Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])O.[Na+].[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32](ON2C(=O)CCC2=O)=[O:33])[CH:27]=[CH:28][CH:29]=1)#[N:23]>O1CCOCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(C=CC(=O)ON2C(=O)CCC2=O)c1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(C=CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To water (80 mL)-dioxane (80 mL) solution of L-tryptophan (3.0 g) was added sodium hydrogencarbonate (1.3 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Next, dioxane (80 mL) solution of the compound obtained in Example 117 (4.2 g) was added to the mixture solution at 0° C., the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, thereafter the solution was made acidic with a 10% aqueous citric acid solution, and the crystals precipitated were filtered. The crystals were washed with water, to give the captioned compound (4.6 g, 87%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O)(=O)C.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:4][CH2:1][CH:2]=[CH2:3])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Allylamine (0.45 mL, 0.34 g, 6.0 mmol), acetic acid (0.300 mL, 315 mg, 5.24 mmol), and 3 Å molecular sieves (2.00 g) were added to a solution of 1-(t-butyoxycarbonyl)-4-piperidone (1.00 g, 5.01 mmol) in 1,2-dichloroethane (14 mL). The resulting mixture was stirred for 30 min at rt, then treated with sodium triacetoxyborohydride (1.62 g, 7.6 mmol). The reaction was stirred at rt for 3 h, then partitioned between EtOAc (30 mL) and sat'd NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (30 mL) and the organic layers were washed with 20 mL of sat'd NaCl, combined, dried over Na2SO4, and evaporated to give 1.20 g of crude 1-(t-butoxycarbonyl)-4-(N-prop-2-enyl)aminopiperidine.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:27]=[N+:28]=[N-:29].[Na+].CCOC(C)=O>CN(C=O)C>[N:27]([C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (135 mg, 0.33 mmol, prepared according to Example 30, Step 16.1) and sodium azide (108 mg, 1.66 mmol) in DMF (1 mL) was heated at 60° C. and stirred for 4 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (144 mg, 0.33 mmol, quant.) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=2.77.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(NS(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-aminobenzyl)piperidine (1.2 g, 4.15 mmol) was dissolved in tetrahydrofuran (20 mL). To the solution was added triethylamine (0.64 mL, 4.57 mmol). To the mixture was added dropwise methanesulfonyl chloride (0.39 mL, 4.95 mmol) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into ice-water (20 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the titled compound (1.43 g) as colorless powdery crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]([NH2:27])=[N:24][NH:25][CH:26]=1)=[O:21])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]([NH2:27])=[N:24][N:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=1)=[O:21])[CH3:18]
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2nccc(-c3ccc(N(C)C)cc3)n2)nc1N
Temperature: 105 °C
Yield: 36.7 %

Procedure:
A mixture of [4-(2-Chloro-pyrimidin-4-yl)-phenyl]-dimethyl-amine (2.0 g, 8.58 mM), 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (1.32 g, 8.58 mM), Cs2CO3 (4.4 g, 13.58 mM) in DMF (15 ml) was heated 2 hr at 105° C. The reaction was then cooled to room temperature and diluted with water (100 mL) and the yellow precipitate collected via filtration and was washed with water (2×30 ml) then ethyl ether (2×30 ml). The solid was dried under vacuo and comprised a mixture of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester and 5-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester in a ratio of approximately 6:4. The solid is flushed thru a pad of silica eluting with 5% MeOH/dichloromethane/1% TEA and the material is pooled and evaporated to a solid. Crystallization from dichloromethane/MeOH afforded the slower of the two isomers 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.1 g, 36.4% yield) as a bright yellow solid. ES-MS MH+353, 1H NMR (300 MHz, ppm, DMSO-d6): 8.84 (s, 1H), 8.63 (d, 1H), 8.15 (d, 2H), 7.77 (d, 1H), 6.93 (d, 2H), 5.85 (br s, 2H) 4.27 (q, 2H), 3.04 (s, 6H), 1.32 (t, 3H). Chromatography of the filtrate on silica eluting 1% TEA/EtOAc can provide the other faster isomer 5-Amino-1-[4-(4-dimethylamino-phenl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester as an off-white solid. ES-MS MH+ 353, 1H NMR (300 MHz, ppm, DMSO-d6): 8.7 (d, 1H), 8.12 (d, 2H), 7.83 (d, 1H), 7.79 (s, 1H), 7.64 (br S, 2H), 6.84 (d, 2H), 4.28 (q, 2H), 3.04 (s, 6H), 1.28 (t, 3H).
Reaction SMILES: C1C(=O)N(O[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[N+:18]=[N-:19])=[CH:13][CH:12]=2)=[O:10])C(=O)C1.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27]>C1COCC1>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:10])=[CH:16][CH:15]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: NCCCCCCN
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCCCCN)cc1
Reaction time: 8 h

Procedure:
2.6 g (10 mmol) HSAB 1 are dissolved in 70 ml THF and dropwise added to solution of 11.62 g (100 mmol) of hexamethylene diamine in THF under stirring and cooled on ice. Subsequently, the ice bath is removed and the temperature is allowed to adjust to room temperature. The solvent is drawn off on the rotation evaporator and excess hexymethylene diamine is removed in a high vacuum as far as possible. The remaining raw product is digested for 20 min in 100 ml of water and subsequently dried overnight in an exsiccator. Product 2b is a slightly yellow to brown solid material.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl.CO>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:9]3[C:4]4[O:3][CH2:2][O:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: c1cc2c(c(C3CCNCC3)c1)OCO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Benzo[1,3]dioxol-4-yl-piperidine (0.680 g, 3.31 mmol,) in dichloromethane (35 ml) and methanol (1 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.04 g, 4.31 mmol) and the solution was allowed to stir for 120 min. Sodium triacetoxyboron hydride (1.26 g, 5.96 mmol) was added portion wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude material was purified by flash chromatography on silica gel The crude material was purified by flash chromatography (methanol in dichloromethane 0-10%) to yield trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.43 g, 74%), MS (ISP) m/z=431.5 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:8]([C:7]1[C:2]([O:1][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncccc1[N+](=O)[O-])c1ccccc1
Yield: 50 %

Procedure:
A solution of 2-hydroxy-3-nitropyridine (0.42 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.41 g, 50% yield) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:20]2[C:24]([CH3:25])=[N:23][N:22]=[N:21]2)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])(=[O:9])[CH3:8].I[CH2:27][CH3:28]>CC(C)=O>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:20]2[C:24]([CH3:25])=[N:23][N:22]=[N:21]2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:27][CH3:28])=[O:17])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccc(-n2nnnc2C)c(C(=O)O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)ccc1-n1nnnc1C
Yield: 92.2 %

Procedure:
Cesium carbonate (176 g, 1.13 mol) was added to a solution of 5-acetoxy-2-(5-methyltetrazol-1-yl)benzoic acid (164 g, 0.620 mol) in 1.8 L of acetone. The mixture was stirred vigorously and iodoethane (116 g, 0.682 mol) diluted with 100 mL of acetone was added dropwise over a one-hour period. The reaction was stirred overnight at ambient temperature and was then concentrated under reduced pressure. The resulting solid was partitioned between dichloromethane and water. The aqueous fraction was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated to give 166 g of ethyl 5-acetoxy-2-(5-methyltetrazol-1-yl)benzoate as a brown oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([C:39]2[N:40]=[N:41][NH:42][N:43]=2)[CH:36]=[CH:37][CH:38]=1.[Si:44]([O:51][CH2:52][CH2:53][CH:54](O)[CH3:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C1COCC1>[Si:44]([O:51][CH2:52][CH2:53][CH:54]([N:41]1[N:42]=[N:43][C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=2)=[N:40]1)[CH3:55])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:45])[CH3:46]
Reactant: Clc1cccc(-c2nn[nH]n2)c1
Reactant: CC(O)CCO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCO[Si](C)(C)C(C)(C)C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 98.1 %

Procedure:
To triphenylphosphine (2.6 g, 10 mmol) in THF (50 mL) at 0° C. under argon, DEAD (1.6 mL, 10 mmol) added during 5 minutes. After stirring for 40 minutes at 0° C. 5-(3-chlorophenyl)-2H-tetrazole (0.90 g, 5 mmol) followed by a solution of 4-{[tert-butyl(dimethyl)silyl]oxy}butan-2-ol (1.53 g, 7.5 mmol) (Tett. 2003, 59, 4739-4748) in THF (5 mL) was added. Stirring at 0° C. for 10 minutes was followed by 21 h at r.t. The mixture was concentrated and purified by flash column chromatography (SiO2, Heptane-EtOAc 7:1) to give 1.8 g (98%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1cccc(C)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=O)[CH3:3].C(O)C.[S-:18][C:19]#[N:20].[K+]>O>[CH2:2]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:20]=[C:19]1[SH:18])[CH3:3]
Reactant: CCNCC(=O)c1ccc(O)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCn1cc(-c2ccc(O)cc2)nc1S
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred and refluxing mixture of 21.5 parts of 2-(ethylamino)-1-(4-hydroxyphenyl)ethanone hydrochloride, 60 parts of ethanol and 75 parts of water is added dropwise a solution of 12 parts of potassium thiocyanate in a small amount of water. Upon completion, stirring is continued overnight at reflux temperature. Another portion of 4 parts of potassium thiocyanate in a small amount of water is added and the whole is stirred for 8 hours at reflux temperature. The reaction mixture is concentrated. The product is filtered off and crystallized from a mixture of ethanol and water, yielding 10 parts (91%) of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol; mp. 251.7° C.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCCC1.[NH2:17][C:18]1[C:25]([OH:26])=[C:24]([F:27])[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([CH3:34])[C:19]=1[C:20]#[N:21].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:20]([C:19]1[C:22]([CH3:34])=[C:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24]([F:27])=[C:25]([OH:26])[C:18]=1[NH:17][C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:21]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C#N)c(NC(=O)/C=C/c2ccccc2)c(O)c(F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under nitrogen atmosphere, cinnamoyl chloride (378 mg, 2.27 mmol) was dropwise added to a tetrahydrofuran solution (10 ml) of 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (500 mg, 2.06 mmol) and sodium hydrogencarbonate (399 mg, 4.75 mmol) cooled with ice, followed by stirring at room temperature for 17 hours and stirring at 60° C. for 1 hour. After cooling, ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure.
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[CH2:24][OH:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[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[CH2:24][O:25][CH3:28])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3CO)cc2)c1Sc1ccc(Cl)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[(1S,2S)-2-(4-{5-[(5-Chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)cyclopropyl]methanol (product of Example 23, 20 mg, 0.054 mmol) was dissolved in DMF (1 mL), to which was added NaH (0.25 mmol) and MeI (0.25 mmol) at 0° C. The reaction was warmed to rt and stirred for 30 min. The reaction was quenched with 1 mL of aqueous NH4Cl and diluted with 5 mL of EtOAc. The mixture was washed with water (two times) and brine. The organic layer was dried and concentrated to give the crude product that was purified by column (60-100% EtOAc in hexanes) to afford the title compound. 1H NMR (500 MHz, (CDCl3): 9.82 (s, 1H), 8.37 (s, 1H), 7.88 (d, 2H), 7.58 (d, 1H), 7.15 (d, 2H), 7.07 (d, 1H), 3.97 (s, 3H), 3.42 (d, 2H), 3.39 (s, 3H), 1.82 (m, 1H), 1.44 (m, 1H), 0.99 (m, 2H). LCMS: m/z 386 (M+H)+. Human FAAH lysate assay: IC50=35.5 nM.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:21])[C@@H:6]([C:18]([OH:20])=[O:19])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=[O:3])[CH3:2].[F:22][C:23]([F:41])([F:40])[C:24]([NH:26][C@H:27]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:28]O)=[O:25]>C(Cl)Cl>[C:1]([O:4][C@H:5]([CH3:21])[C@H:6]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:18]([O:20][CH2:28][C@@H:27]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:26][C:24](=[O:25])[C:23]([F:22])([F:40])[F:41])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H](CO)NC(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of O-acetyl-N-benzyloxycarbonyl-L-threonine (1 g) and benzyl N-trifluoroacetyl-L-serinate (987 mg) in methylene chloride (20 ml) was added N,N-diethylaminopropyl-N'-ethylcarbodiimide hydrochloride (1.22 g) and 4-N,N-dimethylaminopyridine (77.8 mg) at room temperature. After stirring for an hour at room temperature, the reaction mixture was washed successively with aqueous hydrogen chloride, water, 10% aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the methylene chloride extract was filtered and concentrated. The residue was chromatographed on silica gel (20 g) eluting successively with a mixture of hexane and methylene chloride (1:1), methylene chloride and a mixture of methylene chloride and acetone (125:1) to give benzyl O-[3(R)-acetoxy-2(S)-benzyloxycarbonylamino-1-oxo-butyl]-N-trifluoroacetyl-L-serinate (1.42 g).
Reaction SMILES: B.[CH2:2]=[C:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.[OH-:17].[Na+].OO>C1COCC1.CCCCCC>[OH:17][CH2:2][CH:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1
Reactant: C=C1COCCN(C(=O)OC(C)(C)C)C1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(CO)C1
Temperature: 25 °C

Procedure:
1M borane in THF (450 mL, 0.45 mol, 0.9 eq) was added under stirring and cooling on an ice bath to a stirred in a stream of argon solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (Preparation 79, 107 g, 0.5 mol, 1 eq) in THF (300 mL). The reaction mixture was heated to 25° C. and stirred at this temperature for 3 h. Then the reaction mixture was cooled to 0-10° C. and treated at this temperature sequentially with 3N sodium hydroxide (170 mL) and 30% hydrogen peroxide (66 mL). The obtained homogenous mixture was stirred overnight, then treated with hexane (45 mL), and dried over potassium carbonate. The organic layer was decanted from the precipitate, which was washed with DCM. The organic layers were evaporated in vacuo, and the residue was purified rapidly (due to instability of the product on silica gel) by chromatography (carbon tetrachloride/chloroform/isopropanol 100:0:0→0:100:0→0:90:10) on silica gel (1.2 kg; 63-100 μm) to give title compound as a colorless oil in (85 g, 0.368 mol, 72%).
Reaction SMILES: C(O[C:6]([N:8]1[C:20]2[C:11](=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:10]([CH2:22][Cl:23])[CH2:9]1)=[O:7])(C)(C)C.Cl.[OH:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:29]=[CH:30]C(O)=O.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[Cl:23][CH2:22][CH:10]1[C:11]2=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=[C:20]2[N:8]([C:6](=[O:7])/[CH:30]=[CH:29]/[C:28]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:26]([OH:25])[CH:27]=2)[CH2:9]1)[N:16]=[CH:15][CH:14]=[CH:13]3
Reactant: COc1ccc(C=CC(=O)O)cc1O
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(O)c2ncccc32)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 8 %

Procedure:
A suspension of 16 (0.10 g, 0.30 mmol) in dioxane (5 mL) was saturated with HCl, stirred at r.t. over 5 h and evaporated. 3-Hydroxy-4-methoxycinnamic acid (predominantly trans) (0.070 g, 0.36 mmol), EDCI (0.29 g, 1.50 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 3 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (CH2Cl2/MeOH; 93:7) followed by recrystallisation (CH2Cl2/Et2O) gave 18f (0.01 g, 8%) as a yellow solid: mp 215–218° C.; 1H NMR [(CD3)2SO]δ 9.96 (bs, 1 H), 9.13 (s, 1 H), 8.73 (dd, J=4.1, 1.4, 1 H), 8.36 (dd, J=8.5, 1.4, 1 H), 8.17 (bs, 1 H), 7.57 (d, J=15.3, 1 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.25 (d, J=2.0, 1 H), 7.20 (dd, J=8.4, 2.0, 1 H), 6.99 (d, J=8.1, 1 H), 6.96 (d, J=15.0, 1 H), 4.54 (dd, J=10.5, 9.4, 1 H), 4.44 (dd, J=11.1, 2.6, 1 H), 4.00 (dd, J=11.2, 3.3, 1 H),3.88 (dd, J=11.1, 7.5, 1 H), 3.83 (s, 3H). C22H1935ClN2O4 requires M+H 411.1112. Found (FAB) 411.1127.