Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S(Cl)(C)(=O)=O.O.[N-:28]=[N+:29]=[N-:30].[Na+]>N1C=CC=CC=1.CN(C=O)C>[CH2:1]([N:28]=[N+:29]=[N-:30])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a magnetically stirred solution of 50 mg (0.17 mmol) of arachidonyl alcohol in 1 mL of pyridine was added 29.2 mg (0.225 mmol) of mesyl chloride at 0° C. After stirring for 5 hours, the reaction mixture was poured into 2 mL of cold water and extracted with diethyl ether (2×4 mL). The combined ether extracts were washed with 1 N sulfuric acid and saturated sodium bicarbonate solution and evaporated in vacuo. The crude mesylate was dissolved in 2 mL of anhydrous DMF, and then a solution of 6.5 mg (0.85 mmol) of sodium azide in 4 mL of anhydrous DMF was added at room temperature. The reaction mixture was heated to 90° C. for 24 hours behind a safety shield. The mixture was cooled to room temperature, inorganic material was filtered off, and the filtrate was poured into 1 mL of cold water. Extraction with diethyl ether (2×6 mL), drying (MgSO4), and evaporation gave an oily residue which was chromatographed on silica gel (petroleum ether) to afford 39 mg (73%) of arachidonyl azide as a colorless oil: 1H NMR (200 MHZ, CDCl3) δ 5.38 (m, 8H), 3.27 (t, J=6 Hz, 2H), 2.81 (m, 6H), 2.11–2.01 (m, 4H), 1.62 (m, 2H), 1.48–1.25 (m, 6H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (10.2 g, 67 mmol) in acetonitrile (250 mL) was added potassium carbonate (27.6 g, 200 mmol) and methyl iodide (4.1 mL, 66 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the solid was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (250 mL). The solution was washed with 2N NaOH (aq.) (200 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to yield 1-methoxy-2-methyl-4-nitrobenzene (9.5 g, 57 mmol, 85%).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([O:16][CH3:17])[C:5]=2[CH2:4][CH2:3]1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[CH2:10]([N:7]1[C:8](=[O:9])[CH:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:3][CH2:4][C:5]2[C:15]([O:16][CH3:17])=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=[CH:12][C:6]1=2)[CH3:11]
Reactant: CCN1C(=O)C(N)CCc2c1ccc([N+](=O)[O-])c2OC
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN1C(=O)C(N2CCOCC2)CCc2c1ccc([N+](=O)[O-])c2OC
Yield: 33.4 %

Procedure:
Combine 3-Amino-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.8 g), 1-Bromo-2-(2-bromo-ethoxy)-ethane (797 mg) and Potassium carbonate (879 mg) in Acetonitrile (37 mL), heat to 85° C., After 2 days, added another eq of Potassium carbonate and 0.5 eq of 1-Bromo-2-(2-bromo-ethoxy)-ethane and continue heating. Diluted with CH2Cl2, filter, the material was concentrated onto Celite and purified by ISCO chromatography (120 g, SiO2, gradient elution 0% MeOH/DCM/to 10% MEOH/DCM) to give 1-ethyl-6-methoxy-3-morpholin-4-yl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an orange solid (334 mgs). 1H-NMR (CDCl3): 7.86 (d, J=8.8 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 4.32-4.22 (m, 1H), 3.96 (s, 3H), 3.73-3.60 (m, 5H), 3.27-3.23 (m, 1H), 2.97-2.92 (m, 1H), 2.72-2.55 (m, 4H), 2.54-2.45 (m, 1H), 2.39-2.23 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1([CH:20]=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]([OH:21])[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COc1cccc(Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 3-bromoanisole (5.61 g, 30.0 mmol) in dry THF (80 mL) was dropwise added n-butyl lithium-hexane solution (1.6 M, 37.5 mL, 60 mmol) under nitrogen at -78° C. The reaction mixture was allowed to warm to r.t. in 2 h and cooled down again to -78° C. prior to addition of 1-naphthaldehyde (4.69 g, 30.0 mmol, in 10 mL THF). The mixture was warmed to r.t. in 3 h, and then quenched with aqueous NH4Cl solution, extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4. Removal of solvents in vacuo provided 3-methoxy-α-(1-naphthyl)benzyl alcohol (4.25 g, 54%). GC-MS (Rt =10.41 min) 264 (M+), 245, 231, 215, 202, 155, 135, 128, 109.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:32]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:32][CH2:10][C:9]([C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1)=[O:11]
Reactant: CC(=O)c1ncc(C)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1cnc(C(=O)CBr)c(C)n1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a chloroform (2.0 mL) solution of 1-(3,5-dimethylpyrazin-2-yl)ethanone (41 mg), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (54 μL) and trimethylsilyl trifluoromethanesulfonate (59 μL) were added, and the resultant was stirred for 1 hour. Then, N-bromosuccinimide (53 mg) was added thereto, and the resultant was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→67/33) to obtain the title compound (35 mg) as a crude product.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].C([O:18][C:19]([N:21]1[CH2:25][C@H:24]([S:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][C@H:22]1[C:46](=[O:51])N(OC)C)=[O:20])CCC.OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:9]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([S:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:23][C@H:22]1[C:46](=[O:51])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20])[CH2:10][CH2:11][CH3:12]
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Reactant: CCCCOC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)N(C)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)C#Cc1ccccc1
Temperature: -10 °C
Yield: 81.4 %

Procedure:
A solution of 7.69 ml (70 mmol) phenylacetylen in 140 ml THF was treated at −25° C. with 43.8 ml (70 mol) n-butyllithium (1.6 M in hexane). The reaction was warmed up to −10° C. for 1 h. A solution of 7.46 g (14 mmol) (2S,4R)-2-(Methoxy-methyl-carbamoyl)-4-tritylsulfanyi-pyrrolidine-1-carboxylic acid butyl ester in 110 ml THF was then added. After 20 min the reaction was neutralized with 190 ml of an aqueous 10% KHSO4 solution. The mixture was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated 10% NaCl, dried over Na2SO4, evaporated and purified by flash-chromatography on silicagel (Hexane/EtOAc 9:1) to give 6.54 g (81%) of (2S,4R)-2-(3-Phenyl-propynoyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester, MS: 574 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13]([Mg]Cl)([CH3:15])[CH3:14]>C1COCC1>[OH:5][CH:4]([C:3]1[CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[OH:1])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc(O)c(C=O)cc1C
Solvent: C1CCOC1
Product: COc1cc(O)c(C(O)C(C)C)cc1C
Reaction time: 0.5 h

Procedure:
The above prepared 2-hydroxy-4-methoxy-5-methyl-benzaldehyde (1.97 g, 11.86 mmol) was dissolved in 30 mL of abs. THF and treated at −15° C. with iPrMgCl (14.8 mL of 2M [THF], 2.5 eq.) and the mixture kept at this temperature for 0.5 h. Careful pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents left 2.45 g of the title compound as white crystals, almost perfectly pure according to TLC and NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH2:29]([CH:31]([CH2:35][CH3:36])[C:32](O)=[O:33])[CH3:30].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.O>[CH2:29]([CH:31]([CH2:35][CH3:36])[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:33])[CH3:30]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CCc1ccc(N)cc1
Reactant: CCC(CC)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)C(=O)Nc1ccc(CCN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1
Temperature: 50 °C
Yield: 35.6 %

Procedure:
3-[2-(4-Amino-phenyl)-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (56 mg, 0.15 mmol) is dissolved in 10 mL methylene chloride and 2-ethyl-butyric acid (18 mg, 0.15 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (113 mg, 0.24 mmol) and ethyl diisopropyl amine (42 uL, 0.24 mmol) are added. The mixture is stirred and heated to 50° C. for 5 hours. Subsequently water and methylene chloride are added the organic phase is separated, dried and evaporated. The residue is purified by preparative HPLC (Method 1) to yield 2-ethyl-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-ethyl]-phenyl}-butyramide (25 mg, 35%). LC/MS at 254 nm; [M+H] 468; Rt 3.351.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1F.CCN(CC)CC>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Cl)c1
Yield: 63.1 %

Procedure:
To a solution of morpholine (1.1 mL, 12.6 mmol) in DMF (30 mL) were added 2-chloro-1-fluoro-4-nitrobenzene (1.76 g, 10.0 mmol) and Et3N (4.2 mL, 30.1 mmol) with stirring and the mixture was stirred at rt overnight. The mixture was then filtered and the organic phase was poured into 150 mL of DCM, washed with water (150 mL×3) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=10:1) to give the title compound as a yellow solid (1.53 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH:17]1[CH2:22]CN(C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrC[C@H]1CCC[N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][C@H:17]1[CH2:18][CH2:19][CH2:59][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CBr)C1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(C[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl (3S)-3-(bromomethyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH3:19][CH:20]([N:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1)[CH3:21]>C1C=CC=CC=1>[CH3:19][CH:20]([N:22]1[C:26]2[N:27]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25]=2[CH:24]=[N:23]1)[CH3:21]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1cnn2C(C)C
Temperature: 62 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (600 mg, 2.397 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and the reaction mixture was stirred at 62° C. overnight. The mixture was concentrated in vacuo and the residue was dissolved into acetic acid (3 mL). The solution was stirred at reflux for 1 h and concentrated in vacuo. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 530 mg (65%) of product. LCMS E-S (M+H)=340.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3H), 1.61-1.71 (m, 6H), 3.88-3.96 (s, 3H), 4.55 (q, J=7.2 Hz, 2H), 5.46 (m, 1H), 7.03-7.12 (m, 2H), 8.13-8.25 (m, 3H), 8.36-8.43 (m, 1H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]([F:57])([F:56])[CH:49]1[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]1>>[Cl:17][C:18]1[C:19]([O:55][C@H:52]2[CH2:53][CH2:54][C@H:49]([C:48]([F:47])([F:56])[F:57])[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(O[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 4-(trifluoromethyl)cyclohexanol, the title compound was obtained as a colorless solid (0.02 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.40 (d, J=12.6 Hz, 1H), 4.61-4.53 (m, 1H), 2.87 (s, 6H), 2.45-2.32 (m, 1H), 2.18-2.10 (m, 2H), 1.97-1.89 (m, 2H), 1.55-1.44 (m, 4H); MS (ES−) m/z 445.1, 447.1 (M−1).
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])=[CH:17][CH:16]=1
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 5.8 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 5.89 mmol) and methyl urea (654 mg, 8.83 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 16.9 mL, 11.78 mmol) was heated under reflux at 100° C. for 6 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (105.3 mg, 5.8%) as a white solid: mp 145–147° C.; EI-HRMS m/e calcd for C16H21ClN2O2 (M+) 308.1292, found 308.1291. The methyl ester of the starting material was recovered from the reaction mixture due to transesterification.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3](O)=[O:4].S(Cl)([Cl:22])=O>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([Cl:22])=[O:4]
Reactant: CCCCCCCCCCCCCCC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCC(C)C(=O)Cl

Procedure:
2-Methylhexadecanoic acid (27.0 g 0.1 mol) was mixed with 100 ml of thionyl chloride and the resulting mixture was stirred and heated under reflux for eight hours and then stirred at room temperature overnight. The mixture was concentrated under vacuum, diethyl ether was added and the mixture again concentrated under vacuum. The residue was distilled to yield 25.8 g of 2-methylhexadecanoyl chloride, bp 120°-125° C. at 0.25 mm Hg.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Cl:22][C:23]1[CH:24]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][Br:33])[CH:26]=[CH:27][CH:28]=1>CC#N>[Br-:33].[Cl:22][C:23]1[CH:24]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][N+:1]23[CH2:7][C:4]([C:8]([OH:9])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)([CH2:5][CH2:6]2)[CH2:3][CH2:2]3)[CH:26]=[CH:27][CH:28]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: Clc1cccc(OCCCBr)c1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3cccc(Cl)c3)(CC1)C2
Product: [Br-]
Yield: 47.6 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (31.9 mg, 0.114 mmol) and 3-bromopropyl 3-chlorophenyl ether (50.6 mg, 0.203 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (28.7 mg, 48%). EI-MS m/z 448 (M+) Rt (2.0 min).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]2=[O:7])=[CH:11][CH:12]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Product: O=C1CCCC(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The starting material is prepared as follows: The mixture of 34.2 g of glutaric anhydride, 28.2 g of 4-aminopyridine and 650 ml of xylene is refluxed with stirring for 6 hours. It is allowed to cool to room temperature, the solids are filtered off and extracted twice with 200 ml chloroform at reflux. The combined extracts are evaporated and the residue recrystallized twice from ethyl acetate to yield the 1-(4-pyridyl)-piperidine-2,6-dione melting at 153°-155°.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl.[OH2:19]>[Fe]>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:19])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O
Reactant: CC(=Cc1cccc(OC(F)(F)F)c1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: CC(=O)Cc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
29 g (117 mmols) of 1-(3'-trifluoromethoxy-phenyl)-2-nitro-propene, 46 g (0.82 g atom) of iron powder, 0.6 g of ferric chloride and 120 ml of water are introduced into a 500 ml three-necked flask equipped with a mechanical stirrer, a condenser and a dropping funnel, and this mixture is heated at 80° C. 29 ml of concentrated hydrochloric acid are added dropwise, via the dropping funnel, with stirring, over the course of 5 hours, while the temperature is kept at 80° C. The reaction mixture is allowed to cool overnight. The ketone is then steam distilled. The distillate is extracted twice in succession with 100 ml of diethyl ether each time. The two ether extracts are combined, dried over sodium sulphate and filtered. The solvent is evaporated from the filtrate in vacuo on a water bath, and the residue is rectified. 14,15 g (55% yield) of 1-(3'-trifluoromethoxy-phenyl)-2-propanone are thus obtained as a liquid, b.p. 112°- 118° C./18 mm.Hg, nD21°5 =1.448.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[NH:19]
Reactant: CN(C)C#N
Reactant: Cc1ccc(-c2ccccc2N)cc1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1ccc(-c2ccccc2NC(=N)N(C)C)cc1

Procedure:
A mixture of 2-amino-4'-methylbiphenyl hydrochloride (5.3 g), N,N-dimethylcyanamide (2.55 g) and m-cresol (25 ml) was heated at 90°-95° C. for 10 hours to give N,N-dimethyl-N'-(4'-methyl-2-biphenylyl)guanidine (m.p. 147°-148° C.) which was recrystallised from hexane.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:42][C@H:8]([O:9][C@H:10]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C@@H:11]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:7]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:6]1[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:54]([O:53][C@@H:7]1[C@@H:6]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C@@H:5]([OH:4])[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:42][C@@H:8]1[O:9][C@H:10]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C@@H:11]1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](O[C@@H]2[C@@H](COCc3ccccc3)N(C(=O)OCc3ccccc3)C[C@H]2OCc2ccccc2)O[C@@H]1COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
The compound (0.98 g, 1.06 mmol) synthesized in Example 20 (20a) was dissolved in methanol (20 mL) and potassium carbonate (147 mg, 1.06 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 4:1, V/V) to obtain the desired title compound (772.4 mg, 83%) as a colorless oil.