Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:9][O:10][CH3:11])([CH3:8])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:42]([O:44][CH:45]([O:49][CH2:50][CH3:51])[CH2:46][CH2:47][NH2:48])[CH3:43]>C(Cl)Cl.C1COCC1>[CH2:42]([O:44][CH:45]([O:49][CH2:50][CH3:51])[CH2:46][CH2:47][NH:48][C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:8])[CH2:9][O:10][CH3:11])[CH3:43]
Reactant: COCC(C)(COC)C(=O)O
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)C(C)(COC)COC)OCC
Temperature: 25 °C
Reaction time: 23 h
Yield: 80.7 %

Procedure:
5 g of 3-methoxy-2-methoxymethyl-2-methyl-propionic acid (prepared as in EP609058) were dissolved in 49 mL of DCM and 12 mL of THF. 11.4 mL of DIPEA, 5.84 g of HOBt, 7.07 g of EDCI and 5.45 g of 3,3-diethoxy-propylamine were added sequentially. The mixture was stirred for 23 h at rt, diluted with DCM and washed with sat. NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 3/1 to 0/1 as eluant to yield 7.25 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellowish oil.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1>C1COCC1>[Cl:14][C:13]1[C:8]([S:4][CH2:1][CH2:2][CH3:3])=[N:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=1
Reactant: CCCS
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1ncc(C(F)(F)F)cc1Cl
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 99.3 %

Procedure:
23.8 g (0.313 mol) of 1-propanethiol were added in the course of 30 minutes to a mixture of 7.9 g (0.313 mol) of 95% pure sodium hydride in 200 ml of THF while flushing with nitrogen and stirring, a temperature of 25-30° C. being maintained by means of cooling. After the mixture had been stirred for 1 hour, 54 g (0.25 mol) of 2,3-dichloro-5-trifluoromethylpyridine in 50 ml THF were added at 25-30° C. in the course of 20 minutes with stirring, and stirring was continued for 10 hours at 23° C. The reaction mixture was concentrated in vacuo, taken up in methylene chloride, extracted with 0.5 N sodium hydroxide solution, dried over magnesium sulfate and concentrated, yielding 63.5 g (99.4%) of the title compound of nD23=1.5120.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([O:19]C)[CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:19])[CH:5]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: COc1cc(Br)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Oc2cc(O)cc(Br)c2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
1-Bromo-3-methoxy-5-[4-(methylsulfonyl)phenoxy]benzene (18.29 g, 51.2 mmol) synthesized in Example (1b) was dissolved in dichloromethane (400 mL) and cooled to −78° C., and boron tribromide (1.0M dichloromethane solution, 100 mL, 100 mmol) was added using a dropping funnel over 30 minutes under nitrogen atmosphere. The mixture was stirred at −78° C. for 2 hours, followed by raising the temperature naturally, and stirring at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added under cooling with an ice bath to neutralize the reaction solution, and extraction was carried out twice with dichloromethane (500 mL) and methanol (50 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (16.89 g, yield 96%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>CO>[OH:1][C:2]([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:20])=[O:21])([CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)(CNC(=O)c1ccccc1)CS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)CC(O)(CNC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
A solution of 2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-benzenecarbonylamino)-propionic acid, ethyl ester (0.27 g) in 4 mL of methanol is stirred with 1 mL of 1N sodium hydroxide for 3 hours. The reaction mixture is acidified with 1N HCl and the solvent is removed under reduced pressure. The residue is triturated twice with warm ethyl acetate. The ethyl acetate is removed, affording the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15](N2CCCCC2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:6]=1[OH:32])([CH3:4])([CH3:3])[CH3:2].[CH:33](O)=[O:34]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:32][C:33](=[O:34])[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=3)[C:7]=2[CH:8]=1)([CH3:13])([CH3:12])[CH3:14]
Reactant: O=CO
Reactant: CC(C)(C)c1cc(C(c2ccc(C(F)(F)F)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(C(F)(F)F)cc1
Temperature: 140 °C
Yield: 86.5 %

Procedure:
A solution of 12.53 g (28.0 mmol) of compound (201), prepared according to Example 1a, in 150 ml of dry toluene is degassed using argon and then 33.6 mg (0.057 mmol) of dichloro-[1,3bis(diphenylphosphino)propane]palladium(II) and 4.22 ml (112 mmol) of formic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 6 bar is then applied. The reaction mixture is maintained at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Filtration of the residue on silica gel using ethyl acetate and crystallisation of the pure fractions from methanol yields 9.46 g (87%) of compound (101) (Table 1), m.p. 127-128° C. Molecular weight C23H25F3O2 (390.45). Analysis, calculated: C 70.75; H 6.45%. Analysis, found: C 70.96; H 6.53%. 1HNMR (300 MHz, CDCl3, ppm): 1.23 (s, 9H); 1.37 (s, 9H); 4.83 (s, 1H); 6.97 (m, 1H); 7.31 (m, 3H); 7.57 (d, 2H).
Reaction SMILES: [CH2:1]([O:7][CH2:8][C:9]1[O:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]C1OC(CBr)=CC=1>CCOCC>[CH2:8]([O:7][CH2:1][C:2]1[O:6][C:5]([CH3:14])=[CH:4][CH:3]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(CBr)o1
Reactant: c1coc(COCc2ccco2)c1
Solvent: CCOCC
Product: Cc1ccc(COCc2ccco2)o1

Procedure:
d. 5-Methyl-furfuryl furfuryl ether was prepared by the procedure described by J. E. Zanetti in J.Am.Chem.Soc. 49, 1066 (1927) for the difurfuryl ether, starting with 5-methyl-furfuryl bromide (Compt.Rend. 222, 1441 (1946)) instead of furfuryl bromide of Zanetti. The product was isolated by ether extraction of the crude mixture after having diluted with water. For purification the ether extract was distilled twice -- b.p. 68°-70° C. at 0.01 mm./Hg vacuum. The product was a viscous colourless liquid, darkening rapidly on contact with air.
Reaction SMILES: Cl.Cl.Cl.Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H-].[Na+].Br[CH:43]([CH3:45])[CH3:44].O>CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:34]2[CH2:39][CH2:38][N:37]([CH:43]([CH3:45])[CH3:44])[CH2:36][CH2:35]2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)N2CCNCC2)cc1
Reactant: CC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
0.2 g of 1-[2-(4-Fluorophenyl)-2-piperazinoethyl]-4-(4-naphthalen-1-yl-butyl)piperazine tetrahydrochloride was dissolved in 0.7 ml of dimethylformamide, and 74 mg of 60% sodium hydride in oil was added with ice-cooling. The temperature was elevated to room temperature, followed by stirring for 10 minutes. To the reaction solution was added a 0.3 ml of dimethylformamide solution of 0.2 g of 2-bromopropane, followed by stirring overnight. The reaction solution was poured to water and, after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.13 g of 1-[2-(4-fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyl)piperazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:4]([C:5](OC)=[O:6])[C:3]=1[OH:13].[NH3:14]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:4]([C:5]([NH2:14])=[O:6])[C:3]=1[OH:13]
Reactant: N
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1O
Product: NC(=O)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 liter Parr autoclave was charged with 221 g. (1 mole) -dichlorophenyl)- of methyl 3,5-dichlorosalicylate and 140 g. (8 moles) of anhydrous ammonia. The mixture was stirred at 25° C for 24 hours. After venting excess ammonia, the product was ground to a fine powder and triturated with boiling chloroform. The mixture was filtered while hot and the residue weighed 153 g. Analysis by infrared, gas chromatography, and nuclear magnetic resonance confirmed that the product was 3,5-dichlorosalicylamide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([OH:15])[N:5]=1.Br[CH:17]([CH3:19])[CH3:18]>O>[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([O:15][CH:17]([CH3:19])[CH3:18])[N:5]=1
Reactant: Oc1cc2c(Cl)cccc2c(Cl)n1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Sodium hydride (103 mg, 2.57 mmol) was added to a solution of 1,5-dichloroisoquinolin-3-ol (500 mg, 2.336 mmol) and 2-bromopropane (575 mg, 4.67 mmol) and stirred at rt for 3 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1,5-dichloro-3-isopropoxyisoquinoline (598 mg, 100% yield) which was used as is in next step. MS: MS m/z 256.1(M++1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:34])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]([O:32][CH3:33])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]([O:32][CH3:33])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CCCCCN(CCCCC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCCCCN(CCCCC)CCOc1ccc(CCC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 0.2 g of N-(trans-4-methylcyclohexyl)-4-(2-dipentylaminoethoxy)-3-methoxycinnamamide (Example 159), 0.01 g of 10% palladium-carbon, and 35 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.12 g of N-(trans-4-methylcyclohexyl)-3-[4-(2-dipentylaminoethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) was obtained was white crystal, which had the following physiochemical properties:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][N:8]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:7][N:8]=2)=[O:33])=[CH:35][CH:36]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCc3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-benzylthio-1,3,4-thiadiazole (1.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.9 g) and carbonyldiimidazole (1.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 0.7 g of the aimed compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.N([O-])=O.[Na+].O(CC)C([S-])=[S:28].[K+]>O>[SH:28][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(S)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 17.3 g. of ethyl 3-amino-4-cyclohexylphenylglyoxylate in 11.1 ml. of concentrated hydrochloric acid and 20 g. of ice is added 4.1 g. of sodium nitrite in 2 ml. of water. This mixture is stirred for 10 min. and then added gradually to an ice cold solution of 10.3 g. of potassium ethyl xanthate in 14 ml. of water. The reaction is gradually heated over 45 minutes to 50° C. and stirred an additional 45 minutes. The mixture is then cooled, extracted with ether which is then washed with water, dilute sodium hydroxide and water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 35 ml. of boiling ethanol to which is added gradually 13 g. of potassium hydroxide. The reaction is refluxed an additional hour and then evaporated to dryness in vacuo. The residue is dissolved in water and extracted with ether. The alkaline phase is acidified with 6N sulfuric acid and extracted with ether. The ether is washed with water, dried over sodium sulfate and evaporated to dryness to obtain 3-mercapto-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(N3CCN(C)CC3)cc21
Yield: 73.7 %

Procedure:
A mixture of 1-ethyl-6-bromo-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.65 g, N-methylpiperazine 2.5 g and pyridine 2 ml was refluxed for 12 hours by heating. The reaction mixture was evaporated under vacuum. The residue was dissolved in an aqueous solution of acetic acid to separate insoluble matters by filtration and neutralized with an aqueous solution of NaOH. The precipitated crystals were collected by filtration and dried. Recrystallizing the precipitates from a mixed solvent of DMF and ethanol, 1.45 g (74%) of 1-ethyl-6-bromo-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid was obtained as colorless needle crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:18]=[CH:17][O:16][N:15]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1ccon1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)OC)c3ccon3)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged dry THF (5.0 mL) and methyl 3-(4-hydroxyphenyl)-3-(1,2-oxazol-3-yl)propanoate (0.18 g, 0.74 mmol). To the above mixture (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.2 g, 0.74 mmol) was added and the resulting mixture stirred at 0° C. for 5 min. Triphenyl phosphine (0.25 g, 0.96 mmol) was added to the mixture and stirred at 0° C. for 15 min followed by the addition of diisopropylazadicarboxylate (0.19 g, 0.96 mmol). After stirring the resulting mixture at RT for 10 h, the RM was evaporated to remove the THF. The residue was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL) and dried over anhydrous Na2SO4. Concentration of the solvent and purification of the resulting residue by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate (ratio) as eluant, gave the product (0.1 g, yield: 27.47%): MS (ESI, 120 eV): m/z=501.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 8.20 (d, 1H), 7.57-7.60 (t, 2H), 7.22-7.28 (m, 5H), 7.07-7.10 (d, 2H), 6.81-6.85 (m, 4H), 5.99-6.00 (d, 1H), 5.12 (s, 2H), 4.85 (s, 2H), 4.47-4.52 (t, 1H), 3.98 (s, 3H), 3.56 (s, 3H), 3.18-3.26 (q, 1H), 2.82-2.90 (q, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:36])[CH2:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]C1CCCCO1)[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[CH3:12][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[NH:13][C:14](=[O:36])[CH2:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)CCCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)CCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of N-[2,6-bis(1-methylethyl)phenyl)-3-oxo-14-[(tetrahydro-2H-pyran-2-yl)oxyltetradecanamide (0.97 g, 0.001 mol; see Example 6 for preparation) in 190 mL 95% MEOH, p-toluenesulfonic acid (0.055 g, 0.15 eq) was added and the reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then concentrated in vacuo (30° C.) to give a tacky residue. This residue was diluted with water and chloroform, the layers were separated and the aqueous layer was then extracted three times with chloroform. The combined organic layers were then washed two times with saturated NaCl solution, dried (MgSO4), and concentrated in vacuo to yield 0.63 g (0.001 mol, 79.4%) of the desired product.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OCC)(=[O:14])[CH:11]([CH3:13])[OH:12]>>[CH2:1]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)C(C)O
Temperature: 90 °C

Procedure:
388 g (3 mol) of n-octylamine were added to 473 g (4 mol) of ethyl lactate in a round-bottomed flask with a distillation apparatus over the course of two hours with stirring and a nitrogen purge. When the addition was complete, the temperature was increased to 90° C. and the ethanol which formed was distilled. The temperature was then increased to 140° C. and maintained for one hour. The pressure was then reduced to 50 mbar and unreacted ethyl lactate was distilled. 585 g of octllactamide were obtained as a clear, pale pink-colored liquid. 1H-NMR (400 MHz, CDCl3): 0.8 ppm (3H), 1.2 ppm (10H), 1.4 ppm (3H), 1.5 ppm (2H), 3.2 ppm (2H), 4.0 ppm (0.8H, br), 4.2 ppm (1H), 6.8 ppm (1H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])=[CH:19][CH:18]=1>>[C:24]([C@@H:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][C:17]([Cl:16])=[CH:18][CH:19]=1)([OH:26])=[O:25]
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Yield: 63 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-chloro-L-phenylalanine to provide the title compound in 63% yield as yellow needles (recrystallization from EtOH/water).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[S:26][C:25]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)=[CH:24][CH:23]=1
Reactant: OCc1ccc(Cl)s1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (5-chloro-2-thienyl)methanol (552 mg) and tributylphosphine (1.38 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.41 g), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (143 mg) as a white solid.