Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: OCC(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCC(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 2,2,2-trifluoroethanol. Yellow solid. MS (m/e): 262.0 ([M+H-Me2C═CH2]+, 100%)
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[C:7]([Cl:15])=[CH:6][N:5]=1.[CH3:18][O:19][CH2:20]Cl>C(#N)C>[Cl:15][C:7]1[C:8]([OH:10])=[CH:9][C:4](=[O:3])[N:5]([CH2:18][O:19][CH3:20])[CH:6]=1
Reactant: COCCl
Reactant: C[Si](C)(C)Oc1cc(O[Si](C)(C)C)c(Cl)cn1
Solvent: CC#N
Product: COCn1cc(Cl)c(O)cc1=O
Yield: 55 %

Procedure:
The general procedure of Example 61 was followed using 1.75 g of 2,4-bis(trimethylsilyloxy)-5-chloropyridine, 0.66 g of chloromethyl methyl ether and 20 ml of acetonitrile, thereby producing 0.63 g of the title compound in a yield of 49%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccsc3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc(-c2ccsc2)nc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-(4-thiophen-3-yl-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.17 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) dropwise. The resulting solution was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated, then re-dissolved in CH2Cl2 and concentrated. The residue was dissolved in a mixture of CH2Cl2/MeOH (4:1, 5 mL), neutralized with Na2CO3, and stirred at room temperature for 30 min. The resulting solid was filtered, washed with CH2Cl2, and the filtrate was concentrated to yield a yellow gummy solid, which was used without purification.
Reaction SMILES: COC[O:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[CH:25]=3)[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])[CH:25]=3)[C:10]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1cccc(OCCCCSCCCC(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[3-(4-(4,4,5,5,5-pentafluoropentylthio)butyloxy)phenyl]-2,3-dihydro-4H-benzopyran (274 mg, 0.4 mmol) and pyridinium p-toluenesulfonate (508 mg, 2.02 mmol) were dissolved in methanol (10 ml) and then refluxed for 14 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 167 mg (yield: 75%) of the title compound as a white foam.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]1[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11]1>CN(C=O)C>[CH2:10]1[O:19][C:13]2([CH2:18][CH2:17][N:16]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[CH2:15][CH2:14]2)[O:12][CH2:11]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: N#Cc1ccccc1F
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A solution of 2-fluorobenzonitrile (2.75 g, 22.7 mmol) and 4-piperidone ethylene ketal (4.25 g, 29.7 mmol) in DMF (40 mL) was heated to 120° C. for 4 h. The resulting mixture was cooled to room temperature overnight. The solvent was removed in vacuo and the residue dissolved in ether and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (4). The crude product was used directly.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:15])[C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:16][CH2:17]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C1COCC1>[Cl:16][CH2:17][C:10](=[O:12])[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:15]
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])CCl
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of 5.00 g (21.52 mmol) of ethyl (S)-2-(tert-butyldimethylsilyloxy)propionate, 3.76 g (32.3 mmol) of sodium chloroacetate, 2.18 g (21.5 mmol) of triethylamine, and 50 mL of THF was cooled in ice, and 37 mL (64.6 mmol) of a 1.75 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 1 hour. After the completion of the dropwise addition, reaction was performed at 0° C. for another 3 hours, and 6 M hydrochloric acid (about 20 mL) was added to the reaction solution to adjust the pH to 6.0. Subsequently, stirring was performed at 25° C. for 2 hours. A product was extracted with ethyl acetate (100 mL×2). The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.01 g of the title compound as a colorless oil (yield: 98%). 1H-NMR (400 MHz, CDCl3) δ: 0.10 (s, 6H), 0.92 (s, 9H), 1.24 (d, 3H, J=6.8 Hz), 4.35 (q, 1H, J=6.8 Hz), 5.50 (q, 2H, J=17.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])[CH:9]=1)=[O:4].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[NH2:34][C:35]1[C:36]([O:50][CH3:51])=[C:37]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[NH:34][C:35]3[CH:40]=[C:39]([C:41]([F:43])([F:42])[F:44])[CH:38]=[C:37]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:36]=3[O:50][CH3:51])[CH:13]=[CH:12][C:11]=2[CH3:19])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(-c2cc(C(=O)O)ccc2C)nn1
Reactant: COc1c(N)cc(C(F)(F)F)cc1NS(C)(=O)=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(F)(F)F)cc(NS(C)(=O)=O)c3OC)ccc2C)nn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
1-(5-Carboxy-2-methyl-phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (26 mg, 0.101 mmol) was stirred with 21 mg (0.153 mmol) of 1-hydroxy-7-azabenzotriazole (HOAt) in 1 mL of DMF and 24 mg (0.126 mmol) of EDC was added. After 1 h of stirring at about 10° C., 30 mg (0.106 mmol) of N-(3-amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide was added. The mixture was stirred overnight then heated to 60° C. for 6 h. The reaction was then cooled and water was added. The precipitate was collected and chromatographed twice by preparative TLC (5% MeOH in CH2Cl2) and once by flash chromatography (0–4.5% MeOH in dichloromethane). The pure fractions yielded 3 mg (5.6%) of the title compound. ESI MS (m/z 526, 100, M−H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cu](C#N)[C:16]#[N:17]>CN(C)C=O>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[N:17])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Product: N#Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To 5.39 g (24.44 mmol) of 2-chloro-5-fluoro-1,3-dinitro-benzene dissolved in 20 mL dimethylformamide was added 2.63 g (1.2 eq., 29.27 mmol) copper cyanide. The mixture was stirred at 140° C. for 2 hours, cooled and partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography, eluting with ethyl acetate/hexanes, provided 1.44 g of 4-fluoro-2,6-dinitrobenzonitrile.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:32])[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[C:16]2[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:15]=2[O:14]1>ClCCl>[C:30]([C:27]1[CH:28]=[CH:29][C:15]2[O:14][C:13]([CH3:32])([CH3:12])[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:26]=1)#[N:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(C2=CC(C)(C)Oc3ccc(C#N)cc32)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c1
Reaction time: 1 h
Yield: 24 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 552 mg of 2,2-dimethyl-4-(4-methyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 20 ml of dichloromethane and the mixture was stirred for 1 hour. Subsequently, the mixture was washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:4) for the elution. After recrystallization from ethyl acetate there were obtained 140 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-4-methylpyridine N-oxide of melting point 199°-201° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:12]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]1)[CH2:7]2.[CH3:19][O:20][C:21]1[N:26]=[N:25][C:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=2[CH3:34])[NH2:30])=[CH:23][CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[O:17]=[S:14]1(=[O:18])[CH2:15][CH2:16][CH:12]([N:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([C:24]4[N:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH:28]=3)[CH2:7]2)[CH2:13]1
Reactant: COc1ccc(-c2cc(N)ccc2C)nn1
Reactant: O=S1(=O)CCC(N2CCc3c(Br)cccc3C2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(Nc3cccc4c3CCN(C3CCS(=O)(=O)C3)C4)ccc2C)nn1
Temperature: 100 °C

Procedure:
To the reaction vessel containing 5-Bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinoline (460 mg, 1.4 mmol), 3-(6-methoxypyridazin-3-yl)-4-methylaniline (300 mg, 1.4 mmol), Pd2(dba)3 (128 mg, 0.14 mmol), Xantphos (162 mg, 0.28 mmol) and K3PO4 (740 mg, 3.5 mmol) is added anhydrous dioxane. The vessel is flushed with nitrogen, sealed and heated to 100° C. for 15 hours. The reaction is then cooled to ambient temperature, filtered through a celite pad to remove any solids. The filtrate is concentrated and purified by silica gel flash chromatography to afford [2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-[3-(6-methoxy-pyridazin-3-yl)-4-methyl-phenyl]-amine as an off-white solid. MS m/z 465.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 7.73 (d, 1H, J=6.0 Hz), 7.32 (s, 1H), 7.27 (d, 1H, J=6.0 Hz), 7.16 (d, 1H, J=5.6 Hz), 7.04 (m, 2H), 6.95 (m, 2H), 6.69 (dd, 1H, J1=4.4 Hz, J2=2.8 Hz), 4.07 (s, 3H), 3.72 (d, 1H, J=15.0 Hz), 3.65 (d, 1H, J=15.0 Hz), 3.41 (m, 2H), 3.29 (m, 1H), 3.13 9m, 2H), 2.77 (m, 2H), 2.66 (t, 2H, J=6.0 Hz), 2.43 (m, 1H), 2.18 (s, 3H), 2.11 (m, 1H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[C:13]([O:12][C:10]([N:1]1[CH2:23][CH2:22][CH2:21][CH2:20][N:2]1[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A solution of di-tert-butyl hydrazine-1,2-dicarboxylate (10 g, 43.1 mmol) in dry N,N-dimethylformamide (25 ml) was added to a stirred suspension of sodium hydride (3.79 g of a 60% suspension in mineral oil, 95 mmol) in dry N,N-dimethylformamide (175 ml) at 0° C. under nitrogen. The reaction mixture was stirred for 30 minutes and then 1,4-dibromobutane (9.3 g, 43.1 mmol) was added within half a minute. The reaction was stirred at room temperature overnight. Then water (˜20 ml) was added carefully to the reaction mixture at room temperature, and stirring was continued for ca. 5 minutes. Thereafter the quenched reaction mixture was poured into 1 liter of water. The product was extracted twice with diethyl ether (200 ml), and the combined organic layers were washed with three times with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 14 g of crude tetrahydropyridazine-1,2-dicarboxylic acid di-tert-butyl ester. This was dissolved in diethyl ether (200 ml) and 4N hydrochloric acid in dioxane (108 ml, 431 mmol) was added. The resulting mixture was stirred overnight at room temperature. The thus formed white precipitate was isolated by filtration and dried under a flow of nitrogen to yield 4.6 g of crude product. Analysis by 1H NMR indicated that the reaction had not gone to completion. This crude product was combined with the crude product of a similar preparation, dissolved in dichloromethane (200 ml) and treated with 4N hydrochloric acid in dioxane (60 ml, 240 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and triturated with dry diethyl ether. The resulting precipitate was isolated by filtration and dried and a flow of nitrogen to yield 6.3 g of product, which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N+:3]=1[O-].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].C([O-])(O)=O.[Na+]>C(O)C>[C:13]([O:16][CH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(F)(F)F)cc[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCc1cc(C(F)(F)F)ccn1
Reaction time: 0.17 h

Procedure:
2-Methyl-4-(trifluoromethyl)pyridine 1-oxide (4.0 g, 22 mmol) was added to acetic anhydride (12 mL) at 120° C. The mixture was refluxed for 1 h. To it was carefully added 10 mL of ethanol. Reflux was continued for 10 min. The mixture was poured into ice, neutralized with NaHCO3, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. Chromatography on silica gel (5:2 hexanes/EtOAc) provided the product (3.4 g) as a brown oil. MS (M+H) 220.1.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([NH:25][O:26][CH3:27])[CH:22]([NH2:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([NH:25][O:26][CH3:27])[CH:22]([NH:24][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(c1ccc(Cl)cc1Cl)C(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (86 mg, 0.44 mmol) in dichloromethane (1 ml) was added dropwise to a stirred solution of (110 mg, 0.44 mmol) 2-(2,4-dichloro-phenyl)-2-methoxyamino-1-methyl-ethylamine, which was prepared as described in example P4, and triethylamine (50 mg, 0.50 mmol) in dichloromethane (3 ml) at 0° C. The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 1 h. After removal of the solvent the residue was purified by flash chromatography over silica gel (eluant:hexane/ethyl acetate 3:7). 115 mg (64.1% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-methoxyamino-1-methyl-ethyl]-amide was obtained in the form of a resin as a mixture of diastereomeres.
Reaction SMILES: COCCOC.Br[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.C([Li])CCC.[CH2:22]([N:25]1[C@H:29]([CH2:30][CH2:31][CH3:32])[CH2:28]OS1(=O)=O)[CH2:23][CH3:24]>O1CCCC1.O.CCCCCC>[CH2:15]1[O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:28][C@H:29]([NH:25][CH2:22][CH2:23][CH3:24])[CH2:30][CH2:31][CH3:32])=[CH:9][C:10]=2[O:16]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CCC[C@@H]1COS(=O)(=O)N1CCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCCN[C@H](CCC)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 47 %

Procedure:
Under an argon atmosphere, 1,2-dimethoxyethane (7.1 mL) was added to a solution of 4-bromo-1,2-methylenedioxybenzene (8.2 mL) in tetrahydrofuran (140 mL) under stirring at room temperature. Under stirring at −72° C., n-butyl lithium (a 1.57 mol/L hexane solution, 86.9 mL) was added dropwise to the resulting solution over 30 minutes. The resulting suspension was stirred at −50° C. or lower for 1 hour. Under stirring at −45° C., a solution of (R)-3,4-dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (14.14 g) in tetrahydrofuran (34 mL) was added dropwise to the suspension over 20 minutes. The solution was stirred at 10° C. or lower for 2 hours. Water (200 mL) was added to the solution under stirring at room temperature, and the mixture was separated. To the aqueous layer was added concentrated hydrochloric acid (22.8 mL) and then diethyl ether (70 mL) under stirring at room temperature. After vigorous stirring at room temperature for 2 hours, the resulting two-layer solution was separated, and the ether layer was extracted with an aqueous 1 mol/L hydrochloric acid solution (200 mL). The aqueous layer was made basic with an aqueous 1 mol/L sodium hydroxide solution, and the organic layer and diethyl ether (100 mL) were added thereto. The organic layer was separated, washed with a saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (NH-DM1020, AcOEt/Hexane=1/9) to give (R)-1-(3,4-methylenedioxyphenyl)-2-propylaminopentane (8.00 g, 47% yield) as a yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[CH:22][C:21]=1[O:30][CH3:31])=[CH:10][NH:11]2.O>ClCCl>[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[O:30][CH3:31])=[CH:10][NH:11]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC(C)C)cc3OC)c[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3OC)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Aluminum chloride (108 mg, 0.81 mmol) was added to a dichloromethane solution (5 ml) of 5-fluoro-3-(4-isopropoxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (120 mg, 0.31 mmol). The mixture was stirred at room temperature for 1 hour. Water and dichloromethane were added to the reaction mixture, and separated. The organic layer was then washed with water. The washed organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 100 mg of powdery white 5-fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (yield: 90%).
Reaction SMILES: BrC1C(OC)=C(Br)C=C(F)C=1N(C/C=C\C(OCC)=O)C(=O)C.[OH-].[Na+].[OH-].[K+].[CH2:28]([N:30]1[C:38]2[C:33](=[C:34]([OH:40])[CH:35]=[C:36]([F:39])[CH:37]=2)[C:32]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:31]1)[CH3:29]>>[CH2:28]([N:30]1[C:38]2[C:33](=[C:34]([OH:40])[CH:35]=[C:36]([F:39])[CH:37]=2)[C:32]([CH2:41][C:42]([OH:44])=[O:43])=[CH:31]1)[CH3:29]
Reactant: CCn1cc(CC(=O)OC)c2c(O)cc(F)cc21
Agent: CCOC(=O)/C=C\CN(C(C)=O)c1c(F)cc(Br)c(OC)c1Br
Agent: [K+]
Agent: [Na+]
Product: CCn1cc(CC(=O)O)c2c(O)cc(F)cc21

Procedure:
Following the procedure used to prepare compound 8-7 (step 8 scheme 8), NaOH was replaced by KOH, compound 11-2 gave compound 11-3.
Reaction SMILES: [CH2:1]([CH:3]([CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].C(=O)CCC>>[CH2:1]([CH:3]([CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCC(O)C(CC)CO
Solvent: CCCC=O
Product: CCCC(O)C(C=O)CC

Procedure:
The preparation of 2-ethyl-1,3-hexane diol thus takes place in two steps, as shown above in the reaction formulae. In the first reaction step, n-butyraldehyde reacts with itself, forming as the product of the aldol reaction an intermediate-product β-hydroxyaldehyde according to Formula II, i.e. 2-ethyl-3-hydroxy-hexanal. This intermediate-product β-hydroxy-aldehyde is hydrogenated (reduced) into the corresponding alcohol, i.e. into 2-ethyl-1,3-hexane diol according to Formula III. The efficiency, speed and controllability of the aldol step can thus be improved significantly by using an alkali metal hydroxide or alkali earth metal hydroxide catalyst together with a neutral phase-transfer catalyst. The use of this catalyst combination renders the control of the exothermal forming reaction of the intermediate-product β-aldehyde maximally efficient, and thus the amount of readily forming hazardous byproducts can be minimized. In step 2, the intermediate-product aldehyde is hydrogenated completely into the desired end-product alcohol either by using a reducing agent or by catalytic hydrogenation. By this procedure, the desired objective, i.e. the surprisingly high yield of 2-ethyl-1,3-hexane diol, is achieved.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([OH:44])(=[O:43])=[O:42])[CH:40]=1>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: Nc1ccc(O)c(S(=O)(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 mL) and THF (1 mL). CDI (65 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 5-amino-2-hydroxybenzene sulfonic acid salt (77 mg, 0.33 mmol) was added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of TFA and stirred at room temperature for 3 hours, and a solvent was removed therefrom. The obtained product was purified in accordance with the purification process A to obtain a title compound.