Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:20][C@H:19]2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][O:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:20][C@H:19]3[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:14][CH:13]=2)=[CH:4][CH:5]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(O)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.3 %

Procedure:
4-(bromomethyl)benzonitrile (0.47 g, 2.40 mmol) was added to a mixture of Intermediate J, tert-butyl(trans)-2-(4-hydroxyphenyl)cyclopropylcarbamate, (0.50 g, 2.00 mmol), K2CO3 (0.42 g, 3.00 mmol) and NaI (0.03 g, 0.20 mmol) in acetone (15 mL) and stirred at room temperature for 3 d. After removal of the solvent, the crude residue was dissolved in EtOAc (30 mL) and washed with brine (2×25 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (5%-50% EtOAc/Hexanes), affording 0.52 g of tert-butyl(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropylcarbamate [Rf=0.2 (30% EtOAc/Hexanes), pale yellow solid, 71% yield].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([CH2:15][CH2:14][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccncc1
Reactant: BrCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(CCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.32 g (25.0 mmol) of 4-picoline in 40 mL of THF at −78° C. was slowly added 17.5 mL of a 1.6 M solution of n-butyllithium in hexanes (28.0 mmol). The reaction mixture was allowed to warm to rt and stirred for 1 h at rt. This reaction mixture was added via cannula to a solution of 6.8 mL (50.0 mmol) of (2-bromoethyl)benzene in 30 mL of THF at −50° C. The mixture was warmed to rt, quenched by the addition of 50 mL of H2O and extracted with ether. The combined organic fractions were extracted with 2N HCl. The combined aqueous fractions were brought to pH=12 with 5N NaOH and again extracted with ether. The combined ether layers were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=3:1) to give the title compound.
Reaction SMILES: COCCOC.Br[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)c1cc(CBr)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cc2cccc(F)c2)on1
Yield: 60.9 %

Procedure:
1,2-Dimethoxyethane (8 mL) and water (2 mL) were added to the mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (0.710 g; 3.03 mmol), 3-fluorophenylboronic acid (0.481 g; 3.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.176 g; 0.151 mmol) and sodium carbonate (0.646 g, 6.07 mmol). The mixture was irradiated in a microwave oven at 130° C. for 15 min and was evaporated. The residue was partitioned between dichloromethane (30 mL) and brine (20 mL). The organic layer was separated and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) to afford 0.460 g (61%) of ethyl 5-(3-fluorobenzyl)isoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Product: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 355, 2-[2-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-imidazol-1-yl]-N-methyl-acetamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditins to give 405 MS: (ESI+)=497.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.93 (s, 0H), 7.38 (d, J=0.8 Hz, 1H), 7.32 (dd, J=8.3, 1.8 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.05 (d, J=0.8 Hz, 0H), 5.23 (s, 1H), 4.72 (s, 1H), 4.34 (t, J=5.0 Hz, 1H), 4.04 (s, 1H), 2.66 (t, J=4.4 Hz, 2H), 1.08 (s, 6H)
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:23])([C:16]1[C:21]([CH3:22])=[N:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:22][C:21]1[C:16]([C:11]2([OH:23])[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[N:17][CH:18]=[CH:19][N:20]=1
Reactant: Cc1nccnc1C1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nccnc1C1(O)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-Hydroxy-3-(3-methyl-pyrazin-2-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.1 g, 0.41 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1.5 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum to afford the title compound. LCMS m/z 220.1 [M+H]+. R.T.=0.34 min (Analytical Method 3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.C1COCC1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:6]=2[CH:10]=1
Reactant: C1=COCCC1
Reactant: Cc1cc2[nH]cnc2cc1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C#N)ncn2C1CCCCO1
Temperature: 75 °C
Yield: 59.7 %

Procedure:
To a stirred solution of 6-methyl-1H-benzo[d]imidazole-5-carbonitrile (7.9 g, 50 mmol, CASRN 952511-47-6) and THF (85 mL) at RT under nitrogen was added 3,4-dihydro-2H-pyran (34 g, 0.4 mol) and p-TsOH.H2O (0.9 g, 5 mmol) and the resulting mixture was heated at 75° C. for 3 h. The reaction mixture was cooled to RT, diluted with EtOAc (200 mL), and washed sequentially with sat'd. aq. Na2CO3 (300 mL) and brine (300 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 5% MeOH) to afford 7.2 g (60%) of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (176) as a yellow oil: MS (ESI) m/z=242 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:25][OH:26])[CH:13]=[N:14][C:15]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])[CH2:5][CH2:4][O:3]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([CH:35]([CH:42]2[CH2:44][CH2:43]2)[CH2:36][C:37]([O:39]CC)=[O:38])[CH:30]=1.[H-].[Na+].Cl>C1COCC1.O>[CH:42]1([CH:35]([C:31]2[CH:30]=[C:29]([O:26][CH2:25][C:12]3[CH:13]=[N:14][C:15]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=4[F:24])=[C:10]([O:9][CH2:8][CH:6]4[CH2:5][CH2:4][O:3][C:2]([CH3:27])([CH3:1])[CH2:7]4)[CH:11]=3)[N:34]=[CH:33][N:32]=2)[CH2:36][C:37]([OH:39])=[O:38])[CH2:44][CH2:43]1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OCC2CCOC(C)(C)C2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC2CCOC(C)(C)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of (5-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy)-6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methanol (930 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (945 mg) in THF (20 mL) was slowly added, at 0° C., 60% sodium hydride (300 mg) by small portions, and the mixture was stirred at 60° C. for 3 hr. After cooling to 0° C., water (1.0 mL) was added to the reaction mixture, and the mixture was further stirred at 60° C. for 1 hr. The mixture was acidified with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)), and saturated aqueous sodium carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound (192 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)C(C)C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.O>ClCCl>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:38](=[O:39])[C:37]([C:29]1[CH:28]=[C:27]([C:26]([F:25])([F:43])[F:44])[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=1)([CH3:42])[CH3:41])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1cnccc1C(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1cnccc1C(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
A solution of 397 mg (2 mmol) 3-amino-4-benzoylpyridine and 517 mg (4 mmol) N-ethyldiisopropylamine in 8 ml dichloromethane was cooled in an ice bath and a solution of 765 mg (2.4 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 8 ml dichloromethane was added dropwise. The reaction mixture was warmed to room temperature and was stirred overnight. Water (5 ml) was added and the organic layer was separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 235 mg (24%) of the title compound as orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH2:22][CH2:21][CH2:20][N:19]([CH3:24])[CH3:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)CCCO
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCCC(c1ccncc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 3-dimethylamino-1-propanol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 3-dimethylamino-propan-1-ol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (44 mg, 48%) as a white solid. The resulting solid was washed with hexane-ether and then, collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[F:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:14]1
Reactant: Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1CCNC1
Product: Cc1cc(N2CCC(F)C2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 4-chloro-2-methyl-1-nitrobenzene and 3-fluoropyrrolidine following the method used to prepare Intermediate 49. LCMS (ES+) 224.90 (M+H)+, RT 2.90 minutes (method 1).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cnc(N)cc1OCc1cccs1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc(NC(=O)Oc2ccccc2)cc1OCc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyl chloroformate (3.46 ml, 27.6 mmol) was added drop wise to a mixture of 6-amino-4-(thiophen-2-ylmethoxy)nicotinonitrile (intermediate 284, 2.90 g, 12.54 mmol) and pyridine (4.46 ml, 55.2 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 16 h at room temperature and then partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was purified by normal phase chromatography: 80 g RediSep® column, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 3) tR 1.14; ESI-MS 352.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C=O)ccc1OCc1ccccc1

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (0.658 g), benzyl bromide (0.812 g) and potassium carbonate (1.0 g) in acetone (30 ml) was stirred and heated under reflux for 6 hours. The solvent was removed and the residues were partitioned between water and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined organic layers were washed with brine and dried. Removal of the solvent gave the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]([F:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[O:27][C:28]4C=CC([N+]([O-])=O)=CC=4)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C[O-].[Na+]>CO>[F:38][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[O:27][CH3:28])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=C(Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
4-Nitrophenyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamate (1.90 g, 3.55 mmol) was slurried in MeOH (15 mL) and cooled in a −10° C. dry ice/acetone bath. Sodium methoxide (1.33 mL of a 30 wt % solution in MeOH, 7.10 mmol) was added dropwise over 10 min. The resulting bright yellow slurry was warmed to ambient temperature and poured into ice water (150 mL). After stirring vigorously for 10 min, the mixture was filtered on a Büchner funnel. The tan solid was rinsed with water and dried in air. Recrystallization from MeOH/water provided the title compound (0.989 g, 65%) as a tan solid: mp 183-184.5° C.; 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.14 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H), 6.79 (s, 1H), 3.80 (s, 3H); HRMS-FAB (m/z) [M+H]+ calcd for C18H13F5N4O3, 428.0908. found, 428.0903.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](Cl)=[O:31]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:30](=[O:31])[CH2:29][C:28]([CH3:34])([CH3:33])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(C)(C)CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 3,3-dimethylbutyryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 83% yield.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:9]1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:51][C@@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)C(O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>Cl.CN(C=O)C.C(Cl)Cl>[NH2:51][C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)[C:6]([NH:7][CH:8]1[CH2:9][N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:11]1)=[O:22]
Reactant: CC(C)(C)OC(=O)NC1CN(c2ncnc3ccccc23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)NC1CN(c2ncnc3ccccc23)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
The (1-quinazolin-4-yl-azetidin-3-yl)-carbamic acid tert-butyl ester (390 mg, 1.30 mmol) was dissolved in 7 mL, of 4M HCl and allowed to stir at 80° C. to completion after three hours. The aqueous solution was washed with ether (discarded), and the aqueous layer was concentrated in vacuo to afford the de-protected intermediate as a white solid. The flask containing this solid was charged with HOBt (193 mg, 1.43 mmol), EDCI (274 mg, 1.43 mmol), and the 2(S)-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (389 mg. 1.30 mmol). The mixture was suspended/dissolved in 12.0 mL of DMF and treated with TEA (905 μL, 6.49 mmol). The mixture was allowed to stir for four hours to completion. The contents were partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude Boc-intermediate as a white solid. The material was dissolved in 7 mL of DCM and treated with 4.0 mL of TFA. After two hours, the reaction solution was concentrated in vacuo to afford a pale yellow oil. The contents were partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 MeOH:DCM) to afford the pure 2(R)-amino-3-(4-chlorophenyl)-N-(1-quinazolin-4-yl-azetidin-3-yl)-propionamide as a colorless oil (177 mg, 30%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.02 (brs, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.85 (m, 3H), 4.29 (dd, J=15.6, 5.6 Hz, 2H), 3.64 (dd, J=8.8, 4.0 Hz, 1H), 3.22 (dd, J=13.6, 4.0 Hz, 1H), 2.78 (dd, J=14.0, 8.8 Hz, 1H). LCMS (APCI+) m/z 382 [M+H]+; Rt=0.76 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C([Li])CCC.[B:24](OC)([O:27]C)[O:25]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:24]([OH:27])[OH:25])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 28 (9.39 g, 0.03 mol) in anhydrous THF (100 ml), n-butyllithium (12.1 ml, 2.5M in hexane, 0.03 mol), trimethyl borate (6.24 g, 0.066 mol) in anhydrous THF (20 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: CN(C)S(C1C=CC([C:12]2[C:13]3CCN(C)C[C:18]=3[C:19]3[NH:24][C:23](=[O:25])[C:22](=[O:26])[C:20]=3[CH:21]=2)=CC=1)(=O)=O.ON=C1C2C=C(C3C=CC(S(N(C)C)(=O)=O)=CC=3)C3CCN(C)CC=3C=2NC1=O>>[NH:24]1[C:19]2[C:20](=[CH:21][CH:12]=[CH:13][CH:18]=2)[C:22](=[O:26])[C:23]1=[O:25]
Reactant: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)NC(=O)C3=O
Agent: CN1CCc2c(-c3ccc(S(=O)(=O)N(C)C)cc3)cc3c(c2C1)NC(=O)C3=NO
Product: O=C1Nc2ccccc2C1=O
Yield: 67 %

Procedure:
The reaction mixture (i.e. N,N-dimethyl-4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)-benzenesulfonamide and 4-(3-hydroxyimino-8-methyl-2-oxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)-N,N-dimethyl-benzenesulfonamide) was poured onto H2O (3.5 L), heated to reflux and then filtered warm to remove celite. The celite was washed with boiling water (750 mL), and the combined aqueous fractions allowed cooling slowly overnight for precipitation. The precipitate was filtered off, washed with H2O (2×250 mL) and 96% EtOH (2×250 mL) and then air dried to give 69.8 g (67%) of crude isatin derivative as the hydrosulfate. The crude product contained 11.4% (typically 9-13%) of the oxime.