Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH3:13])[C:8](=[O:12])[O:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:10][O:9][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:13])=[O:12])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CN(C(=O)OCCl)C1CCCCC1
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)N(C)C3CCCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 60.5 %

Procedure:
In the same manner as in step b) in Example 125, 165 mg of the title compound was prepared from 122 mg of chloromethyl N-cyclohexyl-N-methylcarbamate and 200 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 87 %

Procedure:
A solution of 4-bromo-2-nitrophenol (297, 1.00 g, 4.59 mmol) (scheme 65) in acetic anhydride (10 mL) was heated in a pressure vessel at 130-140° C. for 16 h. Most of the solvent was evaporated in vacuo and the resulting oil was kept in the freezer for 3 days. Crystallization occurred while thawing. The white crystals were suspended in a mixture of EtOAc/hexanes (9:1) and collected by filtration affording the title compound 328 (1.03 g, 87% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.33 (d, J=2.3 Hz, 1H), 8.02 (dd, J=8.6, 2.3 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 2.33 (s, 3H). LRMS: (m/z): 282.0/284.0 ((M+/M+2)+23).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]1COC[CH2:32]1>O.[Cl-].[Na+].O.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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([CH:31]=[CH2:32])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: C1CCOC1
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: [Cl-]
Solvent: O
Product: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Yield: 89 %

Procedure:
9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (0.5 g, 0.001 mol) and vinyltrifluoroborane/potassium hydride (0.34 g, 0.0026 mol) was dissolved in THF (5 mL) and 1 mL H2O (Tremblay-Morin et al (2006) Tetrahedron Letters 47(18):3043-3046). Cesium Carbonate (1.2 g, 0.0039 mol) was added and mixture was degassed with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.074 g, 0.064 mmol) was added. The reaction vessel was sealed and was heated at 110 C in an oil bath overnight. The reaction mixture was cooled to room temperature and the seal was removed. The crude product was isolated from an aqueous workup using H2O and brine. The crude product was purified using flash column chromatography (0-10% MeOH in DCM) to give 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.300 g, 89% yield
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:20]([C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[OH:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.00 g (26.12 mmol) of 4-chlorobromobenzene were dissolved in 100 ml of tetrahydrofuran at −78° C. Addition of 19.6 ml (31.34 mmol) of a 1.6N solution of n-butyllithium in hexane was followed by stirring for 15 min and then dropwise addition of 4.27 g (31.34 mmol) of 4-methoxybenzaldehyde dissolved in 30 ml of tetrahydrofuran. The mixture was stirred at −78° C. for 1 h, warmed to RT and then stirred for 1 h. The reaction solution was mixed with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solid was filtered. The solvents were removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator, and the aqueous residue was extracted with dichloromethane. Removal of the solvent resulted in 4.20 g (65% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([CH2:23][O:24][CH3:25])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[O-]S([O-])(=O)=O.[Mg+2].[C:32](O)([C:34](F)(F)F)=O.C(=O)C.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.CO>[CH2:32]([NH:1][C:2]1[C:6]2[C:7]([CH2:23][O:24][CH3:25])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1)[CH3:34]
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Reactant: O=C(O)C(F)(F)F
Agent: CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(COC)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (34.8 mg, 0.102 mmol) in chloroform (0.6 ml) and MeOH (0.3 ml) was charged with MgSO4 (45 mg, 0.374 mmol), TFA (24 μl, 0.312 mmol) and acetaldehyde (0.02 ml, 0.354 mmol). The mixture was stirred at RT for 1 hr, then charged with sodium cyanoborohydride (22 mg, 0.350 mmol) before it was stirred at RT for 1.5 hr. The mixture was filtered to remove insoluble matter, rinsing with MeOH and DCM and concentrated in vacuo. The residue was purified by mass-triggered reverse-phase HPLC to provide (R)-1-(3-(ethylamino)-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C19H25N6O2 [M+H]+ 369. found 369. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.96 (s, 1H), 7.33 (m, 4H), 7.23 (m, 1H), 7.15 (s, 1H), 5.56 (t, J=6.5 Hz, 1H), 4.85 (t, J=7.3 Hz), 4.63 (m, 2H), 3.32 (s, 3H, overlaps with H2O peak), 3.22 (m, 2H), 1.39 (d, 6.8 Hz, 3H), 1.20 (t, J=4.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.CN(C=O)C.S(Cl)([Cl:19])=O>>[Cl:19][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2oc(S)nc2c1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Subsequently, the 5-methyl-2-mercaptobenzoxazole (6.2 g, 38 mmol) was dissolved in thionyl chloride (36.9 mL) and 2.79 mL of DMF was added. The reaction mixture was then stirred at r.t. for 30 min. The solvent was removed under reduced pressure and to the residue was added toluene (2×60 mL) followed by evaporation each time to remove excess SOCl2 via an azetrope. The resultant crude product was dissolved in ethyl acetate (100 mL), washed with water (100 mL) and dried over Na2SO4. Evaporation of ethyl acetate gave crude 22 which was purified by silica-gel column chromatography (eluent: petroleum ether) to provide pure 2-chloro-5-methylbenzoxazole, compound 22, (3.5 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1ncc([N+](=O)[O-])c(Cl)n1

Procedure:
A suspension of 2-amino-4-hydroxy-5-nitropyrimidine (5.0 g, 32.1 mmol) in phosphorous oxychloride (100 mL) was refluxed overnight, and the excess phosphorous oxychloride was evaporated under reduced pressure. The residue was mixed with ice (100 g) in an ice-bath, and the mixture was neutralized with concentrated aqueous sodium carbonate solution. A yellow precipitate was collected by filtration and washed with water: yield, 1.39 g (25%); mp 191-194° C. dec.; 1H NMR δ 8.45 (br s, 2H, NH2, exchange with D2O), 9.03 (s, 1H, H-6); MS (EI) calcd. m/z for C4H3N4O235Cl 173.9944, found 173.9934; calcd. m/z for C4H3N4O237Cl 175.9915, found 175.9916.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[CH:15][N:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[C:30]([OH:31])[C:24]([Cl:23])=[CH:25][C:26]=3[F:32])=[CH:15][N:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCc1ccccc1

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride (3.4 g, 10 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline, (prepared as described in EP 061741 A2), (1.84 g, 11 mmol) in DMF (42 ml) was heated at 130° C. for 20 minutes. The resulting solid was filtered off, washed with isopropanol, ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxycinnoline as the hydrochloride salt (yellow solid. 3.5 g, 75%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:18]=[CH:17][C:11]2[NH:12][C@@H:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19].C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>CN(C=O)C>[F:7][C:8]1[CH:18]=[CH:17][C:11]2[N:12]([CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19]
Reactant: C[C@H]1COc2c(ccc(F)c2F)N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Yield: 79.7 %

Procedure:
To DMF (2.5 ml) was added potassium tertiary-butoxide (75 mg) under ice-cooling. After dropping a solution of the compound (100 mg) obtained in Example 78 and diethyl ethoxymethylenemalonate (233 mg) in DMF (0.5 ml), the resultant mixture was stirred for 2 hours. After treating in a conventional manner, the obtained residue was subjected to silica gel column chromatography to thereby give 153 mg (88%) of the title compound as an oily product. The physical constants of the obtained compounds was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4](C(=O)C)[CH2:3]1>O1CCOCC1.Cl>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
2 g 1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-ethanone were dissolved in a mixture of 6 ml dioxane and 6 ml of an aqueous 2 N solution of hydrochloric acid in a process vial. The vial was sealed with a teflon septum and placed in the microwave cavity. The reaction mixture was stirred for 15 minutes at 120° C. by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). After removal of the solvent under reduced pressure the residue was treated with an aqueous saturated solution of sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Filtration and concentration of the solvent under reduced pressure yielded a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:18][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and phenyl isocyanate. m/z (ES+) 264 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([O:21][CH2:22][C@H:23]1[O:28][C@H:27](Br)[C@H:26]([O:30][C:31]([CH3:33])=[O:32])[C@@H:25]([O:34][C:35]([CH3:37])=[O:36])[C@@H:24]1[O:38][C:39]([CH3:41])=[O:40])=[O:20].Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)(Cl)Cl.O>[C:31]([O:30][C@@H:26]1[C@@H:25]([O:34][C:35](=[O:36])[CH3:37])[C@H:24]([O:38][C:39](=[O:40])[CH3:41])[C@@H:23]([CH2:22][O:21][C:19](=[O:20])[CH3:18])[O:28][C@H:27]1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10])(=[O:32])[CH3:33]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)c1c(O)cccc1O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (1 g), potassium carbonate (4.54 g) and benzyltri(n-butyl)ammonium chloride (0.41 g) in chloroform (13 mL) were added water (0.5 mL) and acetobromo-α-D-glucose (2.7 g), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and the mixture was acidified by addition of 2 mol/L hydrochloric acid. The resulting mixture was extracted with ethyl acetate, and the extract was washed with water and brine. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was treated with methanol, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (1.38 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=O)[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>CCO.O=[Pt]=O>[CH2:17]([NH:21][CH2:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COc1cc(C=O)c2ccccc2c1OC
Reactant: CCCCN
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCCNCc1cc(OC)c(OC)c2ccccc12
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A suspension of PtO2 (40 mg) in EtOH (2 mL) was stirred with H2 at 25 psi for 30 min. Naphthaldehyde 18 (596 mg, 2.8 mmol) was dissolved in EtOH and added into the suspension followed by the addition of butylamine (219 mg, 3 mmol). The reaction mixture was hydrogenated for 6 h at 50 psi. The catalyst was filtered through Celite, washed with acetone and the filtrate was concentrated to dryness to give 19 as an oil (665 mg, 87%). The product was utilized in the following step without further purification. 1H NMR (CDCl3) 8.16 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H), 7.40-7.60 (m, 2H), 7.35 (s, 1H), 4.19 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 2.76 (t, J=7.0 Hz, 2H), 1.64 (bs, 1H), 1.45-1.60 (m. 2H), 1.30-1.45 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[CH2:13][C:14]([O:16][CH3:17])=[O:15].O.O.O.C([O-])(=O)C.[Na+]>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(C(F)(F)F)c1

Procedure:
3-Trifluoromethylaniline (80.5 g), methyl chloroacetate (44 ml) and sodium acetate trihydrate (114 g) were treated according to the method of Intermediate 1 to give a solid (84 g), a sample of which (ca. 1 g) was purified by FCC eluting with System A (1:1) to give a solid which was recrystallised from System A to give the title compound, m.p. 60°-63°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].Cl[CH:12](Cl)[C:13](O)=[O:14]>Cl>[CH3:1][C:2]1[C:3]2[N:10]=[C:12]([CH:13]=[O:14])[NH:9][C:4]=2[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(Cl)Cl
Reactant: Cc1ccc(N)c(N)c1C
Agent: Cl
Product: Cc1ccc2[nH]c(C=O)nc2c1C
Temperature: 25 °C

Procedure:
3,4-Dimethylbenzene-1,2-diamine (0.409 g, 3.0 mmol) and dichloroacetic acid (0.768 g, 6.0 mmol) in 4N HCl (10 mL) were heated at 100° C. for two days. After cooling to r.t. the mixture was filtrated and the mother liquor was extracted with chloroform (4 times). The pH was set to 12 using 2M NaOH and the resulting white precipitate was collected by filtration. The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39](=[O:41])[CH3:40])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][CH:35]([NH:38][C:39](=[O:41])[CH3:40])[CH2:34][CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: CC(=O)NC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and N-(piperidin-4-yl)acetamide (69 mg; 0.48 mmol) to give Example 137 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.96 (2H, d, J=8.0 Hz), 7.94-7.88 (1H, m), 7.78-7.68 (2H, m), 7.61 (2H, dd, J=4.5, 1.6 Hz), 7.56-7.48 (4H, m), 3.56 (3H, m), 2.78 (2H, d, J=11.1 Hz), 2.06 (2H, t, J=11.3 Hz), 1.81 (3H, s), 1.73 (2H, d, J=12.3 Hz), 1.43 (2H, t, J=11.6 Hz). LC/MS (Method C): 539 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 99.9%).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[CH:27]1(O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reactant: OC1CCCCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)=CCc1ccc(C(C)C(=O)OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To an ice-cooled solution of 26.0 g of 2-(p-prenylphenyl)propionic acid in 200 ml of benzene were added dropwise 15.7 g of thionyl chloride and 10.4 g of pyridine at the same time with stirring over one hour, and then the mixture was stirred at room temperature for 30 minutes. After ice-cooling, to this mixture were added 13.0 g of cyclohexanol and 10.4 g of pyridine. The resulting mixture was stirred for 2 hours at room temperature, and then washed with 1 N hydrochloric acid, water, 5% aqueous sodium hydroxide and water successively, and dried over anhydrous mangesium sulfate. The solvent was evaporated to give 23.5 g of cyclohexyl 2-(p-prenylphenyl)propionate. b.p. 142° C./0.06 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19])C(=O)C(F)(F)F.[OH-].[Na+]>C(O)C>[CH3:1][NH:2][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: CN(C(=O)C(F)(F)F)c1ccccc1Sc1ccccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1ccccc1Sc1ccccc1C#N
Yield: 90 %

Procedure:
In 20 ml of ethanol was suspended 2.8 g of 2-[2-(N-methyl-N-trifluoroacetylamino)phenylthio]benzonitrile followed by addition of 4 ml of 10% aqueous sodium hydroxide solution, and the mixture was heated on a water bath for 5 minutes. After cooling, the crystals were collected by filtration and washed with 50% aqueous ethanol to give 1.8 g of the title compound as white crystals.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([CH:22]=[O:23])[N:19]([CH3:24])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:25]12CC(C=C1)C=[CH:26]2>O1CCOCC1>[CH3:24][N:19]1[C:20]([CH:22]=[O:23])=[CH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[CH:26]=[CH:25][N:3]=[N:2]4)[O:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[N:18]1
Reactant: Cn1nc(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2)cc1C=O
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2)cc1C=O
Temperature: 90 °C
Yield: 47.3 %

Procedure:
3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5 carbaldehyde (Intermediate 13, 50 mg, 0.15 mmol), bicyclo[2.2.1]hepta-2,5-diene (0.17 ml, 1.58 mmol) and dioxane (1 ml) were combined and warmed to 90° C. for 4.5 hours. The mixture was evaporated and purified by chromatography on silica gel, eluting with ethyl acetate to give the title compound as a white solid (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>Cl.O1CCOCC1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Reaction time: 0.5 h
Yield: 187.4 %

Procedure:
Tert-Butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (0.322 g, 1 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford 3-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride (0.242 g, 0.937 mmol, 94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.14-3.29 (m, 4H) 3.27-3.38 (m, 4H) 7.33 (d, J=8.34 Hz, 1H) 7.80 (dd, J=8.46, 1.89 Hz, 1H) 8.02 (d, J=2.02 Hz, 1H) 9.37 (br. s., 2H); 4H) 7.25 (d, J=8.59 Hz, 1H) 7.77 (dd, J=8.34, 2.02 Hz, 1H) 7.97 (d, J=2.02 Hz, 1H); [M+H] calc'd for C11H12ClN3, 222; found, 222.