Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C[Si](Cl)(C)C.C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>C1COCC1.CCCCCC>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([CH:22]=[O:23])=[C:7]([F:9])[CH:6]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1cc(F)c(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-difluoroaniline (12.9 g, 0.1 mol) in anhydrous THF (400 mL) was cooled at −78° C. and treated with nbutyllithium (2.5 M in hexane, 84 mL, 0.21 mol, 2.1 equv.) dropwise over 25 min. After stirring at −78° C. for 30 min, trimethylsilyl chloride (1.0 M in THF, 210 mL, 0.21 mol, 2.1 equiv.) was added dropwise over 30 min. The temperature was allowed to rise to 23° C. and stirred overnight. After re-cooling to −78° C., additional n-butyllithium (2.5 M in hexane, 44 mL, 0.11 mol, 1.1 equiv.) was added dropwise over 20 min, and the reaction mixture was stirred at that temperature for 5 hours to form the anion. Then dimethylformamide (11.6 ml, 0.15 mol, 1.5 equiv.) was added dropwise over 20 min. The temperature was allowed to rise to 23° C. and stirred overnight. The mixture was cooled in an ice-bah and acidified to pH=1 by slow addition of aqueous HCl (1.0 M, 220 mL, 0.22 mol). After stirring 15 min, the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and evaporated to dry. The residue was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 50% ethyl acetate in hexane. Relevant fractions were combined to give the title compound.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:32][CH3:33])=[C:14]([C:16](=[N:30][OH:31])[CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.ClCCl>[C:34]([O:31][N:30]=[C:16]([C:14]1[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][C:13]=1[NH:32][CH3:33])[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NOC(C)=O
Yield: 85 %

Procedure:
A solution of methyl 4-[2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]-2-(hydroxyimino)ethyl]-3-methoxybenzoate (79.9 mg), 4-(dimethylamino)pyridine (22 mg), and acetic anhydride (0.17 ml) in dichloromethane (11 ml) was stirred under a nitrogen atmosphere for 15 hours. The solution was diluted with dichloromethane, washed with 5% w/v sodium hydrogen sulfate, water, and brine, then dried (MgSO4), and evaporated to give methyl 4-[2-(acetoxyimino)-2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]ethyl]-3-methoxybenzoate (74.1 mg, 85%) as a pink solid; NMR (80 MHz, CDCl3): 1.2-1.8[8H, (CH2)4 ], 2.1(s, 3H, CH3CO), 3.0(d, 3H, NCH3), 3.3(dd, 2H, CH2NH), 3.9(2s, 6H, 2×OCH3), 4.3(s, 2H, ArCH2), 5.8(broad, 1H, NHCO), 6.7(d, 1H), 7.0(d, 1H), 7.4-7.6(m, 3H), 7.8(d, 1H), 8.5(broad, 1H, CH3NH).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][CH2:15]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11](=[O:20])(=[O:19])[NH:12][CH2:13][CH:14]2[O:18][CH2:17][CH2:16][CH2:15]2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)NCC2CCCO2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)NCC2CCCO2)CC1

Procedure:
The reaction was carried out in a manner analogous to that of Example 31, using 32 g of 4-chloro-3-tetrahydrofurfurylsulfamoyl-benzoic acid and 30 g of N-methylpiperazine. The crude product was purified by recrystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].CN(C)CCN(C)C.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30].ICCCC>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:27]([C:8]1[C:7]([O:9][CH2:10][O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]=1[O:2][CH3:1])[CH2:28][CH2:29][CH3:30]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCI
Product: CCCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Reaction time: 0.5 h

Procedure:
10 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 200 ml of anhydrous toluene under argon gas stream conditions, to this solution were added 50 ml of hexamethylphosphoric triamide and 8.75 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA), and the mixture was cooled in a dry ice-acetone mixture bath. To this cooled mixture was added dropwise 39 ml of n-butyllithium (1.5 M, n-hexane solution), then stirred the mixture for 30 minutes. Next, 8.9 ml of 1-iodobutane was added to the reaction mixture, and the temperature was back to room temperature by taking for 12 hours. By procedures similar to those described in Reference Example 1, the above-mentioned reaction mixture was purified to obtain 8.5 g of 3-butyl-1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene. Colorless oily substance.
Reaction SMILES: [C:1](N)(=O)[CH2:2][CH2:3]C(N)=O.CCN([CH:15]([CH3:17])[CH3:16])C(C)C.[C:18]([O-:25])(=[O:24])[CH2:19][CH2:20][C:21]([O-:23])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:3]([O:22][C:21](=[O:23])[CH2:20][CH2:19][C:18]([O:25][CH2:17][CH:15]=[CH2:16])=[O:24])[CH:2]=[CH2:1]
Reactant: NC(=O)CCC(N)=O
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C([O-])CCC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CCC(=O)OCC=C
Temperature: 25 °C
Reaction time: 24 h
Yield: 142.2 %

Procedure:
To a solution of 10 (380 mg, 1.1 mmol), DIPEA (1 mL, 5.7 mmol), and 11 (0.37 g, 1.2 mmol) in DMF (30 mL) was added HATU (0.43 g, 1.1 mmol) and the solution was allowed to stir for 24 h at room temperature. The solution was diluted with EtOAc (150 mL) and washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield an pale yellow oil. This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc) to yield 12 (0.31 g, 44%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.86-6.91 (m, 9 H), 5.82 (m, 2 H) 5.67 (m, 1 H), 5.09 (m, 4 H), 3.48 (s, 3 H), 2.73-2.28 (m, 5 H), 1.92 (m, 1 H), 1.61 (m, 1 H), 1.42 (s, 9 H), 1.27 (m, 1 H), 0.93 (m, 6 H); ESI MS m/z=626 [C35H42F3N3O4+H]+.
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:46])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 150 mg (0.25 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-(3-naphthalen-1-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl) acetamide, prepared as in Example 34, in 5 mL of DMF at 0° C. is added 0.45 mL (0.45 mmol, 1.8 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 28 μL (0.45 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred 3 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 3/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 120 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.93-7.86 (m, 2H), 7.77 (d, 1H, J=8.0), 7.60-7.06 (m, 16H), 6.89 (dd, 1H, J=0.8, 8.1), 4.88 (m, 1H), 4.34 (s, br, 2H), 3.81 (s, 3H), 3.20 (d, 1H, J=14.7), 3.00 (d, 1H, J=14.7), 1.01 (m, 9H); low resolution MS (FAB)m/e 612 (MH+), 611 (M+), 447.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=2[O:22][CH2:23][O:24][CH3:25])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:27][C:28](=[O:30])[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:28]([C:27]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=3[O:22][CH2:23][O:24][CH3:25])=[CH:6][C:3]=2[CH:4]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)CCl
Reactant: CCc1cc(-c2ccc(O)c(C=O)c2)c(OCOC)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(-c2ccc3oc(C(C)=O)cc3c2)c(OCOC)c(C(C)(C)C)c1
Temperature: 60 °C
Yield: 54 %

Procedure:
A mixture of 333 mg (0.969 mmol) of 2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde, 116 mg (1.26 mmol, 0.1 mL) of chloroacetone and 473 mg (1.45 mmol, 1.5 equivalents) of Cs2CO3 in 5 mL of dry DMF was heated to 60° C. overnight. After cooling, water was added (15 mL) and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4. Evaporation of the solvents followed by purification over a short silica plug afforded 2-acetyl-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzo[b]furan as a clear yellow oil (200 mg, 0526 mmol, yield: 54%). 1H NMR(CDCl3), δ:7.85 (d, J=1.4 Hz, 1H), 7.68 (dd, J=8.7, 1.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 4.44 (s, 2H), 3.21 (s, 3H), 2.65 (m, 2H), 2.63 (s, 3H), 1.48 (s, 9H), 1.27 (t, J=7.7 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[C:11]([O:14][CH2:15][CH2:16]Br)(=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:11]([O:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])(=[O:13])[CH3:12]
Reactant: NC(=O)c1cccc(O)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
A mixture of 3-hydroxybenzamide (3.0 g, 21.9 mmol) prepared as in Example 1, 2-bromoethyl acetate (11.9 g, 70.9 mmol), and K2CO3 (5.7 g, 41.2 mmol) in 40 cc dry dimethyl formamide (DMF) was stirred at 25° C. for 48 hours and filtered. The filtrate was evaporated in vacuo and the resulting residue was recrystallized from 90% EtOH(H2O) to give 3.2 g (65%) of the desired product as a white crystalline powder, mp 121°-122° C. Here, as in the other examples, the product compound was identified by elemental analysis as well as by IR and mass spectroscopy methods.
Reaction SMILES: [NH:1]=[C:2]1[N:6]=[C:5]([N:7]([CH3:9])[CH3:8])[S:4][S:3]1.[C:10]([N:14]=[C:15]=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[C:10]([NH:14][C:15]([N:1]=[C:2]1[N:6]=[C:5]([N:7]([CH3:9])[CH3:8])[S:4][S:3]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N=C=O
Reactant: CN(C)c1nc(=N)ss1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1nc(=NC(=O)NC(C)(C)C)ss1

Procedure:
A suspension of 4.75 parts of the hydrobromide salt of 3-imino-5-dimethylamino-3H-1,2,4-dithiazole, two parts of t-butyl isocyanate, two parts of triethylamine, and 50 parts of tetrahydrofuran was stirred and refluxed for two days. The reaction mixture was cooled and the insoluble triethylammonium bromide was removed by filtration and discarded. The filtrate was then evaporated under reduced pressure leaving a white solid, which was recrystallized from isopropanol to afford 3.4 parts of 1-t-butyl-3-(5-dimethylamino-3H-1,2,4-dithiazol-3-ylidene)urea, m.p. 174°-177°C. dec.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[C:34]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:30]=1)=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[C:34]([NH:35][C:36]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:42])=[CH:33][CH:32]=[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:30]=1)/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1C=O
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.1 %

Procedure:
To a slurry of 60% of sodium hydride (110 mg, 2.76 mmol) in THF (8 mL) at 0° C. was added 1A (900 mg, 2.5 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of 1E (680 mg, 2.3 mmol) in THF (8 mL) was added over 10 min at 0° C., then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as an white foam (105 mg, 9%). LC/MS (method A): retention time=4.16 min, (M+H)+=504.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH:15][S:16]([CH2:19][C:20](O)=[O:21])(=[O:18])=[O:17]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:20](=[O:21])[C:19]([S:16]([NH:15][C:14]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:12]([OH:11])[CH:13]=1)(=[O:17])=[O:18])=[CH:7]2
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1O
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CC(=O)O
Product: COc1ccc(NS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1O

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 3-hydroxy-4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 225-226° C.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:27])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[O-].[Na+]>O1CCCC1>[CH3:22][C:21]1[N:17]([CH2:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[S:7][CH:8]=[C:4]([C:3]4[CH:35]=[C:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:1][N:2]=4)[N:5]=3)[CH2:10][CH2:11]2)=[O:27])[N:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C#Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(-c3cc(-c4ccccc4)on3)cs2)CC1

Procedure:
4-[4-[(Hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.2 g, 0.5 mmol) was suspended in tetrahydrofuran (20 mL), and phenylacetylene (1.1 mL, 1 mmol) was added, followed by a slow dropwise addition of Clorox® bleach solution (6.15 wt. % sodium hypochlorite, 10 mL) over 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×0 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give an oil, which was purified by flash column chromatography on silica gel using 10% methanol in ethyl acetate as eluant to give 70 mg of the title product, a compound of present invention, as a clear yellow oil.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CS(C)=O>[C:1]1([C@@H:7]([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([O:20][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC1CCc2c(O)cccc2C1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccc2c1CCC(N[C@@H](C)c1ccccc1)C2
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A solution of (6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino]-1-naphthol (267 mg) in dimethylsulfoxide (3 ml) was added dropwise to a stirred suspension of 60% sodium hydride (44 mg, washed with n-hexane) in dimethylsulfoxide (0.5 ml) at room temperature in a nitrogen atmosphere over 15 minutes, and the mixture was stirred at 50° C. for 10 minutes and cooled to room temperature. Ethyl bromoacetate (167 mg) in dimethylsulfoxide (1 ml) was added thereto and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed twice with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (dichloromethane-ethanol) over silica gel to afford ethyl [(6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino]-1-naphthyloxy]acetate (243 mg) as a brown oil.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26](Cl)=O>ClC(Cl)C>[Cl:24][CH2:25][C:26]1[O:1][N:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[N:4]=1
Reactant: N=C(NO)c1ccc2ccccc2c1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: ClCc1nc(-c2ccc3ccccc3c2)no1
Temperature: 50 °C
Yield: 21.4 %

Procedure:
A solution of N-Hydroxy-naphthalene-2-carboxamidine (364 mg, 1.95 mmol) in dichloroethane (6 mL) and DIEA (683 μL, 3.91 mmol) was treated with a solution of chloroacetyl chloride (157 μL, 2.350 mmol) in dichloroethane (2 mL) which was added dropwise to the reaction vessel at room temperature. After the addition, the reaction mixture was heated at 50° C. for 4 hours. The reaction mixture was then concentrated to dryness and redissolved in dichloromethane. The organic layer was washed with saturated aqueous NaHCO3 and brine, respectively. The organic layer was dried over anhydrous Na2SO4, concentrated onto silica gel and purified by flash chromatography (0-50% ethyl acetate/hexanes gradient) to afford the required intermediate, 5-chloromethyl-3-naphthalen-2-yl-[1,2,4]oxadiazole (102 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[N:11]([C:12]2[CH:13]=[C:14]([CH2:22][C:23]([NH2:25])=[O:24])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.[C:30](Cl)([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(OCC)(=O)C>[NH2:25][C:23](=[O:24])[CH2:22][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([N:11]2[C:7]([NH:6][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[CH:8][C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:10]2)[CH:13]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cc(CC(N)=O)c3ccccc3c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cc(CC(N)=O)c3ccccc3c2)n1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of saturated sodium bicarbonate (20 mL), ethyl acetate (20 mL) and 2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)naphthalen-1-yl)acetamide (300 mg, 0.931 mmol) was added Troc-Cl (296 mg, 1.40 mmol). The mixture was stirred vigorously overnight. The mixture was diluted with ethyl acetate (30 mL) and the organic phase was separated, washed with 5% citric acid (30 mL) and brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give a solid which was triturated with ethyl acetate and filtered to provide 2,2,2-trichloroethyl 1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-tert-butyl-1H-pyrazol-5-ylcarbamate (241 mg, 52% yield). MS (ESI) m/z: 499.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([CH3:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:20][OH:21])[CH:10]([CH3:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)c1cccnc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CC(C(=NO)c1ccc(Cl)cc1Cl)c1cccnc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 3.6 g of 2',4'-dichloro-2-methyl-2-(3-pyridyl)acetophenone in 15 ml of ethanol and 4 ml of water is treated with 1.4 g of hydroxylamine hydrochloride, 3 ml of pyridine and 90 mg of 4-N,N-dimethylaminopyridine and the reaction mixture is heated to reflux temperature. After 16 hours, it is poured into ice-water and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline crude product is recrystallised from methylene chloride/n-hexane. 2',4'-Dichloro-2-methyl-2-(3-pyridyl)acetophenone oxime is obtained as an E/Z isomer mixture in the form of beige crystals, m.p. 163°-165° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=1.[Na+].[Cl-:26]>CN(C=O)C>[ClH:26].[Br:1][C:11]1[C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[CH:23]=[CH:24][C:10]=1[OH:9]
Reactant: [Cl-]
Reactant: Oc1ccc2c(c1)ncn2-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: Oc1ccc2c(ncn2-c2ccccc2)c1Br

Procedure:
A solution of N-bromosuccinimide (0.72 g, 4.04 mmol) in DMF (5 mL) was added dropwise at room temperature to a solution of 5-hydroxy-1-phenylbenzimidazole (0.85 g, 4.04 mmol) in DMF (30 mL). After 1 hour the solution was diluted with aqueous NaCl and extracted into EtOAc, and the extract was worked up to give a solid which was chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:1) gave foreruns, while EtOAc eluted Example 64 (0.88 g, 75%). HCl salt: mp (MeOH/Et2O) 244-246° C.