Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=NC(C)C)=[C:4]([CH3:19])[CH:3]=1.[OH:20]S(O)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=[O:20])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1ccccc1C=NC(C)C
Reactant: O=S(=O)(O)O
Product: Cc1cc(F)ccc1-c1ccccc1C=O
Temperature: 25 °C

Procedure:
A solution of 20.36 g (79.8 mmol) (4′-fluro-2′-methyl-biphenyl-2-ylmethylene)-isopropyl-amine in 110 ml 4N H2SO4 was heated at reflux for 6 h. After cooling to RT, the solution was extracted twice with 150 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/hexane 1:1) to give 4′-fluoro-2′-methyl-biphenyl-2-carbaldehyde as a pale yellow oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>[OH-].[Na+]>[Br:2][C:3]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: COc1ccc(Br)c(CC2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(Br)c(CC2CCNCC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
After 4-(2-bromo-5-methoxybenzyl)piperidine hydrochloride (16.00 g, 50.22 mmol) was suspended in a 1N aqueous sodium hydroxide solution (100 ml), the organic substance liberated was extracted with diethyl ether, and the organic layer was dried over anhydrous potassium carbonate and distilled under reduced pressure to remove the solvent. While cooling a solution of the thus obtained free amine in dichloromethane (100 ml) at 0° C., a 1.0M solution (100 ml) of boron tribromide in dichloromethane was added dropwise thereto over a period of 5 hours and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction was terminated by adding methanol (500 ml), and the reaction mixture was stirred for 10 minutes and then distilled under reduced pressure to remove the solvent. The residue was dissolved in a 4N aqueous sodium hydroxide solution (200 ml) and washed with diethyl ether, and then acetic acid was added dropwise thereto until the aqueous layer became neutral. The gummous substance produced was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby 4-(2-bromo-5-hydroxybenzyl)piperidine (9.93 g, 37.03 mmol) was obtained in a yield of 74%.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10].[N:18]([C:21]1[S:22][C:23]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:24]([CH3:26])[N:25]=1)=[N+:19]=[N-:20]>>[CH2:30]([NH:29][C:27]([C:23]1[S:22][C:21]([N:18]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:20]=[N:19]2)=[N:25][C:24]=1[CH3:26])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#Cc1ccc(F)cc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 8 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 1-ethynyl-4-fluorobenzene to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 8% yield: mp 203-205° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.77-8.75 (m, 1H), 8.36-8.31 (m, 1H), 7.41-7.16 (m, 8H), 6.10 (br s, 1H), 4.64 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.13, 153.3, 142.3, 137.4, 130.3, 130.2, 129.0, 128.9, 128.2, 128.1, 127.9, 127.9, 124.8, 124.7, 119.8, 119.7, 116.1, 115.8, 44.4, 17.5; MS (ES+) m/z 394.3 (M+1).
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1[C:5](=[O:13])[CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18]>O>[C:17]([CH:16]([CH:6]1[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=[N:4][C:5]1=[O:13])[CH2:15][C:14]([OH:21])=[O:20])([OH:19])=[O:18]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: O=C1CN2C=CC=CC2=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC(C(=O)O)C1C(=O)N=C2C=CC=CN21
Temperature: 5 °C

Procedure:
A hot solution of 80 g (2 moles) of sodium hydroxide in 200 ml of water is added in portions, while stirring, to a mixture of 341 g (2 moles) of the hydrochloride of imidazo[1,2-a]pyridin-2(3H)-one in 700 ml of water. Then, a solution of 250.7 g (2.16 moles) of maleic acid in 600 ml of water is added dropwise in such a manner that the internal temperature of the reaction mixture remains between 40° and 45° C. After 30 hours at room temperature (20°-25° C.) the mixture is cooled to 5° C., the resulting precipitate is filtered off, the filtrate is concentrated in vacuo to approximately half its volume, and the resulting product is filtered with suction. The combined residues are washed with a little cold methanol and dried in vacuo at 50° C. 400 g of 3-(1,2-dicarboxyethyl)-imidazo[1,2-a]pyridin-2(3H)-one having a melting point of 193° (decomposition) are obtained. The resulting product is stirred at room temperature for 6 hours with 650 ml of concentrated hydrochlorid acid. After cooling to 5° C., the precipitate is filtered off, the filtrate is concentrated in vacuo to approximately half its volume and the resulting product is filtered with suction. The combined residues are washed with acetone and dried in vacuo at 50° C. In this manner the hydrochloride of 3-(1,2-dicarboxyethyl)-imidazo[1,2-a]pyridin-2(3H)-one having a melting point of 205° C. (decomposition) is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[OH:15][C:9]1[CH:10]=[C:11]([O:12][S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])(=[O:32])=[O:31])[CH:13]=[CH:14][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)c(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(Cc2ccccc2)c(O)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
At 0° C. to a solution of 708 mg (3.54 mmol) of 4-benzylresorcinol in 20 mL of methylene chloride at 0° C. was added 410 μL (3.72 mmol) of N-methylmorpholine followed by 740 mg (3.51 mmol) of 2-chlorobenzenesulfonyl chloride. The reaction mixture was warmed to ambient temperature and stirred for 30 min. An additional 400 μL of N-methylmorpholine was added and the reaction mixture was stirred for another 60 min. The reaction mixture was quenched with 1N HCl, extracted into ether, washed with saturated NaHCO3, dried (MgSO4), and purified by flash chromatography (methylene chloride) to give 336.5 mg (25%) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=1, 8 Hz), 7.55-7.63 (m, 2H), 7.34-7.40 (m, 1H), 7.1-7.3 (m, 5H), 6.98 (d, 1H), 6.61-6.65 (m, 2H), 4.95 (s, 1H), and 3.91 (s, 2H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C19H15ClO4S: 375.0 (M+H), 397.0 (M+Na). Found: 373.6, 396.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].Cl>O1CCCC1.O>[CH2:29]([O:28][C:26](=[O:27])[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH2:8])[C:4]=1[F:9])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 4-chloro-2-fluoro-phenylamine (47, 6.30 mL, 57 0 mmol) in tetrahydrofuran (300 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (2.500 M in hexane, 24.4 mL) slowly. After 20 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at −78° C. for 20 minutes and allowed to warm to room temperature over 60 minutes. The reaction was cooled to −78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of water (80 mL) and concentrated hydrochloric acid (25 mL). The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated and the aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (48, 12.5 g, 78.3%), MS(ESI) [M+H+]+=280.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cnc3ccccc3c2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cn(-c2cnc3ccccc3c2)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A suspension of 1-quinolin-3-yl-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 18.7 mmol) in toluene (100 ml) was cooled to −78° C. Diisobutylaluminum hydride (19 ml of a 1M solution in THF, 19 mmol) was added dropwise keeping T<−70° C. The mixture was stirred at this temperature for 2 h, then the reaction mixture was allowed to slowly reach 0° C. After addition of saturated aqueous Seignette salt solution (10 ml) stirring was continued for 1 h. The mixture was diluted with AcOEt (100 ml), filtered, concentrated and chromatographed [silica, elution with gradient CH2Cl2 to 80% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)]]. The title compound was obtained as a light brown crystalline solid (1.20 g, 28%). Mp. 142-145° C. (AcOEt), MS: m/e=226 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=3[CH3:32])[O:21][CH2:22][C:23]([O:25]C(C)C)=[O:24])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=3[CH3:32])[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CNc2c(C)ccc(OCC(=O)O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of isopropyl 2-[3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (II(at)) (100 mg, 0.22 mmol, 1.0 eq) in THF (10 mL) was added NaOH (1M aqueous solution, 3.0 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 2 h, then the THF was removed under reduced pressure. The remaining aqueous solution was adjusted to pH 3-4 by the addition of diluted HCl. The solid that precipitated was collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (60 mg, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:17](C)[CH2:18][CH2:19][CH2:20]N=C=NCC.C(N(CC)CC)C.C(N)C#C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:17][CH2:18][C:19]#[CH:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: C#CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To a mixture of 4-tert-butoxycarbonylaminobutyric acid (5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.66 g) and triethylamine (7.47 g) in dichloromethane (80 mL) at rt was added 2-propynylamine (1.49 g). After being stirred at rt for 3 h, the mixture was diluted with dichloromethane (80 mL) and washed with 0.5 M HCl (aqueous, 2×), saturated NaHCO)3 (1×) and water (1×). The dichloromethane was dried over sodium sulfate, filtered and evaporated to afford (3-Prop-2-ynylcarbamoyl-propyl)-carbamic acid tert-butyl ester (1.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:17][O:16]2)[CH2:10][C:11]([O:13]C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:17][N:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16][C:11](=[O:13])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNc1ccccc1
Reactant: COC(=O)CC(c1ccc(Cl)c(Cl)c1)C1CO1
Solvent: OCC(F)(F)F
Product: CN(CC1OC(=O)CC1c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 23 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Treat a solution of the product of step 2 (368 mg, 1.34 mmol) in 2,2,2 trifluoroethanol (1 mL) with N-methyl aniline (217 μL, 2.01 mmol, 1.5 eq) and stir for 6 h at 23° C. followed by 6 h at 80° C. Cool to 23° C., concentrate in vacuo and purify by silica gel chromatography (column: 3.5×12 cm; eluant: hexane:EtOAc (4:1)) to provide 446 mg (1.3 mmol, 97%) of 4-(3,4-dichlorophenyl)-dihydro-5-[(methylphenylamino)methyl]-2(3H)-furanone as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:9]=2[N+:10]=1[O-:11])=O)C.[NH3:20]>CO>[C:4]([C:6]1[S:7][C:8]2[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:9]=2[N+:10]=1[O-:11])(=[O:3])[NH2:20]
Reactant: N
Reactant: CCOC(=O)c1sc2c(C)cc([N+](=O)[O-])cc2[n+]1[O-]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cc2c1sc(C(N)=O)[n+]2[O-]
Reaction time: 5 h
Yield: 97 %

Procedure:
160 g (0.57 mol) of 2-ethoxycarbonyl-5-nitro-7-methyl-benzothiazole-N-oxide are initially introduced in 1.0 1 of methanol, 42 g (0.62 mol of NH:) of an aqueous ammonia solution are added and the mixture is stirred at 20° C. to 25° C. for 5 hours. The crystalline product is isolated by filtering off with suction. 140 g (96 % of theory) of 2-carbamyl-5-nitro-7-methyl-benzothiazole-N-oxide of melting point >250° C. are obtained.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[NH:10][C:11]([Br:17])=[C:12]([N+:14]([O-:16])=[O:15])[N:13]=1.Cl[CH2:19][O:20][CH3:21]>O>[Br:8][C:9]1[N:10]([CH2:19][O:20][CH3:21])[C:11]([Br:17])=[C:12]([N+:14]([O-:16])=[O:15])[N:13]=1
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(Br)nc([N+](=O)[O-])c1Br
Reaction time: 5 h
Yield: 84.3 %

Procedure:
Under an ice-cooling condition, sodium hydride (3.56 g) was added to a N,N-dimethylformamide (100 ml) solution of 2,5-dibromo-4-nitroimidazole (20.08 g). 10 minutes later, being added dropwise chloromethylmethyl ether (6.75 ml) thereto at 10 to 15° C., then the reaction mixture was turned back to a room temperature. After being stirred this reaction mixture for 5 hours, under an ice-cooling condition, sodium hydride (0.30 g) and chloromethylmethyl ether (0.56 ml) were added, further stirred at a room temperature for 1 hour. Then the reaction mixture was ice-cooled, water was added and extracted with ethyl acetate. The organic layer was washed with an aqueous solution being saturated with sodium chloride, dried over anhydrous sodium sulfate, then concentrated under a reduced pressure. Thus obtained crude crystals were washed with diisopropyl ether, and dried at 50° C. for 24 hours, there was obtained 2,5-dibromo-1-methoxymethyl-4-nitroimidazole (19.68 g, yield: 84.3%) as yellow powder product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]2)=[O:12])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:30]([SH:32])[CH3:31].C([Li])CCC.C([O-])(O)=O.[Na+]>ClCCl.C(COC)OC>[CH2:30]([S:32][C:21](=[O:22])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:12])[CH2:19][CH2:18]1)[CH3:31]
Reactant: O=C(O)C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reactant: CCS
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: COCCOC
Product: CCSC(=O)C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reaction time: 8 h

Procedure:
2.19 g of Trans-{4-[(Quinoline-4-carbonyl)-amino]-cyclohexyl}-acetic acid (7 mmol) was added in 1300 mL of dichloromethane. Then 1.8 mL of oxalyl chloride is added (21 mmol). The suspension was heated to reflux for 3 hours and then the cloudy mixture is concentrated under vacuum. The residue is taken up in 500 mL of dichloromethane as a suspension and (1.28 g, 21 mmol) sodium ethylthiolate freshly prepared from 1.45 mL of ethanothiol and 12.07 mL of Butyl lithium (1.6 M in toluene) at 0° C. and by stirring in dimethoxyethane (20 mL) for 1 h at room temperature. The reaction mixture was stirred overnight. NaHCO3 was added and the organic phase was extracted three times with dichloromethane. The organic phases were dried and concentrated and the residue was chromatographied with heptane/AcOEt 1:1 to AcOEt to yield the title compound as a solid (1.97 g, 78.9% yield). MS (m/e): 357.3 (M+H+).
Reaction SMILES: [C:1]([N:5]([C:7]([CH3:16])([CH3:15])[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[OH:6])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH:23](Cl)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:16])([CH3:15])[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Product: CC(C)(C)NC(=O)C(C)(C)N(OC(c1ccccc1)c1ccccc1)C(C)(C)C
Yield: 62.7 %

Procedure:
The compound is prepared in analogy to example A13 from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and diphenylmethylchloride in 62.7% yield as colorless crystals, m.p. 89-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([O:17]C)=[O:16].O[Li].O.C1COCC1.O>C(=O)(O)[O-].[Na+].CO>[CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(OC)c(C#N)cc2ccccc12
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C#N)cc2ccccc2c1C(=O)O

Procedure:
A solution of methyl 2-methoxy-3-cyano-1-naphthoate (0.113 g), LiOH.H2O (0.0196 g), THF (3 mL), water (1 mL) and methanol (1 mL) was stirred overnight at room temperature. The solution was diluted with saturated sodium bicarbonate and extracted with Et2O. The aqueous layer was acidified to pH 2 by addition of 1N HCl and extracted with Et2O. The organic layer was washed with water (30 mL) and brine (40 mL), dried (sodium sulfate), filtered, and concentrated to a white solid. 1H NMR (DMSO-d6): δ 14.06 (broad, 1 H), 8.08-8.02 (m, 1 H), 7.83-7.76 (m, 2 H), 7.69-7.63 (m, 1 H), 4.02 (s, 3 H); MS m/z: 226 (M−1).
Reaction SMILES: N#N.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:34][CH2:35][C:36]([OH:38])=O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:36](=[O:38])[CH2:35][CH2:34][C:26]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:44][CH:43]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDC.HCl (80 mg, 0.41 mmol) and Et3N (58 μL, 0.41 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (70 mg, 0.29 mmol) and DMAP (5 mg, 0.04 mmol) and stir the resulting solution for 10 min. Add 4-Amino-benzoic acid methyl ester (51) (42 mg, 0.27 mmol) and stir the reaction solution 2d at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine, dry with Na2SO4 and filtrate it through a short pad of silica gel using EtOAc to obtain 4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acid methyl ester (52) (91 mg, 88%) as a white solid. No further purification. 1H NMR (400 MHz, CDCl3): 2.60 (t, 2H, J=7.6 Hz); 2.91 (t, 2H, J=7.6 Hz); 3.70 (s, 6H); 3.76 (s, 3H); 3.83 (s, 3H); 6.35 (s, 2H); 7.55 (d, 2H, J=8.3 Hz); 7.91 (d, 2H, J=8.6 Hz); 8.09 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[N:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:7]2=[N:8][CH:9]=1
Reactant: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncc(N)cc21

Procedure:
The nitro product of Step D, 340 mg. (0.001 mole), in 30 ml. of methanol was hydrogenated in the presence of 50 mg. of 5% palladium on carbon. The theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate was evaporated to give the product which was crystallized from benzene by addition of hexane, m.p. 177°-178° C.
Reaction SMILES: [C:1]([CH2:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30]>O1CCCC1>[C:1]([CH2:9]/[CH:10]=[CH:11]/[C:12]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)/C=C/CC(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of 4-benzoylcrotonic acid (0.01 mole) in tetrahydrofuran is added 0.01 mole of N,N-carbonyldiimidazole. After stirring for 2 hours, 0.01 mole of L-proline is added. The mixture is stirred for 24 hours to give 1-(4-benzoylcrotonyl)-L-proline. The preceding compound is reacted with thiolacetic acid in carbontetrachloride for 24 hours to give the product of the example as a glass.