Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:29]([O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34])[CH3:30].ON1C2C=CC=CC=2N=N1.CCN(CC)CC.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:38]1[CH:37]=[C:36]([CH2:35][C@H:33]([NH:34][C:13](=[O:14])[CH:12]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:32]([O:31][CH2:29][CH3:30])=[O:41])[N:40]=[CH:39]1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
A solution of 0.5 g (1.5 mmol) of bis-(1-naphthylmethyl)-acetic acid, 0.77 g (3.0 mmol) of histidine ethyl ester dihydrochloride (His-OEt·2 HCl), and 0.22 g (1.6 mmol) of 1-hydroxybenzotriazole (HOBt) in 20 mL of THF was treated with 0.85 mL (6.0 mmol) of Et3N followed by 0.33 g (1.6 mmol) of N,N'-dicyclo hexylcarbodiimide (DCC) and the solution allowed to stir at room temperature overnight. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with a saturated solution of NaHCO3, then with a saturated solution of NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Chromatography on silica gel, eluting with a gradient of methylene chloride (CH2Cl2) to CH2Cl2 /MeOH (96/4) gave 0.15 g of the product as a white foam. The structure was confirmed by NMR and mass spectroscopy; (m+H)+ =506.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N+:46]([C:49]1[CH:64]=[CH:63][C:52]([CH2:53][O:54][C:55]([NH:57][C@@H:58]2[CH2:62][CH2:61][NH:60][CH2:59]2)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:60]2[CH2:61][CH2:62][C@@H:58]([NH:57][C:55]([O:54][CH2:53][C:52]3[CH:63]=[CH:64][C:49]([N+:46]([O-:48])=[O:47])=[CH:50][CH:51]=3)=[O:56])[CH2:59]2)=[O:29])[CH2:10]1
Reactant: O=C(N[C@@H]1CCNC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Yield: 65.8 %

Procedure:
Following a procedure similar to that described in Preparation 18, but using 1.29 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 365 mg of pivaloyl chloride and 1.14 g of (3R)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidine trifluoroacetate, 1.09 g of the title compound were obtained as a powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=O)=[CH:2]1.[NH2:13][CH:14]1[C:27](=[O:28])[N:16]2[CH:17]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]12>>[C:10]([CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([NH:13][CH:14]1[C:27](=[O:28])[N:16]2[CH:17]([C:22]3[NH:23][N:24]=[N:25][N:26]=3)[C:18]([CH3:20])([CH3:21])[S:19][C@H:15]12)=[O:9])([OH:12])=[O:11]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)C(C(=O)O)c1ccsc1
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)O)c3ccsc3)C(=O)N2C1c1nnn[nH]1
Yield: 67 %

Procedure:
(2.69 mmole) of 2-(3-thienyl)malonic acid (British Pat. No. 1,125,557) with 645 mg. (2.69 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CXLVII, affords 810 mg. (67% yield) of 6-(2-carboxy-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its disodium salt. The infrared spectrum of the product KBr disc) shows absorptions at 1775 cm-1 (β-lactam), 1670 cm-1 (amide I), 1620 cm-1 (carboxylate) and 1525 cm-1 (amide II). The NMR spectrum (D2O) shows absorptions at 7.80-7.00 ppm (multiplet, thienyl hydrogens), 5.88 ppm (doublet, C-6 hydrogen), 5.65 ppm (doublet of doublets, C-5 hydrogen), 5.40 ppm (doublet, C-3 hydrogen), 1.60 ppm (doublet, C-2 methyl hydrogens) and 1.00 ppm (doublet, C-2 methyl hydrogens).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([N:24]2[CH2:25][CH2:26][CH:22]([NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[CH2:23]2)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 70.1 %

Procedure:
A solution of 2,3,4-trifluorobenzoic acid ethyl ester (Example 1g, 3.70 g, 18.1 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under nitrogen atmosphere for 4.5 hours. The solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and the mixture concentrated in vacuo. The resulting residue is then purified by column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (4.70 g). 1H NMR (CDCl3): δ 7.59-7.49 (m, 1H), 6.35-6.26 (m, 1H), 4.88-4.84 (bd, 1H), 4.39-4.28 (m, 3H), 3.81-3.50 (m, 3H), 3.48-3.34 (m, 1H), 2.32-2.15 (m, 1H), 2.02-1.76 (m, 1), 1.45 (s, 9H), 1.40 (t, 3H).
Reaction SMILES: [Na].[OH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C[O:11][C:12](=O)[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[CH3:14]>O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][C:12](=[O:11])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[CH:5]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: [Na]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2cccnc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethylpyridine was heated at 65°-70° C. for 10 hours. To this mixture was added 3.8 g of 2-(p-isobutylphenyl)propionic acid methyl ester, and the whole was heated at 95°-100° C. for 8 hours. After cooling to room temperature, 100 ml of water was added. The resulting mixture was extracted with ether, and the ether was distilled away from the extract to leave a residue. The residue was passed through a column of silica gel, and the adsorbate was eluted with chloroform. The eluates were freed of chloroform in vacuo to give 2.9 g of 2-(p-isobutylphenyl)propionic acid-3-pyridylmethyl ester as a colorless oil. The infrared spectrum showed strong C=O absorption at 1730 cm-1 characteristic for ester. Mass spectrum: parent ion 297 m/e.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=1[Cl:15].[C:35]([O:39][C:40]([N:42]1[CH:46]=[CH:45][CH:44]=[C:43]1B(O)O)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:43]2[N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH:46]=[CH:45][CH:44]=2)=[CH:9][C:8]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(Br)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(-c2cccn2C(=O)OC(C)(C)C)cc1Cl
Yield: 92.1 %

Procedure:
N-(4-Bromo-2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.410 g) was coupled with 1-tert-butoxycarbonyl-2-pyrroleboronic acid (0.930 g) in THF (10 mL) as described in Example 7-2) to give 0.435 g of N-[4-(1-tert-butoxycarbonyl-2-pyrrolyl)-2,6-dichlorobenzoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester ESMS: m/z 653 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:20])[C:11](=[C:15]3[S:19][CH:18]=[CH:17][S:16]3)[C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:20])[C:11](=[C:15]3[S:19][CH:18]=[CH:17][S:16]3)[C:12]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C(C(=O)c1ccc2c(c1)OCO2)=C1SC=CS1
Reactant: COC(=O)CN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)C(C(=O)c1ccc2c(c1)OCO2)=C1SC=CS1
Reaction time: 3 h
Yield: 20.9 %

Procedure:
Dissolved in 15.0 ml of N,N-dimethylformamide were 959 mg of 3-(1,3-benzodioxol-5-yl)-2-(1,3-dithiol-2-ylidene)-3-oxopropionic acid and 997 μl of triethylamine, followed by the addition of 469 mg of methyl glycinate hydrochloride. The reaction mixture was ice-cooled, to which 737 μl of diphenylphosphoryl azide were added. The resulting mixture was stirred for 3 hours and, while allowing its temperature to rise to room temperature, was stirred overnight. The reaction mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, shaken together with a saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby crude oil was obtained. The oil was purified by column chromatography (silica gel: "Fuji Davidson BW-300", column: 35 mm across×190 mm long, N2 pressure: 0.3 kg/cm2, developer: ethyl acetate:n-hexane=3:2) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane, whereby 247 mg of methyl N-[3-(1,3-benzodioxol-5-yl)-2-(1,3-dithiol-2-ylidene)-3-oxopropionyl]glycinate were obtained as yellow crystals (yield: 21.6%).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:16]([F:18])([F:19])[F:17])[C:6]=2[CH:5]=[C:4]([O:20][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:3]=1
Reactant: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(9R)-4-Chloro-9-(trifluoromethyl)-9H-fluorene-2,9-diol (200 mg) obtained in step 10 of example 1 was dissolved in N,N-dimethylformamide (2 ml), potassium carbonate (185 mg) and ethyl 4-bromobutyrate (105 μl) were added, and the mixture was stirred at room temperature for 7 hr. To the reaction mixture was added water, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with water (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture at a mixing ratio 5:1 (hexane:ethyl acetate), then successively with a mixture at a mixing ratio 3:1, and further with a mixture at a mixing ratio 2:1) to give the title compound (197 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1(C)C=CC=C[CH:15]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
4-chloro-3-nitrobenzoic acid (40.0 g, 0.2 mol) was refluxed in thionyl chloride (150 ml) for 6 hours. After cooling toluene (50 ml) was added and the mixture was evaporated to dryness. Abs. ethanol (500 ml) was added to the cooled residue, and the resulting mixture was refluxed overnight. The excess of ethanol was removed under reduced pressure and the product crystallized upon addition of aqueous sodium bicarbonate (1M). Yield: 42.5 g (93%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:16]([NH2:18])[CH3:17]>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2](=[O:4])(=[O:3])[NH:18][CH2:16][CH3:17])[CH:6]=1
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Methyl 2-(3-chlorosulfonyl-phenyl)acetate (0.29 g, 1.17 mmol) was dissolved in THF (10 mL) and to this solution 1 mL (2 mmol) of 2M ethylamine in THF was added. Let stir at room temperature 30 minutes, diluted with ethyl acetate and the organic layer was washed with 10% citric acid, brine, dried over sodium sulfate and concentrated to afford (3-ethylsulfamoyl-phenyl)-acetic acid methyl ester as an oil (0.28 g, 1.09 mmol, 93% yield). 1H NMR (CDCl3) 7.72 ppm, 2H, m; 7.41 ppm, 2H, m; 4.32 ppm, 1H, t; 3.68 ppm, 3H, s; 3.67 ppm, 2H, s; 2.98 ppm, 2H, m; 1.07 ppm, 3H, t.
Reaction SMILES: CC1(C)[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8]C=2)[CH:4]([CH2:12][C:13]2C=C[C:16](C)=[CH:15][CH:14]=2)[CH:3]1C.[Cl-].[Cl-].[Cl-].[Al+3].[C:26](Cl)(=[O:28])[CH3:27]>ClCCCl>[C:26]([C:6]1[C:7]([CH3:8])([CH3:11])[C:12]2[C:4]([C:5]=1[CH3:10])=[CH:3][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:28])[CH3:27]
Reactant: Cc1ccc(CC2c3cc(C)ccc3C(C)(C)C2C)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)C1=C(C)c2cc(C)ccc2C1(C)C
Temperature: 29 °C
Yield: 34.9 %

Procedure:
To a mixture of 50.8 g 90.8% pure 1,1,2,5-tetramethyl-3-(4-methyl-benzyl)indane and 52.5 g 1,2-dichloroethane was added with stirring at 28-30° C. a mixture of 26.7 g aluminum trichloride, 14.8 g acetyl chloride and 75 g 1,2-dichloroethane in the course of one hour and twenty minutes. After an additional stirring period of 30 minutes at 20° C. the mixture was poured on ice and stirred for another hour. The organic layer was washed with subsequently 5%-sodium carbonate solution, saturated sodium chloride solution and concentrated by means of a rotatory evaporator yielding 34.9% 2-acetyl-1,1,3,5-tetramethylindene in 45.6 g residue. Recrystallization from methanol gave 99.4% pure 2-acetyl-1,1,3,5-tetramethylindene.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:17][N:18]=1
Reactant: CC(=O)c1ccc(C)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCC(O)CC3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). 4-Hydroxypiperidine (66.1 mg; 0.65 mmol; 2 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, Compound (10) is obtained as white-off solid (33 mg; 23%). 1H NMR (DMSO-d6) δ 1.40-1.60 (m, 2H), 1.72-1.85 (m, 2H), 2.14 (s, 3H), 2.42 (s, 3H), 2.80-2.92 (m, 2H), 3.15-3.30 (m, 2H), 3.59 (m, 1H), 4.71 (d, J=3 Hz, 1H), 7.30 (d, J=4.5 Hz, 1H), 7.58 (d, J=4.5 Hz, 1H), 12.18 (br s, 1H). M−(ESI): 400.20; M+(ESI): 402.10. HPLC, Rt: 2.86 min (purity: 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:11])[CH3:10].C(NC(C)C)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:29]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:30])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)[C@@H](N)CC(F)(F)CC(C)C
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(F)(F)CC(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65.9 %

Procedure:
To a mixture of (S)-2-amino-4,4-difluoro-6-methyl-heptanoic acid methyl ester hydrochloride (238 mg, 0.97 mmol) and diisopropyl amine (2.42 mmol, 313 mg) in dry dichloromethane (5 mL) under N2 is added drop wise morpholine carbonyl chloride (1.45 mmol, 218 mg). The mixture is stirred at room temperature for 23 h, then diluted with dichloromethane (25 mL) and washed with dilute HCl (30 mL), and saturated NaHCO3 (30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. Purification over 12 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-Difluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid methyl ester (206 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:10](OCC)(OCC)OCC.C1(C)C(C)=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nccnc1Cl
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: Clc1nccn2cnnc12
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 1-(3-chloropyrazin-2-yl)hydrazine (0.90 g, 62 mmol), triethyl orthoformate (2.3 mL), 14 mmol), and dry xylene (15 mL) was refluxed with stirring for 2 h. The mixture was brought to RT, diethyl ether was added and the suspension was filtered. The solid collected was washed with diethyl ether to afford 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (0.60 g, 62% yield). MS m/z: 155.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[F:1])[CH3:20]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(F)cc1F
Yield: 97 %

Procedure:
2,4-Difluorocinnamic acid (10.1 g) was dissolved in ethanol (100 ml), and conc. sulfuric acid (1 ml) was added thereto, and the resulting mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure and the residue was poured into ice-cold water and extracted with ethyl acetate. The extract was washed successively with 5% aqueous sodium hydrogencarbonate and a saturated aqueous NaCl solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (11.2 g, 97%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:32][C:7]1[CH:2]=[CH:3][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(Cl)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-Chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-chloro-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([NH:12][NH2:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:10]([NH:12][NH:13][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ncc(Cl)c(C(=O)NN)n1
Solvent: c1ccncc1
Solvent: O
Product: CSc1ncc(Cl)c(C(=O)NNC(=O)Cc2ccccc2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carbohydrazide (1.0 g, 4.6 mmol) and 2-phenylacetyl chloride (0.61 mL, 4.6 mmol) were dissolved in 20 mL pyridine. The solution was stirred at 60° C. for 3 h. Upon cooling to room temperature, the reaction mixture was diluted with excess H2O. The aqueous layer was extracted with EtOAc 3 times. The combined organic layers were washed with 2 N HCl and H2O, dried over magnesium sulfate and concentrated under vacuum. Flash chromatography was required to obtain 0.442 g (26% yield) of product as a white solid. MS (M+H)+ 337.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1CCCCC1>C1(C)C=CC=CC=1>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10](=[O:12])[CH3:11])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(CC(C(C)=O)c2ccc(OC)cc2)cc1
Yield: 46 %

Procedure:
49.2 g of 3-(4-methoxyphenyl)-2-propanone and 61.8 g of 4-hexyloxybenzaldehyde were added to 100 ml of toluene containing 4 ml of piperidine. The resultant mixture was heated at reflux temperature overnight after which the solvent was removed in vacuo to afford the desired subtitled intermediate (46% yield), b.p. 230°-235° C.