Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:46])[CH2:27][C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:46])[CH2:27][C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)[CH3:24]
Reactant: CC(C)=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCC=C(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,5-dimethyl-hex-4-enyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH:10][CH:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH2:6][CH2:7][S:8][CH3:9])=[O:4].[OH-].[Na+]>O>[C:3]([C@@H:5]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH2:6][CH2:7][S:8][CH3:9])([OH:4])=[O:2]
Reactant: COC(=O)[C@H](CCSC)NC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
A solution of N-(1(S)-methoxycarbonyl-3-methylthiopropyl)-DL-alanyl-L-proline (127.5 mg; 0.384 mM) in 2 ml of water is treated under nitrogen with 7.82 ml 0.100 N sodium hydroxide (0.782 mM) and stirred for 21/2 hr. at room temperature. The product is absorbed from the reaction mixture onto 30 ml of Dowex 50 (H+) and eluted with 4% aqueous pyridine to yield 73.5 mg., which is further purified over a LH-B 20 column to yield 55.7 mg. of product. The nmr spectrum in D2O shows S-CH3 at 2.1; CH-CH3 at 1.5 and 1.6δ and no methyl ester. The mass spectrogram on silylated material shows the expected molecular ion at 462 m/e.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20]C3CCCCO3)=[CH:15][CH:14]=2)=[N:3]1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(COC3CCCCO3)cc2)=N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
4.0 g (10.9 mmol) of 4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazoline was dissolved in methanol (50 ml), and 6N hydrochloric acid (15 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.0 g of the title compound (yield 98%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[OH-].[K+].[C:12](=S)=[S:13]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:12]([SH:13])=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a suspension of (6-chloro-pyridazin-3-yl)-hydrazine (1 g, 6.917 mmol) in ethanol (12 mL) was added a solution of KOH (390 mg, 6.917 mmol) in water (12 mL) dropwise. Carbon disulfide (0.84 mL, 13.84 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 48 h. Another 0.84 mL CS2 and 390 mg KOH were added, and the reaction mixture was further stirred for 24 h, before concentrating in vacuo. The residue was treated with 1 M aqueous NaOH and filtered. The filtrate was acidified to pH 3 with 1 N aqueous HCl, and the precipitate was filtered off. The resulting filtrate was extracted with ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, concentrated and dried in vacuo to provide 485 mg of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (38% yield): 1H NMR (DMSO-d6): δ 7.48 (d, 1H), 8.24 (d, 1H); MS (m/z) 187 [M+H+]+.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11](O)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)=O>[OH:10][C:7]1[CH:6]=[C:4]2[O:5][CH2:1][O:2][C:3]2=[CH:9][C:8]=1[CH:11]=[CH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC=Cc1ccccc1
Reactant: Oc1ccc2c(c1)OCO2
Solvent: O=CO
Product: Oc1cc2c(cc1C=CCc1ccccc1)OCO2

Procedure:
The compounds of Category II may be prepared in the following manner: A mixture of sesamol and cinnamyl alcohol in aqueous formic acid is refluxed to yield 2-hydroxy-4,5-methylenedioxy-cinnamylbenzene. This intermediate is then etherified in conventional manner by reaction with an appropriate alkyl halide or alkyl sulphate to yield the desired compound. The synthesis is illustrated by the following formulas. ##EQU4##
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][CH2:23][C:24](=O)[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:4]2[CH2:5][CH2:6][N:1]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2](=[O:8])[C:3]=2[C:24]([CH3:25])=[CH:23]1
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Reactant: CC(=O)CNc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccccc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of [1,1′]bipiperidinyl-2,4-dione, from Step 4 (2.49 g, 12.7 mmol) in dry toluene (240 ml) at room temperature were added 1-(2-chlorophenylamino)propan-2-one (2.33 mg, 12.7 mmol) from Step 5 followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark trap, and 90 ml toluene was collected in the trap. Then 1 molar equivalent of p-TSA was added and the reaction mixture was boiled under reflux overnight. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane: EtOAc gradient) to give 0.93 g (21%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[C:15]([O:19][C:20](=[O:27])[C:21](=[N:25]O)[C:22](=O)[CH3:23])([CH3:18])([CH3:17])[CH3:16].O>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:22]([CH3:23])=[C:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[NH:25][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14])[CH3:2]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Temperature: 75 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A stirred solution of 3-oxo-butyric acid tert-butyl ester (32 g, 0.2 mol) in glacial acetic acid was added dropwise with an aqueous solution of sodium nitrite (13.8 g, 0.2 mol sodium nitrite in 20 ml of water) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the reaction mixture was stirred in an ice-water bath for 1 hour and at room temperature for another 3 hours. The solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester was obtained which was used as such. A mixture of 3-oxo-glutaric acid diethyl ester (40 g, 0.2 mol) in 90 ml of glacial acetic acid was added with the above solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester and zinc dust (26 g, 0.4 mol) alternatively at a rate to maintain the reaction temperature below 65° C. Upon completion of the addition, the mixture was stirred at 75° C. for 2 hours, added with cold water (100 ml), and the mixture was stirred at room temperature for 1 hour. The zinc dust was removed by filtration and the filtrate was extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml×3), saturated sodium bicarbonate solution (100 ml×4), and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (60 g, 88.5%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of N-methyl-N-{2-[5-methyl-5-(piperazine-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.28 g), triethylamine (0.17 ml) and tetrahydrofuran (6 ml) was added methanesulfonyl chloride (0.06 ml) at 0° C., and the reaction mixture was stirred overnight at room temperature, and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.26 g, yield 81%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1B(O)O.C(O)(=[O:18])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1[OH:18]
Reactant: CC(=O)O
Reactant: CC(C)Oc1ccc(F)c(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(F)c(O)c1F
Reaction time: 40 h
Yield: 100 %

Procedure:
To a solution of 2,6-difluoro-3-isopropoxy-phenylboronic acid (10.0 g, 0.046 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 40 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2,6-difluoro-3-isopropoxy-phenol (8.70 g, 100%) as a brown oil.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC=Cc1ccccc1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=CC=Cc2ccccc2)N1

Procedure:
A solution of hydantoin (40 g), freshly distilled cinnamaldehyde (50 g), and fused sodium acetate (80 g) in acetic acid (160 ml) was heated to reflux for 11/2 hours. The solution was poured into cold water (1.5 l) to precipitate the orange product, which was removed by filtration. This product was washed with water until neutral and then with cold ethanol to give 69 g (85% theoretical yield) of virtually pure product. Before use, the product was recrystallised from ethanol to give yellow crystals of 5-cinnamylidenehydantoin, m.p. 268°-270° (decomp.), the infra-red spectrum of which showed the expected main peaks at 1750, 1700, 1640, 1390, 1350, 1020, 970, 895, 825, 750, 690, and 655 cm-1.
Reaction SMILES: C[O-].[Na+].CO.[Na].Cl[C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1.[CH3:29][S:30](C)=O>>[CH3:29][S:30][C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: CS(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 13 °C

Procedure:
To a mixture of sodium methoxide (made from 100 ml (2.47 m) of methanol and 1.50 g (0.652 m) of sodium metal) which had been cooled to 13° C. was added 7.0 ml (0.126 m) of methylmercaptain. The mixture was allowed to warm to room temperature and then 20.0 g of 6-chloro-2-(diphenoxymethyl)pyridine and 150 ml of dimethylsulfoxide was added thereto. The mixture was heated to 90° C. and after 4 days at this temperature, the reaction mixture was cooled to room temperature and poured into 300 ml of ice. The solution was extracted with methylene chloride and the extract was dried over magnesium sulfate and the solvent stripped off under reduced pressure. The residue was further purified using preparative high pressure liquid chromatography with a 2:98 mixture of ethylacetate and hexane. The oil thus obtained crystallized in n-hexane and was purified by recrystallization from n-hexane leaving the above named compound as a white solid in a yield of 49 g (98 percent pure). The product melted at 58°-59° C. and its structure was confirmed by its NMR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 70.42, 5.19 and 4.20 percent, respectively, as compared with the theoretical contents of 70.59, 5.26 and 4.33 percent, respectively, as calculated for the above named compound (Compound 3).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH:41]([OH:43])[CH3:42]>>[OH:43][CH:41]([CH3:42])[CH2:40][NH:39][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1
Reactant: CC(O)CN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CC(O)CNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 45.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1>CO.[Pd].[C]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reaction time: 8 h

Procedure:
3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (3 g, 16.5 mmole) was dissolved in methanol (50 ml) under argon. Pd/carbon (150 mg, 5%) was added and the reaction mixture was hydrogenated for 8 hours at 2 bar. The reaction mixture was worked up by filtering the solution through silica gel and washing with methanol (10×20 ml). The filtrate was concentrated by evaporation and dried. 3-piperidine-4-yl-1H-indole was obtained in a yield of 3.3 g (100%) with an m.p. of 190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[C:19](Cl)(=[O:21])[CH3:20].N1C=CC=CC=1>CCOCC>[C:19]([O:12][C:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:13])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC1=C(C(=O)c2ccc(Cl)cc2Cl)C(=O)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2,4-Dichlorobenzoyl)cyclohexane-1,3-dione (11.4 g, 0.04 mol), acetyl chloride (3.15 g, 0.041 mol) and pyridine (3.2 g, 0.041 mol) were mixed in 100 ml ether and stirred at room temperature for 24 hours. The volatiles were evaporated under reduced pressure, and water and CH2Cl2 were added. The organic layer was then washed three times each with 1N HCl and then 5% Na2CO3, dried with MgSO4 and the solvent evaporated under reduced pressure to yield the product, 8.4 g, 64%. The structure was confirmed as such by nuclear magnetic, infrared and mass spectroscopy.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25](O)=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:29][O:30][C:31](=[O:43])[C@H:32]([CH2:41][OH:42])[NH:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:29][O:30][C:31](=[O:43])[C@H:32]([CH2:41][OH:42])[NH:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:25](=[O:26])[C@H:18]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:10]([C@H:11]([CH2:13][CH3:14])[CH3:12])[NH:9][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.1 g of t-butoxycarbonylisoleucylhistidine hydrochloride and 6.3 g of prolylserine methyl ester hydrochloride are dissolved in 100 ml of dimethylformamide. The solution is cooled to 0° C. To the solution is added 3.4 g of 1-hydroxybenzotriazole, 2.8 ml of N-methylmorpholine and 7.6 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for two hours at 0° C. and then is allowed to stand at 4° C. for sixteen hours. Dicyclohexylurea is filtered from the reaction mixture and is washed with acetone. 300 ml of ethyl acetate is added to the solution. The solution is extracted three times with 300 ml saturated potassium bicarbonate and two times with 300 ml of brine. The product is extracted into 300 ml of 2 M potassium bisulfate. The acidic solution is neutralized with potassium carbonate. The slightly basic aqueous solution is extracted three times with 300 ml of methylene chloride. The methylene chloride solution, which contains the product, is dried over sodium sulfate, filtered and stripped of solvent under vacuum. The residue is dissolved in 100 ml of ethyl acetate. The solution is added to 1 liter of cold rapidly stirring Skellysolve B. The white precipitate was filtered and dried under vacuum at 55° C. to afford the product t-butoxycarbonylisoleucylhistidylprolylserine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH:18]=[CH:19][C:20]=1[Cl:21]>N1C=CC=CC=1>[Cl:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:16][C:15]=1[NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Nc1cc(NC(=O)c2ccccc2[N+](=O)[O-])ccc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 80 °C
Yield: 69.5 %

Procedure:
3,4-Dimethoxybenzoyl chloride (1.55 g) was added to a stirred mixture of N-(3-amino-4-chlorophenyl)-2-nitrobenzamide (1.5 g) and pyridine (20 ml) and the mixture was stirred and heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature and evaporated. The residue was partitioned between methylene chloride and 1N aqueous hydrochloric acid solution. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated. The residue was triturated under ethyl acetate. The resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried under vacuum at 40° C. There was thus obtained the title compound (1.63 g);
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:15]([C:19]#[N:20])=[N:14][C:13]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[O:22])=[C:12]([OH:30])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:46]([NH2:49])[CH2:47][CH3:48]>C(Cl)Cl>[CH2:46]([NH:49][C:27]([CH2:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[N:14]=[C:15]([C:19]#[N:20])[C:16]2[C:17](=[O:18])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10][C:11]=2[C:12]=1[OH:30])=[O:22])=[O:29])[CH2:47][CH3:48]
Reactant: CCCN
Reactant: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)CCCNC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[(7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-butyric acid (30 mg, 0.074 mmol) and triethylamine (0.015 mL, 0.11 mmol) in CH2Cl2 (3 mL) was cooled in an ice bath. Isobutyl chloroformate (0.014 mL, 0.11 mmol) was added, and the mixture was stirred at 0° C. for 10 min. Propylamine (0.1 mL) was then added, and the mixture was slowly warmed to r.t. and stirred for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by silica gel chromatography (0-30% EtOAc/CH2Cl2, then 10-80% EtOAc/hexanes+2% AcOH) to give 23 mg of the title compound as a white solid. MS: (+) m/z 448.35 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.Cl[C:18](=[O:26])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C(Cl)Cl>ClCCCl>[O:26]=[C:18]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: COC(=O)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCCC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of aluminum chloride (9.316 g; 69.87 mmol) in anh. DCE (50 ml) was treated with commercially available 1,3,5-trimethoxybenzene (7.664 g; 45.56 mmol), and stirring at 0° C., under nitrogen, was continued for 10 min. Commercially available methyl 5-chloro-5-oxopentanoate (5.000 g; 30.37 mmol) was then added, and the mixture was stirred at rt for 26 h. The resulting reaction mixture was poured onto crushed ice (150 g), and DCM (100 ml) was added. The separated aq. layer was further extracted with DCM (3×50 ml). The mixed organic layers were washed successively with water (75 ml) and brine (2×75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=10/1 to AcOEt) afforded methyl 5-oxo-5-(2,4,6-trimethoxyphenyl)pentanoate as a yellow oil. LC-MS (conditions D): tR=0.94 min.; [M+H]+: 297.13 g/mol.