethynylcyclohexylamine (6 g, 48.7 mmol) and 1,3-propane sultone (6.55 g, 53.6 mmol) in THF (35 mL) was heated at reflux for 2 hours (thick paste). The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with THF (3×5 mL), air-dried 15 minutes (7.3 g). The solid was suspended in ethanol (30 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature and the solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 10 min, and further dried in a vacuum oven at 60° C. overnight (crop 1, 7.10 g). The combined mother liquors were stirred overnight at room temperature. There was a lot of solid. The solid was collected by filtration, rinsed with acetone (3×5 mL), air-dried for 30 minutes, and then suspended in ethanol (12 mL). The suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature and the solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 2 minutes, and further dried in a vacuum oven at 60° C. overnight (crop 2: 1.85 g). Compound DX was obtained as a fine white solid (two crops in total 8.95 g, 75% yield). 1H NMR (500 MHz, D2O) δ 0.95-1.05 (m, 1H), 1.38-1.54 (m, 5H), 1.60-1.64 (m, 2H), 1.94 (qt, J=7.8 Hz, 2H), 2.85 (t, J=7.3 Hz, 2H), 3.01 (s, 1H), 3.22 (t, J=7.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 21.8, 22.3, 24.2, 34.4, 40.9, 48.0, 59.2, 78.6, 79.3. ES-MS 243.0 (M−1).