Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=O.C([O:8]O)(C)(C)C.[CH3:10][C:11]1([CH3:30])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]2[CH:16]=[C:15]([C:23]([CH3:25])=[CH2:24])[C:14]([O:26][CH2:27][CH2:28][CH3:29])=[CH:13][C:12]1=2.CCCCCC>ClCCl>[CH3:10][C:11]1([CH3:30])[CH2:20][CH2:19][C:18]([CH3:21])([CH3:22])[C:17]2[CH:16]=[C:15]([C:23]([CH3:25])=[CH:24][OH:8])[C:14]([O:26][CH2:27][CH2:28][CH3:29])=[CH:13][C:12]1=2
Reactant: CC(C)(C)OO
Reactant: C=C(C)c1cc2c(cc1OCCC)C(C)(C)CCC2(C)C
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCOc1cc2c(cc1C(C)=CO)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Into a 5 mL round-bottom flask was introduced selenium dioxide (71 mg, 0.64 mmol), 1 mL of dichloromethane, and 90% t-butyl hydroperoxide (0.284 mL, 2.56 mmol). After the mixture had been stirred for 30 min. at room temperature, 2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-propene (366 mg, 1.28 mmol), in 1 mL of dichloromethane was slowly added. The mixture was stirred at room temperature for 3 h. Then quenched with aqueous saturated NaHCO3. The mixture was extracted with dichloromethane (2×10 mL), washed with water (10 mL) and brine (10 mL), and the combined organic phase dried (Na2SO4). Concentrated in vacuo to give an oil which was subjected to chromatography (10% EtOAC/90% hexane) to give 149 mg (40%) of 2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydro naphthalen-2-yl)-propen-1-ol. 1H NMR (400 MHz, (CDCl3) δ 7.14(s, 1H, aromatic), 6.76(s, 1H, aromatic), 5.36(s, 1H, vinylic), 5.22(s, 1H, vinylic), 4.44(d, J=6.1 Hz, CH2OH), 3.93(t, J=6.5 Hz, 2H, CH2), 2.19(t, J=6.1 Hz, 1H, OH), 1.82(sx, J=6.8 Hz, 2H, CH2), 1.66(s, 4H, 2CH2), 1.28(s, 6H, 2CH3), 1.26(s, 3H, CH3), 1.25(s, 3H, CH3) and 1.03(t, J=7.3 Hz, 3H, CH3).
Reaction SMILES: [Si]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])(C(C)(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:58][C:59]1[CH:67]=[CH:66][C:62]([CH2:63][CH2:64][NH2:65])=[CH:61][CH:60]=1.[F-].[NH4+]>CN(C)C(=O)C.CO.O>[F:58][C:59]1[CH:67]=[CH:66][C:62]([CH2:63][CH2:64][NH:65][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=3)([CH3:23])[CH3:24])[CH:15]=2)=[CH:61][CH:60]=1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: NCCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [F-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CO
Product: CC(C)(Cc1cccc(C(=O)NCCc2ccc(F)cc2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methylphenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90 mg, 0.19 mmol) in N,N-dimethylacetamide (1 mL) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) in N,N-dimethylacetamide (0.5 mL) were added to a solution of 4-fluorophenethylamine (33 mg, 0.19 mmol) in N,N-dimethylacetamide (0.5 mL). The resulting mixture was stirred for 72 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. Ammonium fluoride (70 mg, 1.9 mmol) was added to a suspension of the residue in methanol (2 mL) and water (1 mL) and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 91:9:1, followed by trituration with diethyl ether, to afford the title compound in 50% yield, 45 mg. 1H NMR (400 MHz, CD3OD) δ: 7.63 (2H, m), 7.40-7.30 (3H, m), 7.23 (2H, m), 7.14 (1H, m), 7.00 (2H, m), 6.75 (1H, d), 4.65 (3H, m), 3.58 (2H, m), 2.98-2.64 (6H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 481 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Cl[CH2:23][C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)C.CN(C)C(=O)C>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:21][CH:23]=[C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:20]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), ethyl 4-chloro-3-oxobutyrate (0.22 g), ethanol (6 mL) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.25 g, yield 63%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 161-162° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:16][CH2:15][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: NCCO
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CCO
Product: OCCNCc1ccc(C(F)(F)F)cc1
Yield: 96 %

Procedure:
Following the method of Preparation 8, step a, 4-trifluoromethylbenzyl bromide (664 mg, 2.78 mmol) was heated with ethanolamine (1.02 g, 16.7 mmol) in ethanol (3 mL) at 75° C. overnight. The product was isolated to give the title intermediate as a yellowish oil (585 mg). (m/z): [M+H]+ calcd for C10H12F3NO, 220.10. found 220.3. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.59 (d, J=7.8 Hz, 2H), 7.45 (d, J=7.8 Hz, 2H), 3.88 (s, 2H), 3.66-3.70 (m, 2H), 2.80-2.83 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cncc(NC2CCNCC2)c1

Procedure:
A solution of 4-(pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.37 g, 5.00 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 178.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1([S:14](Cl)(=[O:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][S:14]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: NCc1ccco1
Solvent: c1ccncc1
Product: O=S(=O)(NCc1ccco1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a stirred solution of furfurylamine (0.319 g, 3.3 mmol) in pyridine (5 mL) at 0° C. was slowly added cyclohexanesulfonyl chloride (0.500 g, 2.7 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (0.325 g, 49%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, 1H, J=1.8, 0.9 Hz), 6.35 (dd, 1H, J=3.3, 2.1 Hz), 6.30 (d, 1H, J=3.0 Hz), 4.43 (m, 1H), 4.32 (d, 2H, J=5.7 Hz), 2.75 (tt, 1H, J=12.0, 3.3 Hz), 2.15-2.05 (m, 2H), 1.95-1.80 (m, 2H), 1.70 (m, 1H), 1.60-1.40 (m, 2H), 1.30-1.10 (m, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[Cl-].[C:32]1([N:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]([N+]2C=CC=CC=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:39](=[O:40])[N:38]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(=O)N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 110.2 %

Procedure:
A solution of 3.99 g of 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-hydroxymethylimidazole (Example 94) and 10 mL of 1.00N aqueous sodium hydroxide in 60 mL of methanol was added dropwise over 0.25 hour to a solution of 3.73 g of N-(N,N-diphenylcarbamoyl)pyridinium chloride in 30 mL of methanol at 25° C. The resulting mixture was stirred at 25° C. for 0.75 hour and then was diluted with ethyl acetate. This organic solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 6.55 g of crude 2-butyl-4-chloro-1-[(2'-(N,N-diphenylcarbamoyloxycarbonyl)biphenyl-4-yl)methyl]-5-hydroxymethylimidazole which was used in the following step without further purification.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([O:36][CH3:37])[CH:27]=4)[CH:23]=[C:22]([CH3:38])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:37][O:36][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([CH3:38])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[CH:25]=2)[CH:31]=[CH:30][C:29]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COc1cc(-c2cc(C)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)c2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc(C)nc(-c3ccnc(-c4ccc(S(N)(=O)=O)s4)c3)c2)ccc1C(F)(F)F
Temperature: 23 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To 5-[4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-[2,4′]bipyridinyl-2′-yl]-thiophene-2-sulfonic acid tert-butylamide (example 339) (0.100 g, 0.178 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.090 g, 100%). MS (ISP) 506.2 [(M+H)+]; mp 261° C. (dec.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[O:26][CH2:27][CH3:28].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl.O.CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:17])=[C:12]([C:13]([C:23]2[CH:24]=[C:19]([F:18])[C:20]([O:26][CH2:27][CH3:28])=[CH:21][C:22]=2[F:25])=[O:15])[CH:16]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOc1cc(F)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOc1cc(F)c(C(=O)c2cc(Br)ccc2Cl)cc1F
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Oxalyl chloride (1.89 mL, 0.0220 mol) and N,N-dimethylformamide (0.03 mL) were added to 5-bromo-2-chlorobenzoic acid (5.0 g, 0.0212 mol) in chloroform (10 mL) and stirred for three hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (10 mL). To this solution, 2,5-difluorophenetole (3.4 g, 0.0214 mol) was added and then aluminum chloride (2.9 g, 0.0214 mol) was added portion wise at −10° C. over five minutes. After the reaction mixture was stirred at 5° C. for two hours, an iced water was added. This was extracted with chloroform three times. After the combined organic layer was washed with 1M hydrochloric acid, water, brine, it was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain (5-bromo-2-chlorophenyl)(4-ethoxy-2,5-difluorophenyl)methanone (5.59 g, 70%) as a colorless crystal.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[CH2:12][N:13]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][O:31][CH2:32][CH2:33]Br.C(OCC)(=O)C.CCCCCC>COCCOC>[CH2:3]([O:10][C:11]([C:12]1([N:13]=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCOCCBr
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0° C. is added a solution of the N-(diphenylmethylene)glycine benzyl ester (0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) is then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath is removed and the reaction is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether and washed with water. The aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane provides 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester as a clear yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 400 ml of toluene are added 30 g of 1-(4-aminophenyl)propan-1-one and 38 ml (402 mM) of acetic anhydride. The reaction medium is heated at 60° C. with stirring for 1 hour. A solid precipitates out. After filtration and washing with toluene, 37.9 g of N-(4-propanoylphenyl)acetamide are obtained in the form of a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12]>>[OH:21][CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)N1CCCCC1CCO
Product: O=C(CCCN1CCCCC1)N1CCCCC1CCO
Reaction time: 3.5 h

Procedure:
Piperidine (0.83 ml) was added to the crude (0.975 g) of 4-chloro-1-[2-(2-hydroxyethyl)piperidino]-1-butanone. After being stirred for 3.5 hours at 70~80° C., the reaction mixture was concentrated, thereby yielding a crude (1.097 g) of the entitled compound as light yellow syrup.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C)=[O:12].C1(C)C=CC=CC=1.O>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCOC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (II) (16 g, 0.181 mol) dissolved in dry pyridine (100 ml) was added nonyl chloroformate (24.7 g, 0.119 mol) to react these together, followed by sufficiently agitating the reaction mixture, allowing it to stand overnight, adding toluene (100 ml) and water (100 ml), washing the mixture with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, distilling off toluene to obtain 4-nonyloxycarbonyloxyaldehyde (IV) (33.2 g), dissolving this product (20.5 g, 0.07 mol) in acetic acid (60 ml), dropwise adding to the resulting solution being agitated, a solution of anhydrous chromic acid (14 g, 0.140 mol) dissolved in water (11 ml) and acetic acid (17 ml), while keeping the temperature of the system at 30° C. or lower, keeping the inner temperature at 40° C. on a water bath for 4 hours after completion of the reaction, cooling the resulting material, adding water (300 ml), filtering deposited crystals, washing the crystals with water and recrystallizing from ethanol to obtain 4-nonyloxycarbonyloxybenzoic acid (V) (7 g) having a melting point of 118.8°~120.4° C., adding to this product (7 g, 0.028 mol), thionyl chloride (6 g, 0.050 mol), heating the mixture under reflux for one hour, and distilling off excess thionyl chloride to obtain 4-nonyloxycarbonyloxybenzoic acid chloride (VI) (7.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][N:6]([C@H:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:36])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:16])C(OC(C)(C)C)=O)[CH3:2].[ClH:47]>O1CCOCC1>[ClH:47].[CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C@H:14]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:36])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:16])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.150 g of {[2-{2-(S)-[(1-Amino-isoquinolin-6-ylmethyl)-carbamoyl]-pyrrolidine-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester were treated with 5 mL of HCl in dioxane (5M solution) and the mixture was stirred for 3 h at ambient temperature. The solvent was distilled off and the remaining white solid was washed with diethyl ether and dried. Yield 0.100 g (80%); (+)-APCI-MS: 534 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13](=[S:15])[NH2:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O>CC(C)=O>[CH3:12][C:11]1[C:10]([C:13]2[S:15][CH:31]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:14]=2)=[CH:9][N:6]2[C:5]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)=[C:3]([C:1]#[N:2])[CH:8]=[N:7]2
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(C(N)=S)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: CC(C)=O
Product: Cc1c(-c2nc(-c3ccccc3)cs2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 70 °C
Yield: 80.6 %

Procedure:
A mixture of 423A (15 mg, 0.037 mmol) and 2-bromoacetophenone (7.3 mg, 0.037 mmol) in acetone (3 ml) was heated at 70° C. for 1 h. Cooled to rt, hexanes (1 ml) was added, then the resulting mixture was cooled to −50° C., filtered, the solid was washed with hexanes to give the hydrobromide salt of 423 (14.9 mg, 69%) as a yellow powder. It has a retention time of 8.16 min (standard LC1 method, 8 min run). LCMS Found: (M+H)+=500.3
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.CCCCCC.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[CH:29]=[O:30]>C1COCC1.O.C(O)(C)C>[O:6]1[CH2:7][CH2:8][CH2:9][O:10][C:4]2[CH:3]=[C:2]([CH:29]([C:28]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:26]([O:25][CH3:24])[CH:27]=3)[OH:30])[CH:12]=[CH:11][C:5]1=2
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Brc1ccc2c(c1)OCCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCCO3)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepine (1.7 g, 7.4 mmol) in THF (10 mL) was added a solution of n-butyllitium in hexane (2.6 mL, 2.5 N, 6.5 mmol) at −78° C. and kept for 20 min. To the mixture was added a solution of 3,5-dimethoxy-benzaldehyde (1.0 g, 6.0 mmol) in THF (10 mL) at −78° C. After 2 h, isopropanol (2 mL) and water (10 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with HCl (1N, 50 mL), water (50 mL), brine (50 mL) and dried over MgSO4. Removal of solvent and chromatography (Silica Gel) gave (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-(3,5-dimethoxy-phenyl) -methanol as an oil (1.8 g, 95% yield): 1H NMR (CDCl3) δ 2.16-2.22 (m, 2H, CH2), 3.77 (s, 6H, 2CH3), 4.16-4.21 (m, 4H, 2CH2), 5.67 (d, J=3 Hz, 1H, CH), 6.35 (t, J=2 Hz, 1H, Ar), 6.54 (d, J=2 Hz, 1H, Ar), 6.92 (d, J=1 Hz, 2H, Ar), 6.98 (s, 1H, Ar).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:19][O:18][C:13]1[C:12]([CH2:11][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ncccc1CCl
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.2 g of 4-piperidineethanol, 10.0 g of 3-(chloromethyl)-2-methoxypyridine and 17.5 g of potassium carbonate were suspended in 65 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).