Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][CH:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[C:17](O)=[O:18])[CH3:12].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][CH:11]([O:13][C:14]1[CH:15]=[C:16]([C:17]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:18])[CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)O)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)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
DIPEA (0.26 mL, 1.5 mmol) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoic acid (185 mg, 0.5 mmol), 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.6 mmol) and HATU (247 mg, 0.65 mmol) in DMF (2 mL) and the mixture stirred at RT for 16 hours. The mixture was poured onto water (30 mL), extracted with ethyl acetate (3×15 mL), the combined organic extracts washed with 1N citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 60% ethyl acetate in isohexane, to give the desired compound (32 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 1.55 (s, 9H), 3.15 (s, 3H), 3.5 (t, 2H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (s, 1H), 6.7 (m, 2H), 7.1 (d, 1H), 7.8 (d, 1H), 7.95 (d, 1H), 8.7 (s, 1H); m/z 535 (M−H)−
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)[CH:4]=1)[CH3:2].[OH:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:1]([C:3]1[N:8]=[C:7]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[N:6]=[C:5]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-n2cc(C(F)(F)F)cn2)nc(S(C)(=O)=O)n1
Reactant: Oc1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-n2cc(C(F)(F)F)cn2)nc(Oc2ccnc(C(F)(F)F)c2)n1
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A mixture of 0.4 g (1.25 mmol) of 6-ethyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-methylsulfonylpyrimidine, 0.2 g (1.25 mmol) of 4-hydroxy-2-trifluoromethylpyridine and 0.345 g (2.5 mmol) of K2CO3 in 20 ml of acetonitrile is stirred under reflux for 8 h and then allowed to stand at RT overnight. The mixture is put into 40 ml of water and extracted four times with in each case 20 ml of CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. Chromatographic purification on silica gel using heptane/ethyl acetate (1:1) gives 0.33 g (65%) of 6-ethyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-(2-trifluoromethylpyridin-4-yloxy)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.C1C(=O)N([Cl:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][Cl:20])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClCc1ccc2cc(Br)ccc2n1
Temperature: 80 °C

Procedure:
To 6-Bromo-2-methyl-quinoline (2.4 g, 11.0 mmol) in benzene (20 mL) at room temperature was added NCS (1.44 g, 11.0 mmol) and catalytic benzoyl peroxide, and the reaction was heated to 80° C. for 1 hour. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the desired product, 4a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][C:14]=3[N+:23]([O-:25])=[O:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[N+:23]([O-:25])=[O:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Yield: 95.4 %

Procedure:
A mixture of methyl 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoate (1.20 g), 1 M aqueous sodium hydroxide solution (6.6 ml) and tetrahydrofuran (10 ml) was heated under reflux for 30 min. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid was added to acidify the mixture. The crystals were collected by filtration to give 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoic acid (1.10 g, yield 96%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 257–258° C.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16](O)=[O:17].Cl>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17]
Reactant: O=C(O)c1cnccn1
Reactant: CCCCCCCCO
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1cnccn1
Yield: 60.1 %

Procedure:
A four-necked flask was charged with 100 g (0.768 mole) of 1-octanol and 10 g (0.081 mole) of pyrazinecarboxylic acid and while the internal temperature was maintained under stirring at 70°-80° C., 15 g (0.411 mole) of hydrogen chloride was introduced through a gas inlet tube over a period of 3 hours. Upon completion of the introduction of hydrogen chloride, the reaction mixture was cooled and 100 ml of methylene chloride was added. The mixture was transferred to a separatory funnel, in which it was washed with a small quantity of aqueous sodium carbonate solution. From the oil layer which separated, the methylene chloride was first distilled off and the residue was subjected to distillation under reduced pressure to give 11.5 g of octyl pyrazinecarboxylate. Yield: 60% (based on pyrazinecarboxylic acid)
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A 4 g. (10.3 m mole) sample of ethyl 4-(14-methylpentadecyl)aminobenzoate is hydrolyzed with 2.0 g. (3 eq) 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected and dried in vacuo to yield the title compound as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[N:26]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:40][CH:39]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCOCC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(4-morpholin-4-yl-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-morpholin-4-yl-benzoic acid. MS calcd. for C30H29ClN4O4 [(M+H)+] 545.2, obsd. 545.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=4)[N:9]=3)[CH:3]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1

Procedure:
3′-[4-Difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.8) (0.39 g, 0.9 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.51 g), which was subsequently deprotected.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)=[O:6].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][N:4]([CH2:3][C:2]([F:1])([F:17])[F:18])[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)=[O:6]
Reactant: COC(=O)c1ccc(C(=O)NCC(F)(F)F)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)CC(F)(F)F)nc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of methyl 6-[(2,2,2-trifluoroethyl)carbamoyl]nicotinate (3.0 g, 11.5 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% suspension in mineral oil) (1.4 g) at ambient temperature. The reaction mixture was stirred for 1 h and methyl iodide (1.5 mL) was added. The reaction mixture was stirred over night and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1.72 g (61%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (d, 1 H), 4.50 (q, 1 H), 4.23 (q, 1 H), 3.99 (s, 3 H), 3.24 (d, 3 H); MS (ESI) m/z 277[M+H+].
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: C1=COCCC1
Reactant: CC(CS)C(=O)O
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(CSC1CCCCO1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-mercapto-2-methylpropanoic acid (2.4 g.) and freshly distillled 2,3-dihydro-4H-pyrane (1.9 g.) in benzene (60 ml.), boron trifluoride etherate (2.8 g.) is added. After two hours, potassium carbonate (4 g.) is added, the mixture is stirred and filtered. The filtrate is concentrated to dryness to yield 3-(tetrahydropyran-2-ylthio)-2-methylpropanoic acid.
Reaction SMILES: [F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: COc1cccc(C(=O)N(C)OC)c1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a solution of 2-fluoro-3,N-dimethoxy-N-methyl-benzamide (2.30 g, 10.8 mmol) in THF (20 mL) at −78° C. was added 1M DIBAL-H in toluene (12 mL, 12 mmol). The reaction stirred at −78° C. for 3 h and then the remaining 1M DIBAL-H in toluene (4.2 mL, 4.2 mmol) was added to the reaction. The reaction was allowed to stir at −78° C. for 30 min and was then warmed to rt. The reaction was quenched slowly with saturated aqueous NH4Cl. The organic phase was separated and the aqueous phase was extracted with 2×50 mL ethyl acetate. The combined organic phases were washed successively with 1N HCl and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:1] to yield the title compound (1.41 g, 85%): δH (300 MHz, CDCl3): 10.38 (1H, s), 7.43-7.40 (1H, m), 7.24-7.15 (2H, m), 3.95 (3H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:21]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[Cl:21][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Yield: 23 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to the boiling point and left stirring at reflux for 1 hour. 4-chlorobenzyl chloride (14.4 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was stopped by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/1 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 4.4 g of [1-(4-chlorobenzyl)-1H-indazol-3-yl]methanol.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Cl:20]N1C(=O)CCC1=O>C1COCC1>[Cl:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Cl)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 18.7 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.10 g, 0.38 mmol) in THF (5 mL) in a microwave reaction tube was added N-chlorosuccinimide (0.046 g, 0.42 mmol). The mixture was heated at 70° C. in a microwave oven for 20 min. After cooling to room temperature, it was purified using preparative LCMS to provide the product (0.021 g). 1HNMR (300 MHz, CD3OD): δ 4.39 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.91 (m, 2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated for C12H16ClN6O (M+H): 295.1; found: 295.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]2[C:9](=[O:12])[NH:10][N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:4]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([F:49])([F:48])[F:47])=[N:44][CH:45]=1>CCOC(C)=O>[CH3:1][NH:2][C:3]1[N:8]2[C:9](=[O:12])[N:10]([CH2:39][C:40]3[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][CH:41]=3)[N:11]=[C:7]2[C:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:4]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: CNc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of crude 5-(methylamino)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, DMF (0.5 mL), and potassium carbonate (38 mg, 0.28 mmol) was added 5-chloromethyl-2-(trifluoromethyl)pyridine (18 mg, 0.09 mmol). The resulting reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was then diluted with EtOAc, washed with water and saturated aqueous NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by preparative reverse phase HPLC to obtain 25 mg (51% over two steps) of the title compound as a light yellow solid. HPLC/MS: retention time=4.40 min, [M+H]30 =545.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]3[O:28][C:27](=[O:29])[NH:26][N:25]=3)=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.IC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]3[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=3)=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3c3n[nH]c(=O)o3)cc2)c1Sc1ccc(Cl)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc([C@H]3C[C@@H]3c3nn(C)c(=O)o3)cc2)c1Sc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
To a solution of Example 17 (5 mg, 0.012 mmol) and excess cesium carbonate in 0.5 mL DMF was added 2 drops of iodomethane. The reaction was stirred at it for 16 h before filtering and subjecting to purification via reverse phase HPLC. The fractions containing the product were collected, diluted with ethyl acetate, and washed with aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (500 MHz), [(CD3)2CO]: 8.43 (s, 1H), 8.13 (s, 1H), 7.96 (d, 2H), 7.75 (d, 1H), 7.24 (d, 2H), 7.02 (d, 1H), 3.75 (s, 3H), 3.30 (s, 3H) 2.56 (m, 1H), 2.20 (m, 1H), 1.60 (br, 2H). LCMS: [M+1]+=440. Human FAAH lysate assay: IC50=170.6 DM.
Reaction SMILES: Cl.C(N(C(=O)C(C)C)C(N)[C:6](O)=[O:7])C.[NH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18].C(OC(=O)C)(=O)C>C(O)=O>[CH:6]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[O:7]
Reactant: CC(C)(N)C(=O)O
Reactant: CCN(C(=O)C(C)C)C(N)C(=O)O
Agent: Cl
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)(NC=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of ethyl-α -aminoisobutyrylglycinate hydrochloride: To a solution of 10.3 g (0.10 mol) of α-aminoisobutyric acid in 210 ml of 98% formic acid at 0° C, there was added dropwise with stirring 70 ml of acetic anhydride. After stirring at room temperature for 2 hr., 85 ml of ice water was added and the solution evaporated under reduced pressure to give an off-white solid. Recrystallization from absolute ethanol gave 11.2 g (0.085 mol), 85%, N-formyl-α-aminoisobutyric acid, mp 129.5° -131° C; pmr (D2O) δ 1.50 (s, 6H), 4.06 (s, 2H) and 8.16 (s, 1H) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[CH3:14].O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>CC(CC)=O>[Br:7][C:8]1[C:9]([O:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[CH3:14]
Reactant: Cc1c([N+](=O)[O-])cnc(Cl)c1Br
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1c([N+](=O)[O-])cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In a 250 ml three-necked round-bottomed flask, 4.00 g 4-chloro-3-trifluoromethyl-phenol is dissolved in 80 ml of dry methyl-ethyl-ketone. 3.85 g potassium carbonate followed by 4.70 g of 3-bromo-2-chloro-4-methyl-5-nitro-pyridine are added. The resulting brown suspension is heated to 80° C. under stirring for 3 hours. Afterwards, the green suspension is allowed to reach an ambient temperature and it then poured into water. The mixture is extracted with ethyl actetate (3×50 ml). The combined organic phases are washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. After purification of the raw product on silica gel with cyclohexane/ethyl actetae 19:1 (v:v) 7.36 g of the title compound are obtained as a light yellow gum that solidifies upon standing (MP: 73-74° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25])=[O:16].O>CN(C)C=O>[F:14][C:12]1[CH:13]=[CH:8][C:9]2[C:15](=[O:16])[C:17]3[C:18]([O:25][C:10]=2[CH:11]=1)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3
Reactant: COc1ccc(C(=O)c2ccc(F)cc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c3ccc(F)cc3oc2c1
Temperature: 100 °C
Yield: 88.9 %

Procedure:
A mixture of potassium carbonate (2.13 g, 15.4 mmol) and (2,4-difluoro-phenyl)-(2-hydroxy-4-methoxy-phenyl)-methanone (3.4 g, 12.9 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 2 h. The mixture was cooled and poured into water (˜150 mL). A solid was collected by filtration, washed with water, and dried in vacuo to give the title compound (2.8 g), which was used without purification in the subsequent step. MS: m/z 244.9 (MH+). 1H NMR (CDCl3): δ 3.94 (s, 1H), 6.88 (d, 1H, J=2.4 Hz), 6.96 (d of d, 1H, J=2.4 & 8.9 Hz), 7.07 (m, 2H), 8.24 (d, 1H, 8.9 Hz) and 8.34 (d of d, 1H, J=6.5 & 8.8 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27]C3CCCCO3)[CH:22]=2)[CH:20]=1)=O)(C)(C)C.[ClH:34]>CO.CCOCC>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[CH:22]=2)[CH:18]=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(-c2cc(COC3CCCCO3)no2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OCc1cc(-c2cncc(OC[C@@H]3CCCN3)c2)on1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-isoxazolyl]pyridine (145 mg, 0.31 mmol) in MeOH (10 mL) was added at 0° C. 2M anhydrous HCl in ether (10 mL). The reaction mixture was stirred at room temperature for 12 h, then concentrated in vacuo. The residue was purified by HPLC to give the hydrochloride (90 mg). The 1H NMR spectrum (CD3OD, 400 MHz) of this material exhibits signals compatible with the postulated structure, but in addition a second set of signals of somewhat lower intensity for the heteroaromatic protons in close proximity to those of the title compound: δ 9.02 (s, 1H of minor component), 9.01 (s, 1H of major component), 8.74 (narrow m, 1H of minor component), 8.73 (narrow m, 1H of major component), 8.58 (narrow m, 1H of minor component), 8.55 (narrow m, 1H of major component), 7.30 (s, 1H of minor component), 7.28 (s, 1H of major component), 4.74 (s, 2H), 4.71-4.64 (m, 1H), 4.56-4.48 (m, 1H), 4.21-4.32 (m, 1H), 3.49-3.37 (m, 2H), 2.38-2.28 (m, 1H), 2.26-2.06 (m, 2H), 2.04-1.93 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12][CH2:13][C:14](C1C=CC(C)=CN=1)=[O:15]>>[Br:12][CH2:13][C:14]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)=[O:15]
Reactant: Cc1ccc(C(=O)CBr)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: O=C(CBr)c1ccc(C(F)(F)F)cn1

Procedure:
* 2-Bromoacetyl-5-(trifluoromethyl)pyridine was prepared from 2-chloro-5-(trifluoromethyl)pyridine according to the procedure for preparing 2-bromoacetyl-5-methylpyridine described in step 1 of Example 32.