Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][C@H:11]([CH2:13][S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C:9]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:35].[Na+].Cl>CO.C1COCC1.O>[OH:35][C@@H:11]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]([OH:10])=[O:34]
Reactant: [OH-]
Reactant: CCCCCCC[C@@H]1C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.72 g (7.88mmol) of the product of Example 17 in 100 mL of methanol/THF (1:1) at room temperature was added 16.7mL of 1.0N NaOH solution. The reaction was stirred at room temperature for 1 h and then diluted with 100 mL of H2O and carefully acidified to pH 6 with 5% HCl solution. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue, 3.72 g (100%) of the crude hydroxy-acid was used in the next step (Example 25) without further purification. Electrospray Mass Spec: 489.4 (M-H)-.
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[N:20]=[CH:19][C:18]2=[CH:27][CH:28]=[CH:29][N:17]12.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:15][N:16]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[NH:20][CH:19]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:18]2=[CH:27][CH:28]=[CH:29][N:17]12
Reactant: BrCCc1ccccc1
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CN1c2ccncc2NC(CCc2ccccc2)c2cccn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.8 g of magnesium turnings in 20 ml of diethyl ether and 20 ml of tetrahydrofuran was added 1 ml of 1,2-dibromoethane followed by 13.94 ml of 2-bromoethylbenzene (dropwise). After initiating the reaction with external heat, the mixture was stirred at room temperature for one hour and then treated, dropwise, with a solution of 10.0 g of 5-methyl-5H-pyrido[3,4-f]-pyrrolo[1,2-b][1,2,5]triazepine in 100 ml of tetrahydrofuran. The reaction mixture was then stirred at room temperature for two hours, poured into an iced ammonium chloride solution, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate). Flash chromatography of the resultant oil (silica gel; elution with 10% methanol/dichloromethane) afforded a solid which was recrystallized from diethyl ether/ethyl acetate (10:1) to yield 1.25 g of 10,11-dihydro-5-methyl-10-(2-phenylethyl)-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 92°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[NH3:12]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: N
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15.70 g (91.0 mmol) 4-fluoro-3-methyl-benzoic acid chloride dissolved in 30 ml THF are added dropwise to 300 ml of conc. ammonia solution and then stirred for 2 hours at ambient temperature. The precipitate formed is filtered off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7](=[CH:22][N:23](C)C)[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:9])=[CH:4][CH:3]=1.Cl.NO>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[CH:22]=[N:23][O:9][C:8]=2[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CN(C)C=C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1oncc1Cc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 75.3 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-(4-chlorobenzyl)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate (580 mg, 1.5 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (210 mg, 3 mmol). The resulting solution was heated at 70° C. for 2 h and then concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-tert-butyl 2-(4-(4-chlorobenzyl)isoxazol-5-yl)pyrrolidine-1-carboxylate (410 mg, 75%). LCMS: calculated: 365, found (M-tBuH+): 307
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of 8.70 g (49.4 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step E) in 100 mL of methylene chloride was treated with 10.73 g (49.4 mmol) of 3-t-butoxycarbonylamino-3-methylbutanoic acid (Step H) and 13.8 mL of triethylamine (10.0 g, 99 mmol, 2 eq.). The reaction flask was immersed in an ambient temperature water bath then 26 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (59 mmol, 1.2 eq) was added all at once and the mixture stirred at room temperature for 2 hours. The reaction mixture was added to 300 mL of ethyl acetate and washed three times with 5% aqueous citric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (4:1), to afford 17.42 g (46.4 mmol, 94%) of the product as a white solid. 1H NMR (200 MHz,CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz,1H), 2.59 (d,15 Hz,1H), 2.60-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz,1H), 6.98 (d,8 Hz, 1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:20]=[N+:21]=[N-:22])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Temperature: 120 °C

Procedure:
To a solution of (1R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate (3.55 g, 10.2 mmol) in dimethylformamide (21.8 mL) and water (2.43 mL) was added sodium azide (95%, 2.09 mg, 30.5 mmol) and the reaction was heated at 120° C. for 23 hours. The reaction was cooled to room temperature, diluted with water (400 mL) and extracted with ethyl acetate (4×400 mL). The combined organic layers were washed with aqueous lithium chloride solution (1N, 400 mL), washed with water (400 mL), and dried over magnesium sulfate. Filtration and removal of solvents in vacuo afforded (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether as an orange oil, which was used in the next step without additional purification. Yield: 2.85 g, 9.62 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 1.36-1.48 (m, 2H), 1.62-1.76 (m, 4H), 1.96-2.07 (m, 2H), 3.63 (m, 1H), 4.43 (m, 1H), 6.85 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=O)=[CH:13][CH:12]=1)(=[O:9])=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:15][CH:16]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(C(=O)N3CCOCC3)cc2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(CN3CCOCC3)cc2)c(OC)c1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-C-[4-(morpholine-4-carbonyl)phenyl]methanesulfonamide (440 mg) in THF (5 ml) was added, at 0° C., LAH (96 mg), and the mixture was warmed up to room temperature and stirred for a further 60 minutes. After the addition of water (100 μl), sodium hydroxide solution (300 μl) and water again (300 μl), the mixture was filtered and the filtrate was concentrated. This gave the product (415 mg) with a molecular weight of 420.5 g/mol (C21H28N2O5S).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])=[N:11]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:28]([C:34]([F:35])([F:36])[F:37])([C:30]([F:31])([F:33])[F:32])[OH:29])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(homopiperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 409, triethylamine (22.0 uL, 0.16 mmol) and methanesulfonyl chloride (5.0 uL, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[I-].[Na+]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: C1=CCCC2OC2CCC=CCC1
Agent: [I-]
Agent: [Na+]
Product: O=C1CC=CCCC=CCCCC1
Yield: 98.7 %

Procedure:
Also, German Patent No. 3,601,380 discloses that, by isomerization of 1,2-epoxy-5,9-cyclododecadiene in the presence of a catalyst consisting of sodium iodide in a reaction medium consisting of a polyethylene glycol (NaI: 3 wt %, 195° C., 9 hours), cyclododeca-3,7-diene-1-one is produced with a yield of 98.7%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH2:15][CH2:14]1.O>CN(C=O)C>[O:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([NH:23][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:18]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Nc1cccc(CN2CCOCC2)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2ccc(Nc3cccc(CN4CCOCC4)c3)nc12
Temperature: 140 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (30 mg, 0.166 mmol) in DMF was added 3-(morpholinomethyl)aniline (233 mg, 1.213 mmol). The mixture was heated in microwave for 40 minutes at 140° C. Water was added and the solid formed was isolated by filtration to yield 5-(3-(morpholinomethyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=338)
Reaction SMILES: [OH-].[NH4+].C([S:6][CH2:7][CH:8]([C:20]([F:23])([F:22])[F:21])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])(=O)C.S(=O)(=O)(O)[O-].[K+].C(OCC)(=O)C>O.CO.C(O)(=O)C.CCCCCC>[F:21][C:20]([F:22])([F:23])[CH:8]([CH2:7][SH:6])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:10]
Reactant: CCCC[C@H](NC(=O)C(CSC(C)=O)C(F)(F)F)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)C(CS)C(F)(F)F)C(=O)O
Reaction time: 0.25 h

Procedure:
Concentrated ammonium hydroxide (3 mL) was added to a suspension of the product of Example 29 (1.95 g.) in 12 mL of deoxygenated water. The reaction mixture, which became homogeneous in less than one minute, was stirred for 15 minutes. At this time, the pH was adjusted to about 1.5 with potassium bisulfate and the resulting aqueous mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to afford an oily residue. This residue was flash chromatographed on a 5×12 cm silica gel column using hexane:ethyl acetate:acetic acid, 65:35:1. The pure fractions were concentrated and the residue was coevaporated from heptane several times to afford a white solid. Trituration with hexane and drying 18 hours under high vacuum afforded 1.175 g. of the title isomer A compound as a white solid, m.p. 96°-98° C., TLC Rf =0.38 (ethyl acetate:hexane:acetic acid, 40:60:2). [α]D =-43.2 (c=0.60, methanol).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)=[CH:10][C:11]2[C:12]([CH3:20])=[CH:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:33](=O)[CH3:34]>>[CH2:33]([N:21]([C:9]1[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:17][C:16]2[C:15]([CH3:19])([CH3:18])[CH2:14][CH:13]=[C:12]([CH3:20])[C:11]=2[CH:10]=1)[C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)[CH3:34]
Reactant: CC=O
Reactant: CCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Product: CCCCCCOc1cc2c(cc1N(CC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure D ethyl 4-(3-n-hexyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 112, 0.03 g, 0.07 mmol) was reacted with acetaldehyde and the resulting crude product, residue was purified by flash column chromatography (hexane:ethyl acetate=4:1) to afford 0.030 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1I)=[C:8]([OH:14])[CH:7]=[CH:6][CH:5]=2.[CH3:16][CH:17]([OH:20])[C:18]#[CH:19]>N1C=CC=CC=1.[Cu]=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:20][CH:17]([C:18]1[O:1][C:2]2[C:3](=[O:15])[C:4]3[C:9]([C:10](=[O:13])[C:11]=2[CH:19]=1)=[C:8]([OH:14])[CH:7]=[CH:6][CH:5]=3)[CH3:16]
Reactant: O=C1C(O)=C(I)C(=O)c2c(O)cccc21
Reactant: C#CC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cu]
Solvent: c1ccncc1
Product: CC(O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of 2,5-dihydroxy-3-iodonaphthalene-1,4-dione (30 mg, 0.095 mmol) in pyridine (3.5 ml) were added copper oxide (1) (13.5 mg, 0.095 mmol), 3-butyn-2-ol (75 μl, 0.949 mmol) and dichlorobis(triphenylphosphine)palladium (2 mg, 3 mol %), and the mixture was stirred at 80° C. of the reaction temperature for 30 minutes. The reaction solution was cooled to room temperature, and then the reaction was quenched by the addition of 2M hydrochloric acid. The reaction solution was extracted with chloroform. The organic layer was washed with ice water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (17.2 mg, 70%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16]/[C:17](/[C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:34]\[OH:35])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(CO)CC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(CO)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-[4-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=444.4 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])(=[O:3])[CH3:2].[Se](=O)=[O:15]>O1CCOCC1.O>[CH3:9][C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][C:4]=1[C:1](=[O:3])[CH:2]=[O:15]
Reactant: CC(=O)c1sc2ccccc2c1C
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)C=O)sc2ccccc12

Procedure:
A 52.9 g portion of 2-acetyl-3-methylbenzothiophene was added to a solution of 36.9 g of selenium dioxide in 95 ml of dioxane and 13 ml of water at 55°-60° C. The mixture was refluxed overnight, filtered, washed with dioxane and evaporated. The residue was purified by flash column chromatography, eluting with hexane:ethyl acetate (8:2), giving 5.1 g of 3-methyl-a-oxobenzo[b]thiophene-2-acetaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:24]1([NH:28][C:29](=[O:40])[NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:24]1([NH:28][C:29](=[O:40])[NH:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([N:11]3[CH2:12][CH2:13][N:8]([CH2:14][C:15]4[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=4)[CH2:9][CH2:10]3)=[O:36])=[CH:38][CH:39]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1coc(CN2CCNCC2)n1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NC1CCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1coc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 15 %

Procedure:
To a N,N-dimethylformamide (3 mL) solution of methyl 2-(piperazin-1-yl-methyl)oxazole-4-carboxylate 2,2,2-trifluoroacetate (174 mg, 513 μmol) and 4-(3-cyclobutylureido)benzoic acid (120 mg, 513 μmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (357 μL, 2.05 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (293 mg, 770 μmol; HATU). The mixture was stirred at room temperature for 22 hours and was then concentrated under vacuum. The residue was taken up in ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum. The crude residue was applied to a silica gel column and eluted with 25% ethyl acetate in n-hexanes to give the title compound (34 mg). MS (ESI) m/z 442.1 [M+H]+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([NH:20][S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:15])=[O:14])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)CCCCCCCCCCCBr
Product: O=S(=O)(CCCCCCCCCCCBr)NC1CC1
Yield: 96 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 3 except for using 11-bromoundecanesulfonyl chloride (2.29g, 6.85 mmol) in place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (860 mg, 15.1 mmol), to give N-cyclopropyl-11-bromoundecanesulfonamide (2.33 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[ClH:11]>CO.[Pt]=O>[ClH:11].[F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: FC(F)(F)c1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: FC(F)(F)C1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under atmosphere of argon, a solution of 4-(trifluoromethyl)pyridine (9.33 g) in methanol (80 mL) was added by concentrated hydrochloric acid (16 mL) and platinum oxide (510 mg) and stirred for three days at room temperature under hydrogen pressure. The reaction mixture was filtrated by celite (trade name) and the filtrate was concentrated. The residue was added by saturated sodium dicarbonate aqueous solution and extracted by ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtrated. The filtrate was added by 4N hydrogen chloride/ethyl acetate solution (50 mL) and then concentrated to give the title compound (13.0 g) having the following physical data.
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][NH:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(O)(=O)C.[Zn]>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([CH2:10][CH2:11][NH2:12])=[CH:2]1
Reactant: ONCCC1C=Cc2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: NCCC1=CCc2ccccc21

Procedure:
N-(2-(1H-Indene-1-yl)ethyl)hydroxylamine (85 mg, 0.486 mmol) was added to a slurry of zinc dust (104 mg, 1.59 mmol) in glacial acetic acid (3 ml), and the mixture was heated at 65° for 2 hours. The mixture was cooled and filtered, then made basic with conc. ammonium hydroxide and extracted with ether. The ether layer was washed with water, then with brine, dried ober sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 90:10:1 of CH2Cl2 :MeOH:NH4OH. The product fractions were evaporated to dryness in vacuo to give (2-(1H-indene-3-yl)ethyl)amine.