Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([NH:6][OH:7])([CH2:4][CH3:5])[CH3:3].C(=O)(O)[O-].[Na+].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>COCCOC>[C:13]1([NH:19][C:20]([N:6]([CH:2]([CH2:4][CH3:5])[CH3:3])[OH:7])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(C)NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C)N(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 500 ml of ethylene glycol dimethyl ether, 209.1 g (1.5 moles) of 90% pure N-sec.-butylhydroxylamine hydrochloride and 151.2 g (1.8 moles) of sodium bicarbonate was stirred at room temperature for 1 hour and 178.5 g (1.5 moles) of phenyl isocyanate were then added at 0° to 5° C. The mixture was subsequently stirred at 10° C. for 1 hour, the salt was then filtered off and the filtrate was evaporated in vacuo. 310 g (99% of theory) of N-phenyl-N'-sec.-butyl-N'-hydroxyurea remained as a colourless powder with a melting point of 107° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 57.7 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (0.74 g, 3.2 mmol) and methyl thiosalicylate (1.1 g, 6.4 mmol) were dissolved in toluene (3 ml). Triethylamine (1.4 ml, 9.7 mmol) was added thereto. The reaction mixture was refluxed for 7.5 hrs, subjected to a silica gel (75 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol-hexane to give the titled compound (0.68 g, 57%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N:46]1([C@H:51]2[CH2:55][CH2:54][NH:53][CH2:52]2)[CH:50]=[N:49][CH:48]=[N:47]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:53]3[CH2:54][CH2:55][C@H:51]([N:46]4[CH:50]=[N:49][CH:48]=[N:47]4)[CH2:52]3)=[O:28])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: c1ncn([C@H]2CCNC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 150.2 %

Procedure:
768 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid were dissolved in 8 ml of dry tetrahydrofuran, and the resulting solution was cooled to 0° C. 191 mg of triethylamine were added to the solution, followed by 218 mg of pivaloyl chloride, and then the mixture was stirred at the same temperature for 5 minutes. At the end of this time, a mixture of 238 mg of (3S)-3-(1-1,2,4-triazolyl)pyrrolidine trifluoroacetate, 440 mg of diisopropylethylamine and 7 ml of dry acetonitrile was added to the mixture, and the mixture was gradually heated and then stirred at 0° C. for 15 minutes and at room temperature for 2 hours. The solvent was then removed by evaporation under reduced pressure, and the residue was diluted with ethyl acetate, after which the diluted solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, using a 7:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 803 mg of the title compound, as a powder.
Reaction SMILES: [CH3:1][N:2]([Sn](C)(C)C)[CH3:3].[C:8]([O:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[O:20][C:21]3[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:25]=[CH:24][C:22]=3[CH:23]=2)[O:15][C:14](=[O:36])[C:13]=1[CH3:37])(=[O:10])[CH3:9]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([O:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[O:20][C:21]3[CH:27]=[C:26]([N:2]([CH3:3])[CH3:1])[CH:25]=[CH:24][C:22]=3[CH:23]=2)[O:15][C:14](=[O:36])[C:13]=1[CH3:37])(=[O:10])[CH3:9]
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3o2)oc(=O)c1C
Reactant: CN(C)[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C)c(-c2cc3ccc(N(C)C)cc3o2)oc(=O)c1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Tetrakis(triphenylphosphine)palladium (3 mg) and dimethylaminotrimethyltin (34 mg) were added to a solution of 4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy) benzofuran-2-yl)-2H-pyran-2-one (45 mg) in toluene (5 ml), and the mixture was stirred at 50° C. overnight. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1) to obtain 4-acetyloxy-3,5-dimethyl-6-(6-dimethylaminobenzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCCCCCCCC

Procedure:
Compound VI-11 (324 mg, 97.6%) was obtained in the same manner as that in Reference Example 5, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 100 mg, 0.517 mmol) and hexadecyl methanesulfonate (Nu-Chek Prep, Inc; 415 mg, 1.29 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl.O>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: Cc1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NC(=O)C(C)(C)C
Yield: 93 %

Procedure:
A biphasic solution of o-toluidine (107.2 g, 1.0 mol) in methylene chloride (500 ml) and water (150 ml) containing sodium carbonate (69 g, 0.65 mol) was treated with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at gentle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo. The crude N-[(2-methyl)phenyl]-2,2-dimethylpropanamide was slurried in 2% aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50° C., 20 mm), N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (178 g, 0.93 mol) was obtained in 93% yield. (mp 109°-110° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>CO.CC#N.COC(OC)N(C)C>[F:10][C:6]1[CH:5]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:12])=[O:13])[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][OH:9]
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(C=O)c(F)c1
Agent: COC(OC)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(F)c1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a solution of N′-(3,5-difluoro-4-formylphenylsulfonyl)-N,N-dimethylformimidamide (171 g, 619 mmol) in MeOH (1 L) was added NaBH4 (23.4 g, 619 mmol) at 0° C. After 1 h, the reaction mixture was concentrated, neutralized to pH 6 with 1N HCl, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4 and evaporated in vacuo. To a solution of this residue in CH3CN (1 L) was added N,N-dimethylformamide dimethylacetal (166 mL, 1.24 mmol, 2 eq). The solution was evaporated in vacuo and then purified by chromatography (silica, DCM/EtOAc, 1:1) to give N′-(3,5-difluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethylformimidamide (80 g). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.45-7.40 (m, 2H), 4.8 (d, J=3.6 Hz), 3.17 (s, 3H), 3.05 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH:5]3[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:14][CH:13]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.49 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.38 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH3:20].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH3:20])[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1ccsc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2sccc2C)C1=O
Yield: 56.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84 mmol) was reacted with 2-bromo-3-methyl-thiophene (150 mg, 0.84 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium phosphate (445 mg, 2.1 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 130 mg of the product (56.7% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:20]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC(Oc1ccccc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromohexanoate (0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@@H:16]([CH2:19][NH2:20])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@@H:16]([CH2:19][NH:20][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CN)C3)c2n1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(Cl)c(CCN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 9.7 %

Procedure:
To a stirred solution of [((3S)-1-{2-[3-Chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (100 mg, 0.31 mmol) in dry CH2Cl2 (5 mL) and dry EtOH (5 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (67 mg, 0.34 mmol) along with a small amount of Na2SO4 and NaHCO3. After 24 h at RT, NaBH4 (12 mg, 0.32 mmol) was added. After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica gel afforded the title compound as a light yellow solid (15 mg, 9.4%): LC/MS (ES) m/e 499/501 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.78 (s, 1H), 8.25 (d, J=9.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.35 (s, 2H), 4.1 (s, 3H), 3.9 (m, 4H), 3.66 (s, 4H), 3.5 (m, 4H), 3.3 (m, 2H), 2.9-3.0 (m, 1H), 2.2-2.3 (m, 1H), 1.95-2.05 (m, 1H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (50 mg, 51%), MS (ISP) m/z=394.3 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-cyano-acetic acid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]12([CH2:33][CH2:34][N:35]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:36]([NH:38][CH2:39][CH2:40][CH:41]([OH:48])[C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[O:37])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.C(OCC)(=O)C>[C:23]12([CH2:33][CH2:34][N:35]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:36]([NH:38][CH2:39][CH2:40][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[O:37])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(O)c1ccncc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (221 mg, 0.520 mmol) was added to a solution of 1-[2-(1-adamantyl)ethyl]-3-[3-hydroxy-3-(4-pyridyl)propyl]-1-pentylurea (100 mg, 0.234 mmol) in anhydrous dichloromethane (2 ml) under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred for one hour. The reaction mixture was cooled with ice again, ethyl acetate (10 ml), a saturated aqueous sodium sulfite solution (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml) were added to the reaction mixture, and the whole was stirred for 15 minutes. The reaction mixture was distributed with ethyl acetate (50 ml) and water (10 ml), and the organic layer was washed with a saturated aqueous sodium sulfite solution (5 ml), a saturated aqueous sodium hydrogencarbonate solution (5 ml) and a saturated aqueous sodium chloride solution (25 ml) successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 87.3 mg (87.8%) of the titled compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][N:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH2:10][C:11](OC)=[O:12])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>CO>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][N:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CC(C)(C)OC(=O)CCN(CCO)c1ccc(C(F)(F)F)c(Cl)c1
Yield: 84 %

Procedure:
In analogy to the procedure described for intermediate 40C, 3-[(3-chloro-4-trifluoromethyl-phenyl)-methoxycarbonylmethyl-amino]-propionic acid tert-butyl ester and LiBH4 (2 M in THF)/MeOH gave the title compound in 84% yield as yellow oil. MS: 368.12 (MH+, Cl).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[C:8]1([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH:9]=1
Reactant: Clc1ccc(-c2cccc(Cc3c[nH]cn3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ccc(-c2cccc(Cc3c[nH]cn3)c2)cc1

Procedure:
Prepared in analogy to Example 67 from 4-(4′-chloro-biphenyl-3-ylmethyl)-1H-imidazole, hydrogen and palladium in methanol. White crystalline solid. MS (ISP): 235.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:24]([CH2:37][CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26][CH2:25][N:24]([CH2:21][CH2:22][CH3:23])[CH2:37][CH2:38][CH3:39])[CH2:33][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CC#N
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 22 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 22% of theory. Colourless crystals, m.p. 174°-175° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:6]1=[O:24].Cl.CC(O)C>CO>[F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Yield: 95.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (370 mg, 0.757 mmol) in methanol (5 mL) was added, 5 M HCl in IPA (1.51 mL, 7.57 mmol) and the mixture was stirred at ambient temperature for 6 hours and concentrated in vacuo. The residue was stirred in 1M NaOH (20 mL) and DCM (25 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo to give (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one as light brown foam (282 mg, 0.726 mmol, 96% yield). Mass spectrum (apci) m/z=389.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (50 gm, 300 mmol) in acetone (1 L) was added potassium carbonate (150 gm) and benzyl bromide (37 mL, 1.1 eq). The mixture was refluxed for 6 hours and cooled to ambient temperature. The reaction was poured into ice cold aqueous 1M HCl (1 L) and the aqueous mixture was extracted with ether (3×500 mL). The combined organic extracts were dried over MgSO4 and filtered and the solvent was removed under reduced pressure. Methyl 2-hydroxy-4-benzyloxybenzoate was obtained by crystallization from EtOH in 60% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([Br:33])[S:14](=O)[C:13]=2[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(Cl)(Cl)Cl.ClCCl.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([Br:33])[S:14][C:13]=2[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1C(Br)=C(Oc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc21
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Dissolve 1-{2-[4-(6-benzyloxy-2-bromo-1-oxo-1H-1λ4-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (22.36 g, 40.3 mmol) in methanol (160 mL) and chloroform (80 mL). Add a 30% solution of titanium trichloride in aqueous HCl (31.4 mL, 80.6 mmol) and stir at ambient temperature for 2 hours. Quench reaction mixture with saturated aqueous sodium bicarbonate (500 mL) and dilute with dichloromethane (500 mL). Separate layers and wash the organic layer with saturated aqueous sodium bicarbonate (500 mL), water (500 mL), and brine (500 mL). Dry with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol (containing 10% NH4OH) in dichloromethane (0 to 2%) to give 19.2 g of the title compound (88%).