Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[C:16]([Br:20])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2nc3c(OC)ccc(Br)n3n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a stirred solution of 1-(8-methoxy-[1, 2, 4]triazolo[1,5-a]pyridine-2-yl)-cyclopropanecarboxylic acid ethyl ester (25 g, 95.7 mmol) in acetonitrile (300 mL) at RT, N-bromosuccinimide (34 g, 191.5 mmol) was added portion wise. After addition the reaction mixture was stirred at RT for 6 hours. The reaction mixture was diluted with EtOAc (600 mL), washed with water (100 mL×2), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (0 to 10% EtOAc in dichloromethane as eluent) to afford the title compound (25 g, 77%, colorless solid). 1H NMR (400 MHz, DMSO): δ=7.44 (d, J=8.4 Hz; 1H), 7.07 (d, J=8 Hz; 1H), 4.13-4.08 (m, 2H), 3.97 (s, 3H), 1.60-1.57 (m, 2H), 1.48-1.45 (m, 2H), 1.13 (t, J=7.4 Hz; 3H) ppm.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[OH-].[Na+].[N:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16](OCC)=[O:17])=[N:10][CH:9]=1>C(O)C>[CH3:3][C:2]1[NH:4][C:16](=[O:17])[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccncn2)cc(=O)[nH]1
Yield: 50.4 %

Procedure:
To a suspension of 200 g (2.11 mol) of acetamidine hydrochloride (1:1) in 1.2 L of ethanol were added 84 g (2.11 mol) of sodium hydroxide and 410 g (2.11 mol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582). The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was treated with water and the precipitate was filtered, washed with diethyl ether and ethyl acetate. The precipitate was stirred in a mixture of ethanol/water in the proportions 2/1 for 30 minutes to afford 200 g (50%) of the desired compound as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:1]([C:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCCC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=CC(=O)OCC)Nc1ccccc1

Procedure:
A solution of aniline (6 mmol), ethyl 3-oxodecanoate (6 mmol) and toluene-p-sulfonic acid (50 mg) in dry toluene (60 ml) was heated under reflux for 24 hours using Dean-Stark apparatus for the azeotropic removal of water. The solvent was removed in vacuum to afford the title product as an oil which was used without purification in the next step.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1.CN(C)C=O>O1CCCC1.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>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])[CH:2]=[CH2:3]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C=CCc1cc(C(C)=O)ccc1O
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: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(C)=O)ccc1-c1cc(F)ccc1OC
Temperature: 120 °C

Procedure:
A mixture of 3′-allyl-4′-hydroxyacetophenone (0.352 g, 2.0 mmol), N-phenyl-bis(trifluoromethane) sulfonimide) (0.710 g, 2.0 mmol) and potassium carbonate (0.830 g, 6.0 mmol) in tetrahydrofuran (3.0 ml) was heated in a microwave oven at 120° C. for 10 min. The resultant mixture was treated with 5-fluoro-2-methoxyphenyl boronic acid (0.680 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.05 mmol) and dimethylformamide (1.0 ml) and heated in a microwave oven at 120° C. for 10 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 9:1 heptane/ethyl acetate. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone. A solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone (0.319 g, 1.1 mmol), sodium cyanoborohydride (0.140 g, 2.2 mmol) and ammomium acetate (1.7 g, 22 mmol) was stirred under nitrogen at ambient temperature for 72 h, evaporated to dryness under reduced pressure and partitioned between dichloromethane and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (19.0 mg, 0.07 mmol) in dichloromethane (1 ml) was added triethylamine (6.7 mg, 0.07 mmol) and 3,4-di-fluorophenyl sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight and the solvent evaporated. The residue was purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound. 1H NMR (400 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.13 (q, 1H), 7.04-6.90 (m, 4H), 6.88-6.83 (m, 1H), 6.77 (q, 1H), 5.67 (dt, 1H), 4.99-4.82 (m, 3H), 4.57 (dq, 1H), 3.71 (s, 3H), 3.09 (br s, 2H), 1.51 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[H-].[Na+].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>CN(C=O)C>[S:13](=[O:16])(=[O:15])([O:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[NH2:14]
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccccc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1CCOS(N)(=O)=O
Yield: 43 %

Procedure:
A mixture of 2.65 g (0.019 mole) of 2-methylphenethyl alcohol in 10 ml DMF was added dropwise to a suspension of sodium hydride (1.1 g, 60% in oil; 0.08 mole) in 35 ml DMF at 0°-5° C. The suspension was stirred for 20 min under argon after which sulfamoyl chloride (2.86 g, 0.02 mole) was added portion wise at 0°-5° C. After stirring for 20 min the resultant suspension was poured into ice and extracted twice with Et2O. The combined organic phases were washed with saturated brine, dried over potassium carbonate and concentrated in vacuo to a syrup which was purified by preparative HPLC with hexane/EtOAc (1:1, v/v) as the eluant to give 1.76 g (43%) of the title compound as a solid, mp 50°-52° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][C:9](=[CH2:22])[S:8]1)=[O:5])[CH3:2].C[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])[CH3:2]
Reactant: C=C1CN(c2cccc(C(F)(F)F)c2)C(=NC(=O)OCC)S1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-tri-fluoromethylphenyl)-5-methylenethiazolidine (2.0 g) and sodium methoxide (28 % methanolic solution; 1.2 g) in ethanol (50 ml) was refluxed for 30 minutes. After removal of the solvent under reduced pressure, the concentrated residue was extracted with chlorofom (200 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 1.6 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methyl-thiazoline (Compound No. 1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[OH-].[Na+].CO.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:41][N:42]([CH3:47])[CH2:43][C:44]([N:17]1[CH2:18][CH2:19][CH:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=2)[CH2:15][CH2:16]1)=[O:45]
Reactant: CN(C)CC(=O)O
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(C3CCN(C(=O)CN(C)C)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) (as prepared in Example 35, 20.0 mg, 0.0320 mmol) in 2 mL of 1:1 1N NaOH/MeOH solution was stirred at RT for 1 h. Treated with 20 mL of EtOAc, the mixture was washed with H2O (3×5 mL). The aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid. The solid was added to a mixture of N,N-dimethylglycine (5.0 mg, 0.048 mmol), EDCI (9.2 mg, 0.048 mmol), HOBt (6.5 mg, 0.048 mmol) and DIEA (16.7 μL, 0.096 mmol) in 0.80 mL of DCM. The resulting mixture was stirred at RT for 4 h. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×5 mL), brine (5 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-5% MeOH/DCM) gave 12 mg (78%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 11.0 (s, 1H), 9.17 (s, 1H), 8.31 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=1.3 Hz), 7.05 (d, 1H, J=1.8 Hz), 7.01 (dd, 1H, J=8.4, 1.8 Hz), 6.87 (d, 1H, J=1.3 Hz), 4.77 (d, 1H, J=13.3 Hz), 4.24 (d, 1H, J=13.3 Hz), 3.07-3.25 (m, 3H), 2.96 (d, 2H, J=11.8 Hz), 2.61-2.77 (m, 4H), 2.33 (s, 6H), 1.82-1.94 (m, 4H), 1.53-1.70 (m, 3H), 1.32-1.47 (m, 2H), 1.09 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C27H36N6O2, 477.3 (M+H), found 477.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH:13]([NH2:22])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NC1COCCC1=O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1COCCC1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.4 %

Procedure:
(4-Oxo-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (CAS 477584-38-6, 446 mg, 2.07 mmol) was dissolved in 20 mL methanol. Ammonium acetate (1.63 g, 21 mmol) and sodium cyanoborohydride (507 mg, 8.1 mmol) were added and the reaction mixture was stirred at room temperature for 2 days. Ethyl acetate and 2N sodium carbonate solution were added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica eluting with a gradient (dichloromethane/methanol/ammonia 100:0:0→140:10:1) to provide 199 mg (44%) of the title compound as a white solid. MS (m/e): 161.2 (M-butene)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12]SCCCCCC)[NH:4][N:3]=1.[CH2:20](SCCCl)[CH2:21][CH2:22][CH2:23]CC>>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:20][CH2:21][CH2:22][CH3:23])[NH:4][N:3]=1
Reactant: CCCCCCSCCCl
Reactant: CCCCCCSCCSCCSc1nc(N)n[nH]1
Product: CCCCCCSCCSc1nc(N)n[nH]1
Yield: 86 %

Procedure:
Compound 6 was prepared using the procedure used for Compound 12, but with 2-chloroethyl hexyl sulfide as the starting material. The yield was 86%. A portion was recrystallized from ligroin/ethyl acetate to obtain a solid, m.p. 76.5°-78° C. Analysis: Calculated for C10H20N4S2 : C, 46.12; H, 7.74; N, 21.51. Found: C, 46.00; H, 7.56; N, 21.56.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])[C@@H:18]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[O:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])[C@@H:18]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[O:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](Oc3ccc([N+](=O)[O-])cc3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](Oc3ccc(N)cc3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 17 h

Procedure:
To 27.4 g of 4-nitrophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranoside suspended in 150 ml of acetic acid was added 2.7 g of 10% palladium-on-charcoal catalyst in a Parr hydrogenation bottle, and this was hydrogenated on a Parr hydrogenator for 17 hours. The catalyst was filtered from the solution through diatomaceous earth and washed thoroughly with methanol. The solvents were evaporated in vacuo. The residue was dissolved in one liter of toluene and again evaporated. The residue was dissolved in methylene chloride and passed through a pad of magnesium silicate and the solvent was evaporated to yield the title compound as a light yellow oil. A 3.5 g portion of this was crystallized from methanol to yield 2.6 g of an off-white crystal, m.p. 173°-175° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[C:30]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:29][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[NH:22][C:18]=2[CH:17]=1)=O>CO.O>[CH3:41][S:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:30]2[C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][NH:11]3)=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[N:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:33][CH:34]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of potassium carbonate was added to a solution of 40 mg of 2,2,2-trifluoro-1-(2-(6-(4-methanesulfonyl-phenoxy)-2-pyrazin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone in a mixture of 1.6 ml of methanol and 0.4 ml of water, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and aqueous saturated ammonium chloride was added to the residue, then extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol/aqueous ammonia=90/10/1) to obtain the entitled compound as an oily substance.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@H:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:40]1([C:46]2[CH:53]=[CH:52][C:49](C=O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[B-]C#N.[Na+].C(O)(=O)C>C(Cl)Cl>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:52][CH:53]=2)[CH:45]=[CH:44][C:43]([CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C@@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][N:10]4[CH2:9]3)[CH2:18][CH2:17]2)=[CH:42][CH:41]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H]2Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](CN1CCN(Cc3ccc(-c4ccccc4)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of tert-butyl (S)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 394 (7.2 g, 20.26 mmol), trifluoroacetic acid (24 ml) and methylene chloride (72 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (100 ml), then neutralized with triethylamine (20 ml, 143.49 mmol). The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (72 ml). To the solution, 4-phenylbenzaldehyde (7.38 g, 40.52 mmol), sodium cyanotrihydroborate (3.82 g, 60.78 mmol), and acetic acid (3.48 ml, 60.78 mmol) were added in this order followed by stirring at room temperature for 24 hours. The precipitates were filtered off, washed with methanol, and purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford (S)-2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (5.52 g, yield 65%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH2:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[OH:30][CH2:29][C:28]([O:27]/[N:26]=[C:22](/[C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)\[CH3:23])([CH3:32])[CH3:31]
Reactant: CC(C)(CO)ON
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Product: C/C(=N\OC(C)(C)CO)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 97.7 %

Procedure:
The title compound (12.0 mg, 89%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (8.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.94 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.46 (dd, 1H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1.95 (1, 1H), 1.41 (s, 6H). LCMS (method A): [MH]+=410, tR=5.39 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:31][CH2:32][OH:33])[CH2:20][C:21]([N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:31][CH:32]=[O:33])[CH2:20][C:21]([N:23]([CH3:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C(=O)CC(CC=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reaction time: 0.5 h
Yield: 117.3 %

Procedure:
Oxalyl chloride (7.74 g) in CH2Cl2 (80 mL) was added to a -78° C. solution of DMSO (9.5 g) in CH2Cl2 (30 mL) over 15 mins. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (50 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (17.15 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (14.76 g) in CH2Cl2 (20 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was washed with water (100 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (20 g). Silica gel chromatography eluting with 5-15% EtOAc/Hex gave the title compound (15.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.I[C:20]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[F:26][C:25]1[C:24]([F:27])=[C:23]([F:28])[C:22]([F:29])=[C:21]([F:30])[C:20]=1[C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Reactant: COc1ccc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 93 %

Procedure:
Compound 10 (11.3 g, 45.54 mmol, 1 equiv) and iodopentafluorobenzene (10.6 g, 36.2 mmol, 1 equiv) were dissolved in toluene (200 mL) and 1.0M potassium carbonate solution (200 mL). Tetrabutylammonium bromide (1.6 g, 5 mmol, 0.11 equiv) was added and the solution sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.63 g, 2.28 mmol, 0.05 equiv) was added and the reaction was refluxed for one day. The reaction was cooled to room temperature, then the layers were separated. The aqueous phase was back extracted with ethyl acetate (2×200 mL). Combined organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over silica gel (200 g), eluting with heptanes to give 2,3,4,5,6-pentafluoro-2′-methoxy-5′-methyl-1,1′-biphenyl (11) (9.7 g, 74% yield) as a pale-yellow oil. This material contained a small amount of unreacted iodopentafluorobenzene which was identified by 19F NMR. The material was used subsequently.