Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C.C(OCC)(=O)C>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:15]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:16][CH2:17][CH2:18][NH2:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 176.1 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to an ethanol solution (2 ml) of t-butyl N-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]carbamate (104 mg, 0.226 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was then concentrated. The residue thus obtained was recrystallized from ethanol-ethyl acetate, whereby the title compound (78.9 mg, 0.199 mmol, 88%) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-methylisatin (8.05 g, 50 mmol) and K2CO3 (8.16 g, 60 mmol) in DMF (100 mL) was added BnBr (6.5 mL, 55 mmol) dropwise over 2 min. After addition, the resulting mixture was heated in an oil bath at 75° C. for 1.5 h. After cooling to rt, the reaction mixture was poured onto ice/cold water (250 mL), rinsed with H2O (50 mL) and stirred for 5 min. The resulting precipitates were collected by suction filtration and air dried to give 1-benzyl-5-methylisatin as dark red solid. MS ESI 252.0 [M+H]+, calcd for [C16H13NO2+H]+ 252.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.[H-].[Na+].Cl>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:37]\[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (28.0 g), tetraethyl methylenediphosphonate (17.5 g) and N,N-dimethylformamide (300 mL) was added sodium hydride (60% in oil, 2.43 g) at 0° C. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (2:3, v/v) to give diethyl (Z)-2-(3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (1.94 g, yield 5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)=[CH:13][N:12]=1.C(=O)=O.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S@:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)=[CH:13][N:12]=1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4F)nc3)CC2)n1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc([S@](C)=O)cc4F)nc3)CC2)n1
Yield: 20 %

Procedure:
The racemic sulfoxide 2-[2-fluoro-4-(methylsulfinyl)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (prepared as in Example 176, 195 mg) was subjected to Chiral HPLC [column: Chiralpak AS-H, column mobile phase: 65% CO2: 35% (80% MeOH: 20% CHCl3) (2 mL/min), pressure 140 bar, temperature 30° C., 280 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (39 mg) was isolated as an off-white solid with Tr of 16.69 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N+:11]([O-])=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=1
Reactant: Cn1c(=O)c2c[n+]([O-])ccc2c2ccc(Cl)cc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c2c(Cl)nccc2c2ccc(Cl)cc21
Yield: 56 %

Procedure:
A stirred solution of 8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine 3-oxide (0.5 g, 1.918 mmol) in POCl3 (3.58 mL, 38.4 mmol) was heated to reflux for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was then partitioned between dichloromethane (100 mL) and saturated sodium bicarbonate solution (200 mL). The organic layer was separated and washed again with brine solution (50 mL), dried over sodium sulphate, and concentrated to afford 4,8-dichloro-6 methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.3 g, 1.075 mmol, 56% crude yield). The material was carried on without further purification. LC/MS (ESI) m/e 280.8, [(M+2H)+, calcd for C13H9Cl2N2O, 280.8]; LC/MS retention time (method C): tR=2.06 min.
Reaction SMILES: [C-:1]#[N:2].[K+].FC(F)(F)S(O[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:19])[C:11]=1[CH3:20])(=O)=O.S([O-])(O)(=O)=O.[K+].O>O1CCCC1>[CH3:20][C:11]1[C:12]([CH3:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C#N)ccc([N+](=O)[O-])c1C
Reaction time: 10 h
Yield: 91 %

Procedure:
Potassium cyanide (2.26 g, 34.7 mmol) was added to a solution of 2,3-dimethyl-4-nitrophenyl trifluoromethane-sulfonate (5.20 g, 17.4 mmol) in tetrahydrofuran (21 ml) at room temperature, followed by deaeration. After tetrakistriphenylphosphine (1.00 g, 0.865 mmol) was added thereto, deaeration was conducted again and then the reaction was carried out under reflux conditions for 10 hours. A 0.5M-aqueous potassium hydrogensulfate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/chloroform) to obtain 2,3-dimethyl-4-nitrobenzonitrile (2.79 g, 90.9%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=[C:3]1[C:18]([O:20]CC)=[O:19].Cl>C(O)(=O)C>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1nc2cccnc2n(-c2ccccc2)c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1nc2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
10.74 g (36 mmol) of ethyl 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate was dissolved in acetic acid (270 mL), and 6N hydrochloric acid (80 mL) was added thereto at room temperature. Then, the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and water (100 mL) was added. The solid thus obtained was separated by filtration and dried, to obtain 6.50 g (yield: 67%) of 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid as pale brown crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10]CCN.[OH-].[K+].[C:16]1(=[O:21])[O:20][CH2:19][CH2:18][O:17]1>>[C:16]1(=[O:21])[O:20][CH2:19][CH2:18][O:17]1.[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10]
Reactant: NCCNCCNCCNCCN
Agent: [K+]
Agent: [OH-]
Solvent: O=C1OCCO1
Product: NCCNCCNCCN
Temperature: 160 °C

Procedure:
Add 37.8 g of tetraethylene pentaamine (with an AV of approximately 1050 mg KOH/g) to a 250 ml flask fitted with a stirrer, condensor and nitrogen inlet. Add 52.6 g ethylene carbonate to the system. Heat the system at 160° C. for 3 hours under N2. Strip the system to yield an ethylene carbonate-triethylene tetraamine adduct having an AV of approximately 180 mg KOH/g.
Reaction SMILES: [CH:1]1([C:11](O)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
200 mg (1.10 mmol) of 1,2,3,4-tetrahydro-naphthalen-1-carboxylic acid compound was dissolved in 9 mL of tetrahydrofuran, and then 129 mg (3.30 mmol) of lithium aluminum hydride was added at 0° C. and stirred at room temperature for 1 hour. Water was slowly added to quench the reaction, and when a gel was formed by adding ethyl acetate, the celite was filtered. Then, the residue was dissolved again in 20 mL of ethyl acetate and the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 180 mg of colorless oil (yield: 97%).
Reaction SMILES: C([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]#[N:13])[CH2:7][CH2:6]1)=C.Cl.O>ClCCl.O1CCOCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]#[N:13])[CH2:7][CH2:6]1
Reactant: C=COCC1CCC(CC#N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#CCC1CCC(CO)CC1
Reaction time: 0.5 h

Procedure:
4-[(Vinyloxy)methyl]cyclohexylacetonitrile (0.9 g, 0.005 mol) was dissolved in dichloromethane (5 mL), and 1.5 mL of 4 N hydrogen chloride (0.22 g, 0.0060 mol) in dioxane was added with water (0.2 mL). The reaction was stirred for 30 min. and then concentrated to give the product as a 3:1 mixture of diastereomers, (0.75 g). 1H NMR (400 MHz, CDCl3): δ 3.451-3.467 d, 2H, J=6.4 Hz), 2.58 (br s, 1H), 2.271-2.288 (d, 2H, J=6.8 Hz), 1.85-1.93 (m, 4H), 1.2-1.8 (m, 4H), 0.95-1.19 (m, 4H) (major diastereomer).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([Cl:21])=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.ClC1N=C(N2CCNCC2)C(Cl)=CN=1.[C:43]([O:47][C:48](=[O:57])[NH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH2:56])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[C:43]([O:47][C:48](=[O:57])[NH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C:5]([Cl:21])=[CH:4][N:3]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)ncc2Cl)CC1
Agent: Clc1ncc(Cl)c(N2CCNCC2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a solution of tert-butyl 4-(2,5-dichloropyrimidin-4-yl)piperazine-1-carboxylate (0.1 g, 0.3 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 2,5-dichloro-4-(piperazin-1-yl)pyrimidine (0.3 mmol) in Dioxane (4.0 mL) was added TFA (0.060 mL, 0.75 mmol) and tert-butyl(2-aminophenyl)carbamate (0.094 g, 0.45 mmol) and the mixture was stirred at 100° C. for 24 h. reaction. After cooling to room temperature the reaction mixture was diluted with EtOAc and washed with aqueous saturated sodium bicarbonate solution. The organic mixture was dried over sodium sulfate and loaded onto silica gel and purified using 0-10% MeOH/DCM gradient containing 10% NH4OH to give the title compound (28 mg, 23%) as a white solid. MS (ES+) C19H25ClN6O2 requires: 404. Found: 405 [M+H]+
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([CH2:45][OH:46])[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:46][CH2:45][C:32]3([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:36][CH2:37]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Solvent: C1CCCCC1
Solvent: CC(Cl)Cl
Product: CCn1cnc2c(C(C)OCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.7 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (772 mg, 2.5 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 281 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.20-7.33 (m, 3 H), 7.00 (t, J=8.7 Hz, 2 H), 5.10 (q, J=6.6 Hz, 1 H), 4.17-4.30 (m, 2 H), 3.56-3.78 (m, 2 H), 3.24-3.40 (m, 2 H), 2.93-3.12 (m, 2 H), 2.02-2.21 (m, 2 H), 1.80-1.99 (m, 2 H), 1.56 (t, 3 H), 1.37-1.47 (m, 12 H). 550.40 (MH)+.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.[OH-].[NH4+]>O>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OCCCCCCBr)cc1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
Concentrated sulfuric acid (1036 ml) was added gradually to 338 ml of water, followed by 622 g of ethyl 4-(6-bromohexyloxy)benzoate. The mixture was heated at 100°-110° C. for 35 minutes and then poured onto 2.5 kg ice with stirring. The mixture was treated with 2520 ml of ammonium hydroxide to bring the pH to 6.0. The product was collected by filtration, washed with water and hexane, and dried in an oven to give 452 g of 4-(6-bromohexyloxy)benzoic acid.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](F)[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[C:23]([CH:24]=1)[O:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxyheptyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluoronitrobenzene.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7])[CH3:4]>ClCCl>[N+:23]([C:19]1[CH:18]=[C:17]([C:15]2[C:16]3[C:8]([C:6]([NH:5][CH:3]([CH3:4])[CH:2]=[O:1])=[O:7])=[CH:9][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: CC(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Solvent: ClCCl
Product: CC(C=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(1-hydroxypropan-2-yl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (800 mg, 1.70 mmol) in dichloromethane (10 mL), was added DMP (1.20 g, 2.83 mmol). The resulting solution was stirred for 2 hours at room temperature and quenched by addition of saturated aqueous NaHCO3. The resulting solution was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 1-50% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford 4-(3-nitrophenyl)-N-(1-oxopropan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide as a yellow oil. LRMS (ESI) calc'd for C22H28N5O5Si [M+H]+: 470, found 470. 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 9.12 (s, 1H), 9.09 (s, 1H), 8.57-7.68 (m, 5H), 5.80-5.78 (s, 2H), 4.54-4.51 (m, 1H), 3.66-3.62 (m, 2H), 1.36-1.27 (m, 3H), 1.02-0.98 (m, 2H), 0.02 (s, 9H).
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]([NH:26][CH2:27][CH2:28][F:29])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:33].O>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[C:24]([N:26]([CH2:27][CH2:28][F:29])[CH3:33])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: CI
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3C(=O)NCCF)cc2)c1Sc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCF)C(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1

Procedure:
To a solution of Example 10 (10 mg, 0.023 mmol) in DMF (1 Ml) was added sodium hydride (60% in mineral oil), (6 mg, 0.139 mmol) and iodomethane (0.009 Ml, 0.139 mmol). The reaction mixture was stirred at rt for 30 min Water was added and the mixture was extracted with ethyl acetate. The organics were dried (MgSO4), concentrated, and purified on 4 g of silica gel eluting a gradient of 0-5% triethylamine in ethyl acetate to give rise to the title compound. 1H NMR (500 MHz), [CD3OD]: 8.34 (s, 1H), 8.04 (s, 1H), 7.73 (m, 2H), 7.63 (d, 1H), 7.14 (m, 2H), 6.92 (d, 1H), 4.58 (m, 1H), 4.48 (m, 1H), 3.66 (s, 3H), 3.19 (s, 3H), 3.00 (br, 2H), 2.37 (m, 1H), 2.18 (m, 1H), 1.53 (m, 1H), 1.31 (m, 1H). LCMS: [M+1]+=445. Human FAAH lysate assay: IC50=3.0 nM.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1cccc(C2(O)CCNCC2)c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(C2(O)CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-8.13 (c=0.69, methanol).
Reaction SMILES: CN(OC)[C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CCCCCC.C([Li])CCC>O1CCCC1.C(OC(=O)C)C.O>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:23][NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH:29]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Yield: 45.1 %

Procedure:
A solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (24.8 g) and N-tert-butoxycarbonyl-3-bromobenzylamine (22.0 g) in tetrahydrofuran (300 ml) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution (1.6 mol./L)(240 ml) of n-butyl lithium. To the mixture were then added water (300 ml) and acetic acid ethyl ester (300 ml). The organic layer was washed with water, which was dried over anhydrous MgSO4, then the solvent was distilled off. To the residual oily compound was added hexane (400 ml) to cause crystallization. The crystalline product was collected by filtration to give 2-amino-3′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (12.5 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[C:11]2[C:16]([C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[CH:15][CH:14]=[CH:13][CH:12]=2>>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[C:9]2[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:31]=[CH:30][CH:29]=1
Reactant: CN1CCNCC1
Reactant: COc1cccc(-n2c(Cl)c(C(=O)N3CCOCC3)c3ccccc32)c1
Product: COc1cccc(-n2c(N3CCN(C)CC3)c(C(=O)N3CCOCC3)c3ccccc32)c1

Procedure:
This compound was prepared from 2-chloro-1(3-methoxyphenyl)-indole-3-carboxylic acid chloride and morpholine to yield 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid morpholide which was reacted with N-methyl-piperazine according to Example 42. The yield of amorphous product was 85% of the theoretical yield; the amorpheus hydrochloride had a decomposition point above 160° C.