Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:32]([F:35])([F:34])[F:33])=[CH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[O:17][CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+:36]([CH3:39])([O-:38])=[O:37].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:39][N+:36]([O-:38])=[O:37])([C:32]([F:33])([F:35])[F:34])[CH2:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)[O:17][CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
To a stirred solution of tert-butyl 5′-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 10, 1 g, 1.89 mmol) in acetonitrile (10 mL) was added nitromethane (1.013 mL, 18.93 mmol) and DBU (0.275 mL, 1.84 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material; reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure to get brown semi solid (1.41 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to get light yellow sticky liquid (1.02 g, 91.07%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.97 (d, J=18.64 Hz, 1H), 4.10-4.17 (m, 3H), 4.34 (d, J=9.8 Hz, 2H), 5.16 (s, 2H), 5.45 (d, J=12.32 Hz, 1H), 5.58 (d, J=12.36 Hz, 1H), 7.18 (s, 2H), 7.40-7.41 (m, 1H), 7.61 (d, J=7.92 Hz, 1H), 7.81 (s, 1H), 7.98-8.00 (m, 1H), LC-MS (m/z): 587.1 (M−H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[S:17][CH3:18].[C:19](=[O:21])=[O:20].Cl>CCOCC>[CH3:18][S:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: CSc1cc(C(F)(F)F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (2.5M solution in hexane; 25 ml) was added under an inert atmosphere to a stirred solution of 4-bromo-3-methylsulphenylbenzotrifluoride (16.4 g) in ether whilst maintaining the temperature below -70° C. The mixture was stirred at 70° C. for 2 hours and then poured onto solid carbon dioxide pellets. The mixture was stirred for 10 minutes and aqueous hydrochloric acid was added. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated and the residue was triturated with cyclohexane and filtered to give 2-methylsulphenyl-4-trifluoromethylbenzoic acid (12.4 g) as a white solid, NMR (CDCl3 +DMSO-d6): 2.45 (s,3H), 7.2(d, 1H), 7.3(s, 1H), 8.0 (d, 1H), 10.7-11.1 (bs, 1H).
Reaction SMILES: [OH:1]O.O.[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[C:14]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl.[C:36](O)(=[O:38])[CH3:37]>>[CH3:37][C:36]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:13]1[C:14]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:1])=[O:38]
Reactant: OO
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1CO
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1S(=O)c1ccccc1COC(C)=O
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.23 ml of 30% w/v, 2.05 mmol) was added to a mixture of ethyl 3-[2-(hydroxymethyl)phenylsulfanyl]-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 13, 770 mg, 1.71 mmol) in acetic acid (5 ml), and 2M aqueous hydrochloric acid (0.8 ml). The mixture was heated to 100° C. for 3 hours, cooled, and the solvents removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and the organic layer was separated, dried (magnesium sulfate) and concentrated under vacuo. The residue was flash chromatographed on silica gel using a mixture of 75% ethyl acetate and 25% hexane as eluant, to give the title compound as a colourless solid (500 mg).
Reaction SMILES: ClC(OCC)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[O:17][C:18]=2[CH2:19][CH2:20][C:21](O)=[O:22])=[CH:10][CH:9]=1.[NH3:30]>O.O1CCCC1.C(N(CC)CC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[O:17][C:18]=2[CH2:19][CH2:20][C:21]([NH2:30])=[O:22])=[CH:10][CH:9]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(N)=O)o1
Reaction time: 0.67 h
Yield: 90 %

Procedure:
Ethyl chloroformate (395 mg) was dropwise added to a tetrahydrofuran (40 ml) solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid (1.00 g) and triethylamine (365 mg), at −30° C. After stirring for 40 minutes, the reaction mixture was added to a mixture of aqueous ammonia (28%, 30 ml) and tetrahydrofuran (10 ml) at 0° C., and then stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide (900 mg, 90%). This was recrystallized from methanol-ethyl acetate to give colorless needles. mp 215-216° C.
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC2C=CC([N+]([O-])=O)=CC=2)=[O:26])[CH2:9][N:8]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O.[H][H]>O1CCCC1.C([O-])(=O)C.[OH-].[OH-].[Pd+2]>[C:25]([OH:27])(=[O:26])[CH3:14].[CH3:51][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([OH:27])=[O:26])[CH2:9][NH:8]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCN(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCN(C)C)C3)[C@H](C)[C@H]12
Yield: 29.1 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-{2-(dimethylamino)ethyloxymethyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.48 g) in a mixture of tetrahydrofuran (60 ml) and 0.3 M acetate buffer (pH 5.8) (60 ml) was stirred at ambient temperature for 6 hours in the presence of 20% palladium hydroxide on carbon (0.5 g) under atmospheric pressure of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran The resulting aqueous solution was washed with ethyl acetate (50 ml×3) and evaporated to remove the organic solvent The residual solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (60 ml) and eluted with a mixture of acetone and water (2:98 V/V). The fractions containing the desired compound were collected and 0.5M aqueous acetic acid (1.5 ml) was added to the solution The solution was lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-{2-(dimethylamino)ethyloxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monoacetate (0.14 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[NH:12][CH:11]=2)[CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].N.[Cl:31]CCl>C(O)C.CO.CCOCC>[ClH:31].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:17]=3)[NH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: Nc1ccc2[nH]cc(CCCN3CCOCC3)c2c1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: Cl
Product: N=C(Nc1ccc2[nH]cc(CCCN3CCOCC3)c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To an argon purged vial fitted with a magnetic stirbar was charged a solution of 180 (28 mg, 0.108 mmol) in absolute ethanol (3 mL). Methyl thiophene-2-carbimidothioate hydroiodide (62 mg, 0.217 mmol) was added as a yellow solid in one portion. The reaction was stirred at room temperature for 17 hours. The reaction was complete by TLC (10% 2M ammonia in methanol, 90% dichloromethane). The reaction was diluted with ether (15 mL) and the solid which precipitated was collected by vacuum filtration. The precipitate was washed with ether (10 mL). The product was collected by washing the filter with methanol (10 mL) and collecting the filtrate. The filtrate was returned to the reaction vial and DOWEX-66 (3 g) was added. The reaction was stirred for 2 hours. The reaction was filtered and the filtrate concentrated to afford a brown solid. The solid was taken up in dichloromethane (10 mL) and partitioned with saturated sodium bicarbonate (2 mL). The organic phase was treated with brine, dried over magnesium sulfate and filtered. The filtrate was treated with 1M hydrogen chloride in ether (3 mL). After stirring for 1 hours the reaction was concentrated on the rotary evaporator. The resulting yellow solid was dried further on the high vacuum line. Yield: 45 mg of yellow solid, compound 181 (96%). 1H NMR (DMSO) δ 10.91 (br s, 1H), 7.96 (s, 2H), 7.42-7.39 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.29-7.25 (t, J=4.5 Hz, 1H), 7.24 (s, 1H), 6.92-6.89 (d, J=8.7 Hz, 1H), 3.58 (s, 4H), 2.72-2.67 (t, J=7.5 Hz, 2H), 2.38 (m, 6H), 1.83-1.78 (m, 2H). MS (ESI+): 369 (MH+, 100%). NOS In Vitro Inhibition Assays
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[H-].[Na+].I[CH3:17].O>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:17])[C:10](=[O:12])[O:9][C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
5-bromoisatoic anhydride (3 g, 12 mmol) was stirred in 50 mL of DMF at 0° C. and sodium hydride (60% dispersion in mineral oil) (0.4 g, 15 mmol) was added in portions, with stirring for 1 hour at room temperature. Iodomethane (0.8 mL, 12 mmol) was added drop wise and the reaction mixture was allowed to stir for 4 hours. Water (50 mL) was added slowly and 50 mL of Dichloromethane (DCM) was also added. A white solid precipitated out and was filtered off. The layers were separated layers. Aqueous layer extracted with DCM (2×25 ml). The combined organic layers were extracted with water (4×25 ml) and once with brine (25 ml). The organic layer was dried with MgSO4 and the solvent removed. The residue was purified by flash chromatography (0-3% MeOH/DCM) to afford 1.57 g of product. Yield 49%
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=O)[CH3:2].Cl[Si:33]([CH3:36])([CH3:35])[CH3:34].[N-:37]=[N+:38]=[N-:39].CN(C)C(=[NH2+])N(C)C.[N-]=[N+]=[N-]>N1C=CC=CC=1.ClCCl.O>[CH3:2][C:1]1[N:4]([CH2:5][CH2:6][S:7][C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@H:12]3[C@@H:15]([O:17][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[N:39]=[N:38][N:37]=1
Reactant: C[Si](C)(C)Cl
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)O)[C@H]2C1
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnnn1CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)O[Si](C)(C)C)[C@H]2C1
Temperature: 25 °C

Procedure:
p-Nitrobenzyl (5R, 6R)-3-(2-acetamidoethylthio)-6-[(1S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, e1 (232 mg) was suspended in pyridine (3 ml) and treated with chlorotrimethylsilane (350 mg). After 15 min. the pyridine was evaporated in vacuo and ethyl acetate (20 ml) and water (20 ml) were added to the residue. After shaking, the layers were separated and the ethyl acetate layer was washed with brine, dried (MgSO4) and evaporated in vacuo. Toluene (10 ml) was added to the residue and evaporated in vacuo. The resultant trimethylsilyl ether was taken up in dry dichloromethane (6 ml), cooled to -30° and N-methylmorpholine (0.25 ml) was added. A solution of phosgene in toluene (0.90 ml; 12.5% w/w, d 0.91), diluted with dry CH2Cl2 (1 ml), was added dropwise. The mixture was allowed to warm to room temperature and the i.r. spectrum of the reaction mixture indicated that the imidoyl chloride had formed. Tetramethylguanidinium azide in dichloromethane (0.90 ml, 100 mg/ml) was added and after stirring at room temperature for 15 min. a further portion (0.20 ml) of the azide solution was added, and after another 15 min. more azide solution (0.15 ml) was added. After 15 min. the solution was diluted with dichloromethane (15 ml), water (15 ml) was added, the layers separated and the dichloromethane layer was washed with brine, dried (MgSO4) and evaporated in vacuo to dryness. Toluene (2×20 ml) was added to the residue and evaporated in vacuo. The product was chromatographed on silica gel (230-400 mesh ASTM) (15 g) eluting with ethyl acetate to give, after combination and evaporation of appropriate fractions, the title compound, e2, (210 mg), λmax (EtOH) 311 (ε10932) and 265 (11509) nm, νmax (CH2Cl2) 1785, 1705, 1525, 1345, 1150, 845 cm-1, [M+ found m/e 546.1677; C23H30N6O6SSi requires m/e 546.1714].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21](O)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:47][C:48](=[NH:60])[C:49]1[CH:54]=[CH:53][C:52]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:51][CH:50]=1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[O:22][N:60]=[C:48]([C:49]3[CH:50]=[CH:51][C:52]([O:55][C:56]([F:57])([F:58])[F:59])=[CH:53][CH:54]=3)[N:47]=2)[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: N=C(NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(C(=O)O)sc1Cc1cccc(N2CCN(C)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)sc1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
A mixture of 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid (70 mg, 0.21 mmol), EDC.HCl (49 mg, 0.25 mmol) and HOBT (34 mmol, 0.25 mmol) in DMF (2 mL) was stirred at RT for 30 min. N-hydroxy-4-(trifluoromethoxy)benzimidamide (55 mg, 0.25 mmol) was added and the reaction mixture was stirred for 1 h at RT and then at 140° C. for another 2 h. The reaction mixture was cooled to RT, diluted with H2O (5 mL) and taken into EtOAc (10 mL). The organic layer was separated, washed with H2O (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm*150 mm) to give 5-(4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow solid (2.0 mg, 2%). MS (ES+) C25H24F3N5O2S requires: 515, found: 516[M+H]+; 1H-NMR (500 MHz, CD3OD) δ ppm 8.24 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 8.24 (t, J=8.0 Hz, 1H), 6.94-6.92 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 4.23 (s, 2H), 3.23 (t, J=4.5 Hz, 4H), 2.63 (t, J=4.5 Hz, 4H), 2.54 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([OH:7])=[O:6].P(=O)(Cl)(Cl)Cl.[CH3:18]O>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H](O)c1ccccc1Cl
Yield: 95 %

Procedure:
15 g of (R)-2-chloromandelic acid was mixed with methanol (CH3OH, 150 ml) and phosphorus chloride oxide (POCl3, 0.76 ml) in a flask by stiffing using a magnetic stirrer at the room temperature for 6 hours. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na2SO3) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (15.64 g, yield 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[B-](F)(F)(F)[F:31].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[F:31][CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: F[B-](F)(F)F
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 80 °C

Procedure:
To a solution of 10.0 g (43 mmol) of benzyl-4-oxo-1-piperidinecarboxylate in 25 mL of DMF was added 14.3 mL (103 mmol) of triethylamine and then 6.53 mL (52 mmol) of TMSCl. The reaction was heated at 80° C. overnight, cooled to room temperature, and then dumped into hexanes in a separatory funnel. The mixture was partitioned with saturated aqueous NaHCO3, separated, washed with brine, dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 500 mL of CH3CN and treated with 16.7 g (47 mmol) of Selectfluor. After 90 min the reaction was concentrated to about half the original volume, partitioned between EtOAc and brine, separated, dried over MgSO4, filtered, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with EtOAc/hexanes to provide 2-2 as a colorless oil.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[N:20]([CH3:21])[CH:19]=[NH+:18][C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[CH2:30][C@@H:29]3[C:31]3[N:32]=[N:33][NH:34][N:35]=3)=[CH:24][CH:23]=2)=[N:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.IC>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C@H:28]3[CH2:30][C@@H:29]3[C:31]3[N:32]=[N:33][N:34]([CH3:2])[N:35]=3)=[CH:26][CH:27]=2)=[N:13][CH:14]=1
Reactant: Cn1c[nH+]c(-c2ccc([C@H]3C[C@@H]3c3nn[nH]n3)cc2)c1Sc1ccc(Cl)cn1
Reactant: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc([C@H]2C[C@@H]2c2ccc(-c3ncn(C)c3Sc3ccc(Cl)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 37 (10 mg, 0.024 mmol) and excess potassium carbonate in DMF (0.5 mL) was added 3 drops of iodomethane. The reaction was stirred at rt for 1 h, before filtering and subjecting to purification via reverse phase HPLC. The fractions containing the major 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), [CD3OD]: 8.38 (s, 1H), 7.78 (d, 2H), 7.76 (br, 3H), 7.30 (br, 3H), 3.83 (s, 3H), 3.66 (s, 3H), 2.66 (m, 1H), 2.45 (m, 1H), 1.85-1.72 (br, 2H). LCMS: [M+1]+=424. Human FAAH lysate assay: IC50=37 nM
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13](=O)[CH2:14][CH2:15][O:16][CH3:17])[CH:3]=1.[OH-].[Na+].O1CCOCC1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH3:9])[C:13]([CH2:14][CH2:15][O:16][CH3:17])=[N:12]2)=[CH:10][CH:11]=1
Reactant: CNC(=O)c1ccc(Br)cc1NC(=O)CCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCCc1nc2cc(Br)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 124.9 %

Procedure:
The mixture of 4-bromo-2-(3-methoxypropanamido)-N-methylbenzamide (0.05 g, 0.159 mmol), 2.5 N NaOH (1 mL) and dioxane (1 mL) was stirred for 3 h at room temperature, then diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, filtered, and evaporated to give 59 mg of the target compound. MS (ESI): 297, 299 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:23]=[C:22]([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:35]=3[N:34]=[C:33]2[CH:43]([F:45])[F:44])[N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:45][CH:43]([F:44])[C:33]1[N:32]([C:22]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:25]=[C:20]([N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:6]3[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]3)[N:21]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:35]=2[N:34]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(NCCCO)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.6 %

Procedure:
A mixture of tert-butyl 3-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate (516 mg, 2.00 mmol), 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (610 mg, 1.54 mmol), and DIPEA (1.5 mL, excess) in DMF (20 mL) was stirred at room temperature for 2 days. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×30 mL). The combined extracts were washed with water, dried over Na2SO4, and concentrated. Chromatography of the residue on SiO2 eluting with a gradient of CH2Cl2/EtOAc (0-40%) gave tert-butyl 3-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)-amino]-1-piperidinecarboxylate (854 mg, 90%): mp (CH2Cl2/hexanes) 109-191° C.; 1H NMR (DMSO-d6) (rotamers) δ 8.00 and 7.88 (2d, J=8.3, 8.4 Hz, 1H), 7.79 and 7.63 (2t, JHF=53.0 Hz, 1H), 7.40-7.33 (m, 1H), 6.94 (dd, J=8.0, 4.13 Hz, 1H), 4.60-4.48 and 4.29 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.97-3.48 (m, 16H), 2.93-2.88 and 2.66-2.64 (2 m, 2H), 1.99-1.69 (m, 3H), 1.52-1.17 (m, 10H); Anal. Calcd. for C29H40F2N8O5: C, 56.3; H, 6.5; N, 18.1. Found: C, 56.4; H, 6.4; N, 18.1%.