Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=O)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(-c2ccc(C3CCNC3=O)cc2F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(-c2ccc(C3CCNC3)cc2F)n1
Temperature: -70 °C
Reaction time: 48 h

Procedure:
To a 25 mL round-bottomed flask equipped with N2 inlet were added 160 mg (0.59 mmol) 6-[2-fluoro-4-(2-oxo-pyrrolidin-3-yl)-phenyl]-pyridin-2-ylamine and 8 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 5.9 mL (5.9 mmol) of a 1.0 M solution was lithium aluminum hydride in tetrahydrofuran was added. The reaction was warmed to room temperature and stirred 2 days. The reaction was carefully quenched with dilute aqueous sodium hydroxide solution, then taken up in ethyl acetate and aqueous sodium hydroxide solution, and the combined organic layer washed with water, dried over sodium sulfate, and evaporated to afford a crude oil, which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]([CH3:19])([CH3:18])[CH2:4][C:5]1[N:9]([CH2:10][CH2:11][OH:12])[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=1)#[N:2].I[CH3:21].[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]([CH3:18])([CH3:19])[CH2:4][C:5]1[N:9]([CH2:10][CH2:11][O:12][CH3:21])[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=1)#[N:2]
Reactant: CCOC(=O)c1cc(CC(C)(C)C#N)n(CCO)n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CC(C)(C)C#N)n(CCOC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of ethyl 5-(2-cyano-2-methylpropyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate (6.12 g, 23.1 mmol) in THF (50 mL) was cooled to approximately 0° C. under nitrogen, and iodomethane (3.28 g, 23.1 mmol) was added. Sodium hydride (0.924 g of 60% in mineral oil, 23.1 mmol) was added in one portion. The mixture was allowed to warm to room temperature slowly and stirred overnight. Saturated aqueous ammonium chloride was added, and the mixture was extracted three times with tert-butyl methyl ether. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow oil. The oil was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with ethyl acetate) to provide 3.68 g of ethyl 5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)cc1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinoline-5(6H)-one was reacted with 4-methoxybenzoyl chloride according to the procedure of Part b) of Example 1 to give 7,7-dimethyl-1,2,3,4, 7,8-hexahydro-1-(4-methoxybenzoyl)-quinoline5(6H)-one (21) as a yellow waxy solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]2[CH:26]([NH2:29])[CH2:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]2[CH:26]([NH:29][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COCCOc1cccc2c1C(N)CO2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.04 g, 5.0 mmol) in 1-methyl-2-pyrrolidone (10 mL) with the above described rac-4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-ylamine (1.14 g, 5.5 mmol) and N-ethyldiisopropylamine (1.27 mL, 7.5 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as an orange solid (1.24 g, 65%); MS: m/e=382.3 (M+H−).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([CH2:23][CH3:24])[CH:14]=1.Br[CH2:26]C(O)=O.[OH-].[Na+]>O.O1CCOCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:26])(=[O:21])=[O:20])=[C:15]([CH2:23][CH3:24])[CH:14]=1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: O=C(O)CBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Br)ccc1S(C)(=O)=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a mixture of sodium sulfite (4.44 g, 35.3 mmol) and sodium bicarbonate (2.96 g, 35.3 mmol) in water (100 mL) at 70° C. was added 4-bromo-2-ethyl-benzenesulfonyl chloride (5 g, 17.6 mmol) in dioxane (20 mL) drop-wise via an addition funnel. After an hour, the mixture was heated at 100° C. and bromoacetic acid (4.90 mL, 35.3 mmol) was added. After an hour, the reaction mixture was cooled to 90° C., and sodium hydroxide (2.82 g, 70.5 mmol) was added. The resulting mixture was stirred at 90° C. overnight. After cooling to room temperature, water was added to the resulting suspension. The aqueous layer was extracted with dichloromethane (250 mL×3). The collected organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 4-bromo-2-ethyl-1-methanesulfonyl-benzene (4.62 g, 100%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 7.89 (d, J=8.5 Hz, 1 H), 7.56 (d, J=1.5 Hz, 1 H), 7.51 (dd, J=8.5, 1.5 Hz, 1 H), 3.07 (s, 3 H), 3.05 (q, J=7.4 Hz, 2 H), 1.33 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[CH3:15][Mg]Br.Cl>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2c(Cl)cccc2nc1Cl
Temperature: 0 °C

Procedure:
Dissolved 2,5-dichloroquinoline-3-carbaldehyde (2.46 g, 11 mmol) in THF (70 mL) and submerged in an ice-bath. Added methylmagnesium bromide (5.4 mL, 16 mmol) and removed the ice-bath. After 10 min. the reaction mixture was poured into 1.0 N HCl and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was chromatographed on 80 g silica gel column with 0-40% EtOAc:Hex. The desired fractions were combined and concentrated to yield an off white, crystalline solid. 1H NMR (400 MHz, DCM-d2) δ ppm 1.60 (d, J=6.26 Hz, 3 H) 2.35 (br. s., 1 H) 5.36 (q, J=6.39 Hz, 1 H) 7.61-7.67 (m, 2 H) 7.87-7.94 (m, 1 H) 8.75 (s, 1 H). LC-MS (+esi, M+H+=242.1).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:9]([CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[N:18]=CN(C)C)=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C.C(OC(=O)C)C>[CH3:25][C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([S:17](=[O:24])(=[O:23])[NH2:18])=[CH:15][CH:16]=2)=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 97.5 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Ethyl-3-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-4-methyl-5-morpholinothiophene-2-carboxylate (compound 24d, 0.36 g, 0.77 mmol) was suspended in ethanol (20 ml) and combined with 2N solution of NaOH (1.55 ml) at 25° C. The reaction mixture was heated at 95-100° C. under stirring for 1 hr. The progress of the reaction was monitored by TLC. The resulting reaction mixture was concentrated at a reduced pressure. The residue obtained was diluted with mixture of ethylacetate:water (30:15 ml). To this was added aqueous 10% HCl to bring the pH to between 5 and 6. The aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure from the dried organic layer to obtain the title compound (0.196 g, 66%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[I-].[Na+].[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CN
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CNCCN1CCCCC1
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 8.0 g of N-(2-chloroethyl)piperidine hydrochloride and 0.5 g of sodium iodide in 60 ml of methanol which contained 40% of methylamine was reacted at 70° C. in a sealed tube for 20 hours. After allowing the reaction mixture to cool down, the reaction mixture was concentrated under reduced pressure. The residue was added with ether, followed by a further addition of 10 g of ground sodium hydroxide. The resulting mixture was stirred for 2 hours. The insoluble material was filtered off and the filtrate was concentrated under the atmospheric pressure. The residue was distilled under reduced pressure to give 4.5 g of a fraction at 80° C./18 Torr (yield: 73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])[CH3:2].[NH:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1)[NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:17]([C:19]2[CH:24]=[N:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:18]=1)=[O:16])[CH3:2]
Reactant: COc1ccc(NN)cn1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Solvent: CCO
Product: CCOC(=O)C1=NN(c2ccc(OC)nc2)C(O)(c2ccccn2)C1

Procedure:
4-(2-Pyridyl)-2,4-dioxobutanoic acid ethyl ester (1.10 g) obtained from Referential Example 31 and 5-hydrazino-2-methoxypyridine (0.692 g) obtained from Referential Example 2 were dissolved in ethanol (22 mL). The resultant mixture was refluxed under heat for 14 hours, followed by cooling in air. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), followed by purification through silica gel column chromatography (toluene-acetone), to thereby give 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazole-3-carboxylic acid ethyl ester as a solid substance (0.575 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[N:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[N:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:33](=[O:36])[CH2:34][CH3:35])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: Cc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(N)cc3)n2)n1
Reactant: CCC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(-c2nc(SCc3cccc(C)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
The compound of Example 8 (170 mg) and triethylamine (0.2 mL) were added to 10 mL of acetonitrile, 0.12 g of propionyl chloride was added dropwise to the solution, and then the mixture was stirred at room temperature overnight. The resulting crystal was filtrated, washed with diethyl ether, and then dried under reduced pressure to give 85 mg of N-{4-[6-amino-5-cyano-2-(6-methylpyridin-2-ylmethylsulfanyl)-pyrimidin-4-yl]phenyl}propionamide as a white powder.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)nc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)nc1
Temperature: 50 °C
Yield: 21.2 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (84 mg, 0.23 mmol) and 10% palladium on activated carbon (50 mg) in methanol (150 mL) was heated at 50° C. under hydrogen (5 atm) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (18 mg, 21%): LC/MS m/e calcd for C20H23N3O2S [M+H]+ 370.49, observed 370.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (m, 2H), 1.47 (m, 2H), 1.61 (m, 3H), 1.77 (m, 2H), 2.25 (m, 2H), 3.08 (s, 3H), 4.44 (t, J=7.7 Hz, 1H), 6.44 (s, 1H), 7.11 (dd, J=4.9, 7.8 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.13 (dd, J=2.3 Hz, J=8.2 Hz, 1H), 8.27 (d, J=4.9 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H), 10.97 (br, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.O>[C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCOc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)O)cc1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
4-(9-Methoxycarbonylnonyloxy)benzoic acid tert-butyl ester (858 mg, 2.27 mmol) was dissolved in THF (5 ml), and 1N NaOH (2.27 mmol) was added. The mixture was stirred for 16 h. AcOEt (40 mL) and 1N HCl (2.38 ml) in water (25 ml) were added. The phases were separated, and the organic phase was dried over MgSO4, and concentrated under vacuum to yield a white solid (781 mg, 95% yield).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH2:21].CN1CCOCC1.Cl>[Cu].C(OCC)(=O)C.CN(C)C=O>[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH:21][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1I
Reactant: Nc1ccc(F)cc1F
Agent: [Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To N,N-dimethylformamide 15 mL solution of 2-iodo-4-phenoxybenzoic acid 1.5 g, were added 2,4-difluoroaniline 0.67 mL, copper powder 0.084 g and N-methylmorpholine 1.2 mL, and it was stirred at 100° C. for 5 hours. After the reaction mixture was cooled to room temperature,1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to give 2-(2,4-difluoroanilino)-4-phenoxybenzoic acid 0.60 g of white solid.
Reaction SMILES: N1C=CC=C2C(N)CCC=12.[CH2:11]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:22][CH3:23])=[CH:18][CH:19]=2)[C:14]1=[N:24]O)[CH3:12]>>[CH2:11]([C@H:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:22][CH3:23])=[CH:18][CH:19]=2)[C@H:14]1[NH2:24])[CH3:12]
Reactant: CCC1Cc2ccc(OC)cc2C1=NO
Agent: NC1CCc2ncccc21
Product: CC[C@H]1Cc2ccc(OC)cc2[C@H]1N

Procedure:
Following the procedure for the preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting 2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.03, 1.39, 2.30, 2.63, 2.86, 3.82, 4.26, 6.77, 7.12;
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]([OH:24])([C:18]([F:26])([F:25])[F:17])[C:10]1[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][C:9]=1[C:13]([F:15])([F:16])[F:14]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: O=c1cc(C(F)(F)F)[nH]n1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C(F)(F)F)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-phenyl-3-trifluoromethyl-5-pyrazolone (114 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (172 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][OH:15])[CH3:2]>C(Cl)(Cl)Cl.[Mn+4]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]=[O:15])[CH3:2]
Reactant: CCOC(=O)COc1cc(Cl)ccc1CO
Agent: [Mn+4]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
Ethyl-(2-hydroxymethyl-5-chloro-phenoxy)-acetate (2.44 g, 10 mmol) is dissolved in 40 ml of chloroform. Activated manganese (IV) oxyde (8.7 g, 100 mmol) is added in two portions and the resulting suspension is stirred at room temperature for 5 hours. After fitration on a pad of celite and concentration ethyl-(2-formyl-5-chloro-phenoxy)-acetate (2.18 g, 90% yield) is obtained as a pale yellow oil.
Reaction SMILES: [P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])([O:3]CC)=O.[C:12](Cl)(=[O:14])[CH3:13].C(Cl)C>>[C:12]([P:1](=[O:3])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])(=[O:14])[CH3:13]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC(=O)Cl
Agent: CCCl
Product: CCOP(=O)(OCC)C(C)=O
Yield: 97.7 %

Procedure:
166.2 grams (1 mole) triethyl phosphate was added dropwise with stirring to 78.4 grams (1 mole) of acetyl chloride over a period of 30 minutes at a temperature of 30° to 35° C. maintained by cooling. Ethyl chloride was evolved. The temperature was increased to 60° C. over the next 1 hour and 15 minutes, at which time the evolution of ethyl chloride was complete. The product was distilled under vaccum yielding 176 grams of diethyl acetylphosphonate (DEAP) in 98% yield, B.P. about 80° C. at 5 mm. and having a refractive index of 1.4240 at 200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][OH:26])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(5-methoxycarbonylpentyl)propanamide (507 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (483.5 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[C:23]2=[O:30])=[CH:18][C:17]=1[F:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([F:31])[CH:18]=2)[C:23]1=[O:30])=[O:28]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(F)c2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(Cl)c(F)c2)C1=O
Yield: 41.8 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(4-chloro-3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.115 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (42%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chloro-3-fluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([N:8]([S:16]([C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([S:26][CH2:27][CH3:28])[S:25][C:21]=2[CH:20]=1)(=[O:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.O>[CH3:7][CH:5]([CH3:6])[C@@H:4]([N:8]([S:16]([C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([S:26][CH2:27][CH3:28])[S:25][C:21]=2[CH:20]=1)(=[O:17])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([OH:31])=[O:2]
Reactant: CCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@@H](C(=O)OC)C(C)C)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@@H](C(=O)O)C(C)C)cc2s1

Procedure:
(2R)-3-methyl-2-[(ethylthio-6-benzthiazolsulfonyl) benzylamino]butanoic acid methylester (180 mg, 0.376 mmol) prepared in Example 26 was dissolved in THF/H2O (2 mL/2 mL), and LiOH (0.08 g, 5 equi.) was added. After reflux for 6 days, the reaction solution was distilled under reduced pressure and treated with 1N HCl, and ethylacetate (10 mL) was added to extract the product. The separated organic phase containing product was washed with NaCl solution, dried over MgSO4 and distilled under reduced pressure. The remaining material was purified on silica gel chromatography using ethylacetate/n-hexane (1/1) and ethylacetate/dichloromethane/acetate (1/1/trace amount) as solvent and dried under vacuum to prepare the titled compound, (2R)-3-methyl-2-[(ethylthio-6-benzthiazolsulfonyl)benzylamino]butanoic acid (0.1 g, 57%).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]CC)=[O:9])[C:3]=1[CH3:13]>Cl>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ncnc(O)c1C
Agent: Cl
Product: Cc1c(O)ncnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (27 mmol) ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate were dissolved in 20 mL concentrated hydrochloric acid and stirred overnight at RT. Then the reaction mixture was heated to 75° C. and stirred for 6 h. The reaction mixture was cooled to 5° C., suction filtered, washed with 2 mL concentrated hydrochloric acid and dried.