Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][N:32]4[CH2:37][CH2:36][N:35]([S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.CO>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH2:31][N:32]3[CH2:33][CH2:34][N:35]([S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[CH2:36][CH2:37]3)[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(=O)(=O)N(C)C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide (0.210 g, 0.278 mmol) in trifluoroacetic acid (5 mL, 67.3 mmol) and trifluoromethanesulfonic acid (0.2 mL, 0.278 mmol) was stirred at 80° C. for 2 h. The dark solution was cooled down to room temperature and concentrated to a slurry. The slurry was neutralized to pH 8 with aqueous NaHCO3. The precipitate was dissolved in DCM/MeOH and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 10% 2 M NH3.MeOH in CH2Cl2 to give 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide (0.110 g, 0.214 mmol, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.75 (s, 1H); 8.70 (d, J=2.15 Hz, 1H); 8.55 (d, J=0.39 Hz, 1H); 8.19 (d, J=2.54 Hz, 2H); 8.17 (dd, J=8.90, 2.84 Hz, 1H); 7.86 (d, J=0.98 Hz, 1H); 7.71 (d, J=1.76 Hz, 1H); 6.82 (d, J=8.80 Hz, 1H); 3.84 (s, 3H); 3.47 (s, 2H); 3.31 (s, 2H); 3.16 (d, J=4.89 Hz, 3H); 2.75 (s, 6H); 2.47 (s, 2H); 2.44 (s, 3H). m/z (ESI, +ve ion) 515.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:34])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:24]2)[O:12]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:34])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24]2)[O:12]1
Reactant: CCOC(=O)CCC1CC(N(C)C[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoate (0.39 g, 0.82 mmol) in methanol (14 mL) was treated with a 1 M aqueous solution of sodium hydroxide (1.56 mL, 1.56 mmol) and the reaction mixture was heated at 50° C. with stirring for 3.5 h; HPLC/LC MS indicated conversion to the desired product. The reaction mixture was concentrated in vacuo and the aqueous residue was diluted with water (10 mL) and extracted with CH2Cl2 (3×5 mL). The aqueous layer was treated with a 1 M aqueous solution of hydrogen chloride (1.44 mL, 1.44 mmol) to adjust to pH 7. The clear, colorless solution was lyophilized to afford the crude title compound (0.487 g, 110%) as a slightly off-white solid, yield accounts for 1.56 mmol NaCl (91 mg): MS (ESI+) for C21H30N6O5 m/z 447.1 (M+H)+; MS (ESI−) for C21H30N6O5 m/z 445.2 (M−H)−; HPLC purity >95% (ret. time, 1.949 min).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]([OH:14])[CH2:9][NH:10][CH:11]([CH3:13])[CH3:12].[O:15]=[C:16](O)[C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18]>O>[O:15]=[C:16]([O:14][CH:8]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH3:1])[CH2:9][NH:10][CH:11]([CH3:12])[CH3:13])[C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18]
Reactant: Cc1csc(C(O)CNC(C)C)c1C
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: Cc1csc(C(CNC(C)C)OC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c1C

Procedure:
To 1.20 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol in 40 ml of water, 1.96 ml of a 50% gluconic acid solution are added. The mixture is heated in water-bath during 1 hour at 70°, then the solution is lyophilised (2.18 g of the salt obtained are soluble in 5 ml of water and give a pH of 4.6).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][C:7](=[O:9])[CH2:6][CH:5](O)[CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]1[O:8][C:7](=[O:9])[CH2:6][CH2:5][CH:4]=1
Reactant: O=C1CC(O)CC(CCl)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1CCC=C(CCl)O1
Yield: 80.3 %

Procedure:
A mixture of 50 mg (0.304 mmol) of (+)-6-chloromethyl-4-hydroxytetrahydropyran-2-one obtained in Example 3, 57.8 mg (0.304 mmol) of p-toluenesulfonic acid and 5 ml of benzene was refluxed for 30 minutes. After completion of the reaction, benzene was distilled off and distilled water were added thereto, and the solution was extracted with dichloromethane, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off, the resultant residue was subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 35.8 mg (yield 81%) of (-)-6- chloromethyldihydropyran-2-one.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[O:32])[N:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]>CS(C)=O>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]4[CH2:2][O:32]4)[N:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C=O)n3)cs2)cc1OCC
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3cccc(C4CO4)n3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
880 mg of trimethylsulfonium iodide was added to a suspension of 172 mg of 60% sodium hydride in 15 ml of dimethyl sulfoxide. The mixture was subjected to a reaction at room temperature for 1 hour. Thereto was dropwise added a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(6-formyl-2-pyridyl)thiazole dissolved in 20 ml of dimethyl sulfoxide. The mixture was stirred overnight at room temperature. The reaction mixture was poured into 150 ml of ice water. The mixture was subjected to extraction three times with 200 ml of ethyl acetate. The ethyl acetate layer was water-washed and dried over anhydrous sodium sulfate. The solvent was removed. The residue was purified by silica gel column chromatography (elutant: n-hexane/ethyl acetate=4/1) to obtain 760 mg of 2-(3,4-diethoxyphenyl)-4-(6-oxiranyl-2-pyridyl)thiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[O:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O.C(N(CC)CC)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]3=[O:19])[CH:27]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(O)c1cccc(N2CCCCC2=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (230 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (7 mL) were added 3-(2-oxopiperidin-1-yl)benzoic acid (169 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg), 1-hydroxybenzotriazole (125 mg) and triethylamine (128 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (53.4 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>>[N:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: ClCCCCCn1ccc2ccccc21
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCC(=O)Nc1ccc(C2CCN(CCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(5-chloropentyl)-1H-indole and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl.O1CCOCC1>[ClH:1].[CH3:21][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Add a solution of HCl 4M in dioxane (4 equiv) to a solution of 4-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (7.77 g, 24.13 mmol) in DCM (73 mL). Stir mixture at room temperature overnight. Add 2 more equiv of the HCl in dioxane solution. After no starting material is detected by LCMS, filter solid and dry under reduced pressure to obtain 6.91 g of 1-(3-methyl-5-nitro-pyridin-2-yl)-piperazine hydrochloride as a yellowish solid (97% yield). ES+(m/z): 259 [M+1].
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:8]=3[S:7](=[O:19])(=[O:18])[NH:6][CH2:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][NH:6][S:7](=[O:19])(=[O:18])[C:8]=2[CH:13]=1)([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Temperature: 40 °C

Procedure:
A solution of the compound of Example 77 (3.5 mmol) in a mixture of methanol/water 1/1 (100 mL) containing NaOH (0.5 g) is heated at 40° C. for 3 hours. The methanol is then removed by distillation under reduced pressure and the resulting aqueous solution is adjusted to pH 2 by adding 6N HCl. The precipitate obtained is collected by filtration, washed with water and dried to yield the title product in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([CH3:21])=[CH:19][S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([CH3:21])=[CH:19][S:18][C:16]=2[N:17]=1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N[CH:2]1[C:13](=[O:14])[N:4]2[C:5](C(O)=O)=[C:6]([OH:9])[CH2:7][S:8][C@H:3]12>CO>[OH:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH2:2][C:13](=[O:14])[N:4]2[CH:5]=1
Reactant: NC1C(=O)N2C(C(=O)O)=C(O)CS[C@H]12
Solvent: CO
Product: O=C1C[C@H]2SCC(O)=CN12

Procedure:
In Chem Pharm Bull, 36(2), 582-591 (1988), the preparation of 7-amino-3-hydroxy-3-cephem-4-carboxylic acid (IX) is described in which 7-amino-3-exomethylene-cepham-4-carboxylic acid (VII) was ozonized in methanol at -75° C. to yield the corresponding 3-hydroxy-3-cephem compound (VIII) which is further reduced with NaBH4 to yield 83% of (IX). It was also observed that when 7-phenylacetamido-3-methylene-cepham-4-carboxylic acid (X) was ozonized in methylene chloride, the desired 3-hydroxy-3-cephem compound (XI) was not obtained, but when ozonolysis of (X) was carried out in methanol at -65° C. followed by treatment of the reaction mixture with excess of diphenyl diazomethane the ester (XII) was obtained. The above process is illustrated in the following Scheme B: ##STR3## F) U.S Pat. Nos. 3,917,587, 3,925,372, 4,064,343, 4,060,688 describe the ozonization of the 7-amino or 7-acylamido-3-exomethylene-cepham-4-carboxylic acid esters in solvents like methylene chloride, methanol, ethyl acetate etc., at a temperature range of -80° C. and -50° C. and the resulting ozonide is always decomposed with a reducing agent such as sodium bisulfite, sulphur dioxide and trimethylphosphite to afford the corresponding 3-hydroxy-3-cephem-4-carboxylic acid esters. Also mentioned is the formation of sulfoxide side products, the 3-exomethylene sulfoxide ester and the 3-hydroxy-3-cephem ester. The formation of the sulfoxides is said to occur as a result of over oxidation in the ozonolysis reaction.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH2:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=O)[N:26]([C:35]2[CH:40]=[C:39]([CH:41]=[N:42][O:43][CH3:44])[C:38]([Cl:45])=[CH:37][C:36]=2[F:46])[C:25]1=[O:47]>C1(C)C=CC=CC=1>[NH2:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=[S:10])[N:26]([C:35]2[CH:40]=[C:39]([CH:41]=[N:42][O:43][CH3:44])[C:38]([Cl:45])=[CH:37][C:36]=2[F:46])[C:25]1=[O:47]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CON=Cc1cc(-n2c(=S)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl

Procedure:
3.4 g of Lawesson's reagent were added to a solution of 1-amino-3-(4-chloro-2-fluoro-5-methoxyiminomethylphenyl)-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine (3.8 g) in 100 ml of toluene. After refluxing for 12 hours, the solvent was removed and the crude product obtained was purified by chromatography. Yield: 2.2 g; m.p.: 172°-174° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.[Li+].[OH-]>CO>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cn1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOP(=O)(Cc1ccc(C(=O)O)cn1)OCC
Reaction time: 2 h

Procedure:
A mixture of methyl 6-[(diethoxyphosphoryl)methyl]nicotinate (108 mg, 0.376 mmol), THF (1.13 mL) and MeOH (0.376 mL) was treated with LiOH (0.376 mL, 3.0M in water, 1.13 mmol) and stirred for 2 h. The mixture was concentrated to a white residue used crude in the next step. 1H NMR (DMSO-d6, 600 MHz) δ 8.95 (m, 1H), 8.22 (m, 1H), 7.48 (m, 1H), 3.96 (dt, J=15.3, 7.0 Hz, 4H), 3.53 (d, J=22.0 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H). MS: cal'd 274 (MH+), exp 274 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[O:13]=[C:7]([C:5]1[N:6]=[C:2]([NH:1][S:23]([C:16]2[C:17]([Cl:22])=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])(=[O:25])=[O:24])[S:3][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: CCOC(=O)C(=O)c1csc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl (2-amino-4-thiazolyl)glyoxylate and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (18.3 mg) with purity >80%. LCMS (pos) m/z 445.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:15](=O)[C:16]([F:19])([F:18])[F:17])[C:13]#[N:14])[CH:5]=[C:6]([Cl:11])[C:7]=1[N:8]([CH3:10])[CH3:9].O=P(Cl)(Cl)[Cl:23].C(N(CC)CC)C>O>[Cl:23]/[C:15](/[C:16]([F:19])([F:18])[F:17])=[C:12](\[C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([N:8]([CH3:10])[CH3:9])=[C:6]([Cl:11])[CH:5]=1)/[C:13]#[N:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1c(Cl)cc(C(C#N)C(=O)C(F)(F)F)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)c1c(Cl)cc(/C(C#N)=C(\Cl)C(F)(F)F)cc1Cl

Procedure:
1 g (3.07 mmol) of 2-[3,5-dichloro-4-(dimethylamino)phenyl]-4,4,4-trifluoro-3-oxobutanenitrile is initially charged in 1.44 ml of POCl3 (15.3 mmol), and 0.43 ml (3.07 mmol) of triethylamine are added slowly. The reaction mixture is then stirred under reflux for 5 hours. After cooling, water is added carefully and the mixture is extracted repeatedly with dichloromethane. The separated organic phases are combined, dried over magnesium sulphate, filtered and concentrated. The residue is used without further purification for the next step.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([OH:31])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:33][NH:34][O:35][CH3:36].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:34]([O:35][CH3:36])[CH3:33])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cc(Cl)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (8.6 g) was added to a solution of (2-benzyloxy-5-chlorophenyl)-acetic acid (10.6 g), N,O-dimethylhydroxylamine hydrochloride (4.4 g), 1-hydroxybenzotriazole (6.9 g) and N,N-diisopropylethylamine (20 ml) in DMF (150 ml) and the mixture stirred at RT for 16 h, then partitioned between ethylacetate and water. The organics were washed with 2M hydrochloric acid, water, dried, and evaporated under reduced pressure. Yield 12.2 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1C(=O)C2CCCC(=C2)[C:16]1=[O:25].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH2:34])([CH3:33])[CH3:32])=[CH:29][CH:28]=1.CN1[CH2:43][CH2:42][O:41]CC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:6]1[CH2:7][CH2:2][CH2:3][CH2:4][C:43]=1[C:42]([NH:34][C:31]([C:30]1[CH:29]=[CH:28][C:27]([Cl:26])=[CH:36][CH:35]=1)([CH3:33])[CH3:32])=[O:41]
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CN1CCOCC1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (0.900 g, 2.74 mmol), 4-chlorocumylamine (0.600 g, 3.54 mmol), N-methylmorpholine (0.300 g, 2.97 mmol), and benzene (15 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-chlorocumyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.404 g, 30.7% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH2:17]CC.O>CN(C)C=O>[CH2:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:12][CH2:16][CH3:17]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNc1ccc(C(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of N-(4-isopropylphenyl)acetamide (1.8 g) in dimethylformamide (18 mL) was added, under ice-cooling, 60% sodium hydride (0.44 g). Further, butyl bromide (1.4 mL) was added and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. 4N Hydrochloric acid (13 mL) was added to the residue and the mixture was refluxed for 7 hr. Water was added to the reaction mixture followed by neutralization and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure to give butyl(4-isopropylphenyl)amine (1.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C:19]1[S:20][CH:21]=[C:22]([Sn](CC)(CC)CC)[N:23]=1>>[CH3:18][C:19]1[S:20][CH:21]=[C:22]([C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[N:23]=1
Reactant: CC[Sn](CC)(CC)c1csc(C)n1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: Cc1nc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)cs1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 1 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 2-methyl-4-triethylstannyl-thiazole. The title compound was obtained as a colourless solid; m/e 314 (MH+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([P:24](=[O:29])([O:25][CH3:26])[O:27][CH3:28])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH3:13]
Reactant: COP(=O)(OC)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COP(=O)(OC)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)N

Procedure:
Dimethyl (1R)-1-[(N-benzyloxycarbonyl-L-alanyl-L-alanyl)amino]-ethylphosphonate was dissolved in methanol and catalytically hydrogenated in the presence of 10% palladium-on-charcoal. The solution was filtered and evaporated to give dimethyl (1R)-1-(L-alanyl-L-alanylamino)-ethylphosphonate in the form of an oil.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:10]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 30.9 %

Procedure:
A mixture of terephthalonitrile (1.50 g, 12 mmol), methyl thiosalicylate (2.95 g, 18 mmol), triethylamine (2.10 g, 21 mmol) and toluene (20 ml) was heated and refluxed under a nitrogen flow for 48 hours. The crystals precipitated were taken by filtration and recrystallized from tetrahydrofuran to give the title compound (0.98 g, 32%) as crystals.