Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:20][CH:21]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)cc2)CC1
Reactant: ON=C1CCCCC1
Product: Clc1ccc(C2=CCN(CCCc3onc4c3CCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as m Example 48 using cyclohexanone oxime and ethyl 4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazole is obtained.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[N:29]=[CH:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:32]([C:30]5[N:29]=[CH:28][N:27]([CH3:26])[CH:31]=5)(=[O:34])=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Product: Cn1cnc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)c1

Procedure:
The title compound, white solid (19.5 mg, 45.3%), MS (ISP) m/z=475.1 [(M+H)+], was prepared in accordance with the general method of example 69 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine (intermediate A) (30 mg, 90.8 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:22]3[CH:35]=[CH:34][C:25]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:24]([CH3:36])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:37]=1)C1C=CC=CC=1>[Pd]>[CH2:18]([C:17]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31])=[C:24]([CH3:36])[CH:23]=1)([C:15]1[O:16][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:37][C:13]=2[CH:14]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Agent: [Pd]
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2o1
Yield: 95.3 %

Procedure:
1-{4-[1-(5-Benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (3.20 g, 6.42 mmol) and Pd—C (0.20 g) are reacted under hydrogen analogous to Example 18-F to give the title compound (2.50 g, 95%).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate (0.10 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.020 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 0.063 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])(=[O:21])=[O:20])=[O:24])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1cc(N)nc(OC)n1
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1cc(NC(=O)NS(=O)(=O)c2ccccc2C)nc(OC)n1
Reaction time: 0.67 h

Procedure:
To a stirred mixture of 2.40 g of 4-amino-2,6-dimethoxypyrimidine in 40 ml methylene chloride at ambient temperature and pressure was slowly added 3.0 g of 2-methylbenzenesulfonylisocyanate. The reaction was stirred 40 minutes, filtered, and the solid thereby obtained was washed with a small amount of acetonitrile; yield 4.0 g, m.p. 174°-175°, NMR (DMSO-d6) relative to tetramethylsilane: δ 2.77, S, area 30; δ 4.05, S, area 60; δ 6.85, S, area 89; δ 7.7-8.6, multiplets, area 45; δ 10.00, S, area 9.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.Cl[CH2:18][CH2:19][CH:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:22]([CH2:21][CH:20]([OH:29])[CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10][CH2:11]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)COc1ccccc1
Yield: 65.9 %

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 3.5 g (0.015 mole) of N-(α, α, αtrifluoro-m-tolyl)piperazine, 3.0 g (0.015 mole) of 4-chloro1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.9 g (66%) of white powder, m.p. 83°-84° C. The recrystallizing solvent used in isopropyl alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[C@H:44]12[CH2:50][C@H:47]([NH:48][CH2:49]1)[CH2:46][O:45]2>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:48]3[CH2:49][C@@H:44]5[CH2:50][C@H:47]3[CH2:46][O:45]5)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3C[C@@H]4C[C@H]3CO4)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-methoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene, diisopropylethylamine and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. LCMS (Method F): 552 (M+H)+, Retention time 4.7 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][N:9]([CH3:11])[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C>O1CCCC1>[CH3:11][N:9]1[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([C:12]([F:13])([F:14])[F:15])=[N:8]1
Reactant: CCOC(=O)c1cn(C)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cn1cc(CO)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 123.4 %

Procedure:
To a cooled solution (0° C.) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, 4.5 mmol) in anhydrous tetrahydrofuran (50 ml), is added a solution of DIBAL-H (20.3 ml, 20.3 mmol). The reaction mixture is stirred at 0° C. for 2 hours and then quenched with saturated aqueous sodium potassium tartrate and stirred for 1 hr. The layers are separated and the aqueous layer is extracted 2 times with ethyl acetate. The combined organic extracts are dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-methyl-3-trifluoromethyl-1H-pyrazol-4-methanol (1.0 g, 98%) which is used without purification. 1H NMR (CDCl3): δ=7.43 (1H, s), 4.63 (2H, s), 3.90 (3H, s), 2.38 (1H, brs).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[NH3+:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.O.C(OC)(C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][C:16]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:22])[NH:23][C:29]2=[O:30])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]c1cccc(Cl)c1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cccc(Cl)c2CN1C1CCN(Cc2ccccc2)CC1
Yield: 36.6 %

Procedure:
16 g 2-((1-benzyl-piperidin-4-ylamino)-methyl)-3-chloro-phenyl-ammonium and 8.2 g CDI in 150 mL DMF were stirred for 3 h at 60° C. Water and tert.-butyl-methyl-ether were added. The precipitate was filtered to give 6.3 g of the desired product. (M+H)+: 356
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=[O:11])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8].[C:13](OC)(=O)C(C)=C.FC(F)=C(F)Cl>C1(C=CC(O)=CC=1)O>[CH3:1][C:2]1([C:10]([O:12][CH3:13])=[O:11])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8]
Reactant: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Reactant: C=C(C)C(=O)OC
Agent: FC(F)=C(F)Cl
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1(C)CC(F)(F)C1(F)Cl
Temperature: 140 °C
Yield: 54 %

Procedure:
One drop of dimethylformamide is added to a mixture 91.2 g (0.45 mol) of 1-methyl-2,3,3-trifluoro-2-chloro-cyclobutane-1-carboxylic acid and 450 ml of chloroform. After this, 80.3 g (0.675 mol) of thionyl chloride are added dropwise at 25°-30° C. with stirring, and the stirred mixture is heated to the boil. After 6 hours the mixture is cooled, the solvent is stripped off, and the residue is subjected to fractional distillation under reduced pressure. 75 g (75% of theory) of 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carbonyl chloride are obtained in form of a liquid of boiling point 65 - 70° C. at 20 mbar. ##STR61## 108.3 g (0.5 mol) of methyl 1-methyl-2-th(oro-2,3,3-trifluoro-cyclobutane-1-carboxylate are added dropwise at 20°-25° C. in the course of 15 minutes to a stirred solution of 127.3 g of potassium hydroxide in 540 ml of methanol. Stirring is continued for 12 hours at 20°-25° C., and part of the methanol is then stripped off under reduced pressure. The residue is diluted with water, and the mixture is extracted using methylene chloride. The aqueous phase is acidified using dilute hydrochloric acid and extracted using methylene chloride. The combined organic phases are dried and concentrated under reduced pressure. 93.3 g of an oil are obtained which consists of 99% 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carboxylic acid. The yield is thus calculated at 90% of theory. 174 g (1.74 mol) of methyl methacrylate and 1.5 g o& hydroquinone are initially introduced into an autoclave, and 200 g (1.74 mol) of trifluorochloroethylene are added at -70° C. 7 bar of nitrogen are injected, and the mixture is then heated to 140° C. The pressure which is established at this temperature is increased to 28 bar by injecting more nitrogen. The mixture is maintained at 140° C. for 17 hours and then allowed to cool, the pressure is released, and the mixture is distilled. In this process, 203 g (54% of theory) of methyl 1-methyl-2-chloro-2,3,3 -trifluoro-cyclobutane-1-carboxylate are obtained in form of a liquid of boiling point 57° C. at 17 mbar.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:34]([OH:36])=O)[CH:27]=[N:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32].O[NH:38][C:39](=[NH:58])[C:40]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:41]=1[CH:42]=[CH:43][N:44]=[C:45]2[CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([C:34]2[O:36][N:58]=[C:39]([C:40]3[CH:49]=[CH:48][CH:47]=[C:46]4[C:41]=3[CH:42]=[CH:43][N:44]=[C:45]4[CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:38]=2)[CH:27]=[N:28][C:29]=1[O:30][CH:31]([CH3:32])[CH3:33]
Reactant: CCOC(=O)CCCc1nccc2c(C(=N)NO)cccc12
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1nccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 0.77 g) and hydroxybenzotriazole (HOBt; 0.54 g) were added sequentially to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (WO 2008128951; 0.43 g) in THF (20 mL) at room temperature and the resulting solution was stirred for 30 minutes. Ethyl 4-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}butanoate (D43; 0.6 g) was added and the resulting suspension was stirred at room temperature for 1 hour. Tetra-n-butylammonium fluoride (TBAF; 1.57 g) was added to the reaction mixture and the resulting solution was heated to reflux for overnight. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The organic phase was washed with water and brine, then dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (0.36 g). δH (CDCl3, 400 MHz): 1.29 (3H, t), 1.47 (6H, d), 2.25 (2H, m), 2.54 (2H, m), 3.50 (2H, m), 4.18 (2H, q), 5.52 (1H, m), 7.81 (1H, dd), 8.45 (1H, d), 8.53 (1H, d), 8.61 (2H, m), 8.79 (1H, d), 8.94 (1H, d). MS (ES): C25H25ClN4O4 requires 480. found 481.2 (M+H+).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[CH:7]=[C:6]([N:15]([C:17]2[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)[CH3:16])[N:5]=1>C(O)C>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[CH:7]=[C:6]([N:15]([C:17]2[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH3:16])[N:5]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)O
Reaction time: 12 h

Procedure:
A slight excess of ethanolic potassium hydroxide was added to a solution of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate in ethanol at room temperature. The mixture was stirred for 12 hrs, then evaporated. The residue was diluted with water, acidified with dilute hydrochloric acid and extracted with dichloromethane. The dichloromethane extract was dried over sodium sulfate and then evaporated to give 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid as a yellow solid, mp 136° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:15][C@@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:16]([NH:15][C:11]([C:9]2[NH:10][C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=3[CH:8]=2)=[O:13])[C:17]([N:19]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]2)=[O:18])=[CH:27][CH:28]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Reactant: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1)c1cc2cnc(Cl)cc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 295 from 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation 116) and 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-one hydrochloride (Preparation 103). The crude product was recrystallised from ethyl acetate to give the title compound. δH (CD3OD): 1.77-1.98 (2H, m), 3.08-3.88 (6H, 6m), 4.30, 4.42 (1H, 2m), 5.07, 5.09 (1H, 2m), 7.00 (2H, m), 7.30 (3H, m), 7.43 (1H, m), 8.67 (1H, s); m/z (ES+)=430.90 [M+H]+; RT=3.29 min.
Reaction SMILES: [C:1]([C:5]([Li])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C(=Cc1ccccc1)C(C)(C)C
Solvent: CO
Product: CC(C)(C)C=Cc1ccccc1
Yield: 95 %

Procedure:
To a dry, two-necked, 1-liter, round-bottomed flask were added 500 ml of dry cyclohexane under an inert argon atmosphere. The cyclohexane was then titrated for proton donating impurities, e.g., water, alcohol, etc., by the addition of 5×10-5 moles of 1,1-diphenylethylene. Sec-butyl lithium initiator (1.4M in hexane) was slowly added dropwise until a permanent faint yellow color became evident and this solution was stirred for one hour. The solution was then back-titrated with cyclohexane containing a trace amount of water until the yellow color disappeared. Under an inert argon atmosphere, 47.6 mls additional sec-butyl lithium initiator (1.4M in hexane) were then added to the flask. A water bath was placed under the flask and 114.9 g of dry t-butyl styrene were added to the flask. Polymerization began as evidenced by a reaction exotherm and the solution becoming bright red-orange in color due to carbanion formation. The reaction temperature rose to 60° C. and was held at 60° C for one hour to produce a deep red t-butyl styrene polymer solution. A 10-percent molar excess of methanol based on the sec-butyl lithium concentration used for polymerization was added to the solution and allowed to react to convert the t-butyl styryl lithium end groups at the terminal portions of the polymer chains to hydrogen atoms. The t-butyl styrene polymer was isolated by precipitation in methanol, washed with water, and vacuum dried to give a 95% yield of a dry, white, powdery solid having a number average molecular weight of 1200, a polydispersity index of 1.11, and a glass transition temperature of 65° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[NH:4][C:3]1=[O:17]>C(O)(=O)C.[Pt](Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:5]([CH3:16])[NH:4][C:3]1=[O:17]
Reactant: COc1ccc(C2=C(C)NC(=O)C(C)C2)cc1
Agent: Cl[Pt]Cl
Solvent: CC(=O)O
Product: COc1ccc(C2CC(C)C(=O)NC2C)cc1
Reaction time: 8 h
Yield: 38.2 %

Procedure:
1 g of platinum chloride was added to a solution of 15 g (65 mmol) of 3,6-dimethyl-5-(4-methoxyphenyl)-3,4-dihydro-2-pyridone (Synthesis 305, 1985) in 75 ml of glacial acetic acid and the mixture was hydrogenated at room temperature and a pressure of 52 psi for 8 hours. The catalyst was then removed by filtration and the glacial acetic acid was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with ammonia (5%), water and a saline solution. The organic layer was dried on sodium sulphate, filtered and evaporated under reduced pressure. The resulting crude product (15 g) was purified chromatographically over a dry column of 700 g of silcagel (Merck, grain size 0.063-0.200 mm) using a mixture of dichloromethane and acetone (95:5) as an eluent. After evaporating the correct fractions, 5.8 g (38%) of the desired 3,6-dimethyl-5-(4-methoxyphenyl)-3,4,5,6-tetrahydro-2-pyridone were obtained in addition to 3.5 g (23%) of the starting compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[NH2:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14](C1C=CC=CC=1)=O.[OH-].[Na+]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[CH:14][C:13]3[C:12](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc(-c2ccc3ccccc3n2)cc1
Yield: 78.3 %

Procedure:
Dissolving 5.0 g (25 mmol) of 4-bromoacetophenone and 5.0 g (25 mmol) of 2-aminobenzophenon into 50 milliliter of ethanol, adding 3.1 g of sodium hydroxide, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 5.56 g of 2-(4-bromo-phenyl)-quinoline (yield: 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[CH:22](N1CCOCC1)=[O:23].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:22]=[O:23]
Reactant: Brc1cccnc1
Reactant: O=CN1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=Cc1ccncc1Br
Reaction time: 0.08 h
Yield: 40 %

Procedure:
3-Bromopyridine (1.582 g) was dissolved in tetrahydrofuran (20 ml), followed by the addition of a 1.5M solution of lithium diisopropylamide/cyclohexane (7.3 ml) in nitrogen atmosphere at −70° C., and the resulting mixture was stirred for 5 min. Continuously, 4-formylmorpholine (3 ml) was added thereto and stirred for 20 min, followed by the further stirring at room temperature for 30 min. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless solid (749 mg, yield; 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])=[CH:5][CH:4]=1.[NH2:28]/[C:29](/[CH3:37])=[CH:30]\[C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[O:23][C:22]([CH3:25])=[CH:21][C:20]4=[O:26])[C:30]([C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32])=[C:29]([CH3:37])[NH:28][C:11]=2[CH3:12])=[O:27])=[CH:7][CH:8]=1
Reactant: CCCOC(=O)/C=C(/C)N
Reactant: COc1ccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)cc1
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(OC)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
230 mg (0.63 mmol) of 1-(4-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 90 mg (0.63 mmol) of n-propyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 74 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([S:13]([CH3:16])(=[O:15])=[O:14])[C:4]=1[OH:17])=[O:2].[Mn]([O-])(=O)(=O)=[O:19].[K+].Cl.[O-]S([O-])=O.[Na+].[Na+]>[OH-].[Na+]>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([S:13]([CH3:16])(=[O:15])=[O:14])[C:4]=1[OH:17])([OH:19])=[O:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1cc(C(=O)O)c(O)c(S(C)(=O)=O)c1

Procedure:
2.56 g (0.01 mol) of 2-formyl-4-(1,1-dimethylethyl)-6-methylsulfonylphenol are introduced into a solution of 1.58 g (0.01 mol) of potassium permanganate in 50 ml of 2N sodium hydroxide solution, and the mixture is heated on a steam bath for 30 minutes. The cooled solution is then adjusted to pH 2 with 2N hydrochloric acid and decolorized with concentrated Na2SO3 solution. The mixture is extracted three times with ethyl acetate, which is evaporated in vacuo and the residue is recrystallized from acetonitrile.