Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:8][C:4]1[N:3]=[C:2]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2cccc(F)n2)cc1
Yield: 69 %

Procedure:
2,6-Difluoropyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (1.32 g) and potassium carbonate (3.60 g) were suspended in acetonitrile (10 mL), and heated under reflux for 21 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a colorless oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=10/0 to 7/3) to obtain the entitled compound (1.48 g) as a colorless solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1)([O-:15])=[O:14].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:27]([C:25]3[O:26][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N+:13]([O-:15])=[O:14])=[CH:23][CH:24]=3)=[O:28])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-nitrophenyl)-2-furoic acid (Aldrich) according to methods A and C; yield 86 mg, 0.21 mmol (59%): 1H NMR (300 MHz, methanol-d4) δ 2.01 (d, J=13 Hz, 2H), 2.19-2.37 (m, 3H), 2.43 (s, 2H), 3.58 (s, 2H), 3.67 (s, 4H), 4.42 (s, 1H), 6.97 (d, J=4 Hz, 1H), 7.28 (d, J=3 Hz, 1H), 7.62 (dt, J=8, 1 Hz, 1H), 7.73 (dt, J=8, 1 Hz, 1H), 7.82 (dd, J=8, 1 Hz, 1H), 7.93 (dd, J=8, 1 Hz, 1H); MS (DCI/NH3) m/z 368 (M+H)+; Anal. C20H21N3O4.HCl.0.2H2O: C, H, N.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10](O)=[O:11]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:13]=[CH:14][N:15]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 908.5 %

Procedure:
Borane-dimethyl sulfide complex (14.30 mL, 14.30 mmols) was added to tetrahydrofuran solution of 2-chloroisonicotinic acid (17.56 g, 11.5 mmols) under cooling with ice, and stirred at room temperature for 2.5 days, followed by further an hour's stirring at 50° C. Cooling the reaction liquid to room temperature, ethyl acetate was added, followed by washing with saturated aqueous ammonium chloride solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the tide compound (15.0 g, 93%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH3:18])[CH:3]=1.C([Li])CCC.C[O:25]B(OC)OC.Cl.OO>O1CCCC1.C1(C)C=CC=CC=1>[CH2:17]([C:4]1[CH:3]=[C:2]([OH:25])[CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18]
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)cc(C)c1OCc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Then, 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene was dissolved in 250 ml of tetrahydrofuran, and 69 ml of n-butyl lithium solution (in hexane; 1.69 mol/liter), while stirring at -70° C. After further stirring at -70° C. for 2 hours, a solution of 12.1 g of trimethoxyboron dissolved in 50 ml of tetrahydrofuran was added dropwise to the reaction mixture. After completion of the dropwise addition, the reaction mixture was returned to room temperature, stirred for 1 hour, and then poured into ice water. The mixture was made weak acidic by the addition of 10% hydrochloric acid, and extracted twice with 500 ml of diethyl ether. The ether layers was combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. To the residue was added 120 ml of toluene, and 33 ml of 30% aqueous hydrogen peroxide was added dropwise, while heating at 70° C. under stirring. After heating under reflux for 1 hours, the reaction mixture was returned to room temperature, washed once with water, twice with 10% aqueous ferrous ammonium sulfate and then once with water. The toluene layer was dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.2 g of 3-ethyl-4-benzyloxy-5-methylphenol (93% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:5]2[N:6]=[C:7]([CH3:21])[C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=O)[NH:10][C:9]=3[N:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:11]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:13][C:8]2[C:7]([CH3:21])=[N:6][C:5]3[N:4]([N:3]=[C:2]([CH3:1])[CH:22]=3)[C:9]=2[N:10]=1
Reactant: Cc1cc2nc(C)c3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2nc(C)c3cc(-c4ccccc4)c(Cl)nc3n2n1

Procedure:
In a 20 mL scintillation vial Compound (19-1) (0.08 g, 0.275 mmol, 1.0 eq.) was heated with 2 mL of POCl3 at 80° C. for 2 hours. The reaction was cooled and concentrated and the residue by silica gel chromatography using CHCl3/MeOH (10%) as eluant to give Compound (19-2).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:11][CH:12]([CH3:14])[CH3:13].Cl.[N:17]([O-])=[O:18].[Na+].[OH-].[Na+]>O>[N:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]([CH3:15])([CH3:1])[CH2:10]2)=[O:18]
Reactant: O=N[O-]
Reactant: CC(C)CN1c2ccccc2CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CN1c2ccc(N=O)cc2CC1(C)C
Temperature: 8 °C

Procedure:
A mixture of 2,2-dimethyl N-isobutylindoline (2.0 g) and concentrated hydrochloric acid (4.5 cm3) was cooled to 8° C. and sodium nitrite (0.8 g) in water (2 cm3) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, made alkaline with sodium hydroxide solution an extracted with ethyl acetate. The ethyl acetate was dried over magnesium sulphate, filtered and evaporated to give 5-nitroso-2,2-dimethyl N-isobutyl indoline.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=O)[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18].C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>CO.O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[N:29][OH:30])[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: NO
Reactant: O=C(O)CC(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CC(F)(F)C(=NO)c1ccc2oc3ccccc3c2c1

Procedure:
A solution of 4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 1) and sodium acetate (1.2 equivalents) in methanol is treated with a solution of hydroxylamine hydrochloride (1.2 equivalents) in water. The solution is heated to reflux for 3 hours, then cooled, concentrated, and filtered. The filter cake is washed with water and dried in vacuo. The crude product is recrystallized from an organic solvent, such as ethyl acetate, to give the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:34])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[C:23]([CH3:34])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.47 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.2, 46%). MS (ISP) 437.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])OC(C)(C)OC2=O)[CH:2]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:19]1([C:1]2[CH:2]=[C:3]3[C:4]([C:14]([OH:15])=[CH:9][CH:8]=[N:7]3)=[CH:5][CH:6]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OC(=O)C(=CNc2cccc(-c3ccccc3)c2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Oc1ccnc2cc(-c3ccccc3)ccc12
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
5-(Biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (160.2 g, 496 mmol) was dissolved in 800 mL of DOWTHERM A heat transfer fluid at 100° C. and added over 40 min by way of a cannula line to 1.3 L of preheated DOWTHERM A heat transfer fluid to 215° C. After complete addition, the reaction was held at 215° C. for 90 min and then cooled to RT. The resulting solid was collected by filtration, sequentially washed with diethyl ether (1.7 L) and acetone (500 mL), and then dried in a vacuum oven at 70° C. overnight. The resulting product (74.5 g) contained approximately 5% of the undesired isomer. This product was combined with material from a separate run (51.4 g) and slurried in 440 mL of refluxing ethanol. Filtration of the slurry while hot followed by sequential ethanol and diethyl ether rinses afforded 106.1 g of 7-phenylquinolin-4-ol as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:16][CH:13]([CH3:15])[CH3:14])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nncc2cc(Br)ccc12
Temperature: 125 °C

Procedure:
In a sealed glass tube, a mixture of 6-bromo-1-chlorophthalazine (18, 0.40 g, 1.64 mmol), isopropyl amine (0.420 mL, 4.92 mmol) in NMP (2.0 mL) was heated in a microwave at 125° C. for 15 minutes. The resulting brown mixture was loaded on a 40 g ISCO column (eluted with 35-100% EtOAc in Hexanes) and purified to provide the title compound a light yellow crystalline solid. MS (ESI, pos. ion) m/z: 266.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13]C(OC(C)(C)C)=O)[CH2:9]2)[CH:3]=1.Cl>ClCCl.O1CCOCC1>[NH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:9]1
Reactant: Cc1ccnc(N2CCC(NC(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(N2CCC(N)C2)c1
Yield: 88.9 %

Procedure:
To a solution of 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (0.72 g) in dichloromethane (5 ml) was added a solution of hydrogen chloride in 1,4-dioxane (5 ml), and the resultant mixture was stirred at ambient temperature for 3 hours and evaporated under reduced pressure. To the residue was added 1N aqueous sodium hydroxide (30 ml) and extracted with ethyl acetate-tetrahydrofuran (2:1) three times. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give 3-amino-1-(4-methylpyridin-2-yl)pyrrolidine (409 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:8](O)=[O:9])[CH2:5][CH2:4][O:3]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:8]([Cl:15])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(C(=O)O)CCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CC(C(=O)Cl)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid (530 mg, 3.35 mmol) in 10 mL of DCM at 0° C. was added 1 drop of DMF followed by oxalyl chloride (0.33 mL, 3.69 mmol) and the reaction stirred at RT for 3 hrs. The reaction was then concentrated and used with out further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[NH2:57][CH:58]1[CH:63]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[CH:65]=2)[CH2:62][CH2:61][N:60]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:59]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:57][CH:58]3[CH:63]([C:64]4[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[CH:65]=4)[CH2:62][CH2:61][N:60]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:59]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:27]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HATU) (88 mg, 0.231 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (100 mg, 0.21 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of tert-butyl 3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate (62 mg, 0.21 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13]O)[N:8]=1)[CH3:6].S(Cl)([Cl:26])=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:26][CH2:13][CH2:12][C:9]1[N:8]=[C:7]([CH:5]([CH3:6])[C:4]2[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([F:1])[CH:3]=2)[O:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCO)no1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCCl)no1
Yield: 87.9 %

Procedure:
To a solution of 2.62 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-hydroxyethyl)-1,2,4-oxadiazole in 60 ml of dry benzene was successively added 2.0 g of thionyl chloride and 0.67 g of pyridine with ice-cooling. After stirring and heating with reflux for 1 hour, the reaction mixture was washed with water. The organic phase was further washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to give 2.44 g of 3-(2-chloroethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, m.p. 72°-72.5° C.
Reaction SMILES: [OH:1][C@:2]1([CH3:35])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:23])[CH3:22])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:34])([F:33])[F:32])=[N:27][NH:28][C:29]=2[CH3:30])=[O:8])[CH2:3]1.Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:35][C@@:2]1([OH:1])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:22])[CH3:23])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:32])([F:33])[F:34])=[N:27][N:28]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:29]=2[CH3:30])=[O:8])[CH2:3]1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cc1sc2c(c1C(=O)N1C[C@](C)(O)CO1)c(=O)n(C)c(=O)n2C(C)C
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(Cc2sc3c(c2C(=O)N2C[C@](C)(O)CO2)c(=O)n(C)c(=O)n3C(C)C)c(C(F)(F)F)nn1-c1ncccn1
Temperature: 100 °C

Procedure:
A mixture of the product of example 10 part b) (279 mg), 2-bromopyrimidine (300 mg), copper(I) iodide (95 mg), trans-cyclohexanediamine (55 mg) and potassium carbonate (300 mg) in dioxane (2 ml) was heated at 100° C. for 16 hours under nitrogen. The reaction mixture was concentrated to dryness and purified by silica chromatography eluting with an ethyl acetate to 10% methanol/ethyl acetate gradient, followed by RPHPLC to give the title compound as a white solid (105 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[F:21][C:22]([F:35])([F:34])[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)=[O:24]>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:31]([CH:28]3[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]([F:35])([F:21])[F:34])[CH2:30][CH2:29]3)=[O:32])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Product: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C1CCN(C(=O)C(F)(F)F)CC1

Procedure:
This compound was prepared according to the procedure of Example 35, Step 2, using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(trifluoroacetyl)piperidine-4-carbonyl chloride as the starting materials. LCMS for C18H14BrF4N6O5 (M+H)+: m/z=549.0, 550.9.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH:12][C:28](=[O:29])[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10][C:9]([C:13]3([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:5][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.6 %

Procedure:
To a solution of 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (574 mg, 2.0 mmol) in DCM (20 mL) was added K2CO3 (423 mg, 3.06 mmol) and phenyl chloroformate (386 μL, 3.06 mmol). The solution was stirred at rt overnight. The reaction mixture was filtered and the solids washed with DCM, the filtrate concentrated and purified using silica gel chromatography eluting with an EtOAC/Hexane gradient (5-20%) to give phenyl 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-ylcarbamate (1.04 g, quantitative yield). 1H NMR (300 MHz, DMSO d6) δ 1.33 (m, 4H), 2.34 (s, 3H), 6.51 (s, 1H), 7.12 (m, 2H), 7.23 (m, 1H), 7.37 (m, 6H), 10.13 (s, 1H); LC-MS (ESI) m/z 402 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O1CCOCC1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O[C@@H]1CCNC1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
8 g (46 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene 1,80 ml of dioxane and 8.14 g (0.095 mol) of (R)-(+)-3-pyrrolidinol are respectively placed in the reactor. The mixture is refluxed for one hour. The reaction medium is poured into a mixture of water (100 ml)-ice (200 g). A yellow product precipitates. This product is filtered off, washed with water (3×30 ml) and then dried under vacuum at 45° C. 8.38 g (75%) of 1-(3-methoxy-4-nitrophenyl)pyrrolidin-3-ol (2) are thus recovered.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:31][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=3)=[O:21])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: O=C(NC1CCCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclohexylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.85 (1H, br), 10.60 (1H, br), 8.33 (1H, br), 7.39 (1H, s), 7.35-7.22 (5H, m), 4.05 (2H, br s), 3.82 (1H, m), 1.85 (2H, m), 1.67 (2H, m), 1.56 (1H, m), 1.38-1.27 (5H, m); HRMS calcd for C22H23N3O3+H+: 378.1810. Found: 378.1822.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([NH2:23])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.CCN(CC)CC>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:14][CH:15]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N)c3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(NC(=O)c3ccc(OC)cc3)c3ccccc23)cc1
Yield: 32.4 %

Procedure:
To a solution of naphthalenyl amine (10) (65 mg, 0.2 mmol) in CH2Cl2 (5 mL) was added p-methoxybenzoyl chloride (45 uL, 0.24 mmol) and Et3N (50 uL, 0.4 mmol). The resultant solution was stirred at 25° C. overnight. The solvent was removed in vacuo and the residue was purified using HPLC to give the title compound (30 mg) as pale yellow solid. 1H NMR (300 MHz, MeOD) δ 8.73 (d, 1H), 8.08 (m, 4H), 7.70 (m, 3H), 7.10 (d, 2H), 6.90 (d, 2H), 6.70 (d, 2H), 3.84 (s, 3H), 3.60 (s, 3H); LC/MS m/z 463 (M+H)+.