Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl[C:28]1[C:37]([CH3:38])=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:25][C:28]3[C:37]([CH3:38])=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: Cc1cc2ccccc2nc1Cl
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 12.2 %

Procedure:
Step 1C [Intermediate 3: 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (1.2 g, 3.2 mmol, 1.0 equiv.), 2-chloro-3-methyl quinoline (2.26 g, 12.7 mmol, 4 equiv.) were dissolved in DMF (30 mL) followed by the addition of NaH (382 mg, 60% in oil, 9.54 mmol, 3 equiv.). The mixture was stirred at 100° C. for 5 hrs, then at room temperature overnight. The reaction mixture was then poured into cold water, solid precipitated from the mixture was collected by filtration and washed with water. Regular column chromatography (Silica gel, 1% MeOH/CH2Cl2) to yield 203 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 12% yield.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:16][CH2:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]O.N1(C2C=CN=CC=2)CCCC1>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:16][CH2:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O:23][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[O:22]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3ccccc3C(=O)O)c2n1
Reactant: CN(C)CCCO
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3ccccc3C(=O)OCCCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 2-9 step (iii) (50 mg) was dissolved in dichloromethane (5 ml), and thereto were added 3-(dimethylamino)propane-1-ol (0.016 ml), 4-pyrrolidin-1-ylpyridine (2 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide iodine methyl (42 mg). The mixture was stirred at room temperature for 96 hours and applied to a cartridge of SCX resin. The resin was washed with acetonitrile and the fractions were collected by application of 10% aqueous ammonium solution-acetonitrile, and purified by RPHPLC to give the titled compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])[CH3:6].NC1C([N+]([O-])=O)=C(C)C([N+]([O-])=O)=CC=1C#N>>[C:5]([NH:8][C:9]1[C:10]([N+:1]([O-:4])=[O:2])=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1C
Reactant: O=[N+]([O-])O
Agent: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Product: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (100 mL, 2.4 mol) is cooled to about 0° C. (ice/acetone/water bath) and 3-(Acetylamino)-4-methylbenzoic Acid (14) (24.567 g, 127.2 mmol) is added in small portions over about 30 minutes, at rate to maintain the internal reaction temperature <5° C. The hetereogeneous reaction mixture is then stirred at about 0° C. for an additional 1 hour. The reaction mixture is then added to ice water (300 mL) and stirred for about 1 hour. The solid obtained is filtered and dried to provide a mixture of 3-N-acetyl-4-methyl-2-nitro benzoic acid (5) and 3-N-acetyl-4-methyl-5-nitro benzoic acid, in ratio of about 78:22 (27.79 g, 92% Combined Yield). A portion of this mixture (23.458 g) is recrystallized from acetic acid (300 mL) to give 3-(Acetylamino)-4-methyl-2-nitrobenzoic Acid (15), as a white solid (15.370 g, 51% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1CCC(=O)C1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-oxocyclopentane-1-carboxylic acid (1.0 g, 7.80 mmol, 1.00 equiv), potassium carbonate (1.62 g, 11.72 mmol, 1.50 equiv), Acetone (20 mL). This was followed by the addition of iodomethane (11.1 g, 78.20 mmol, 10.02 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction progress was monitored by GCMS. The solids were collected by filtration. The filtrate was concentrate. The resulting mixture was diluted with 10 mL of H2O. The resulting solution was extracted with 3×10 mL of ether and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in 1.0 g (crude) of methyl 3-oxocyclopentane-1-carboxylate as yellow oil. The crude could be used for the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[C:22]([CH3:26])[NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[C:22]([CH3:26])[C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)nc2c1C#N
Yield: 68.5 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (243 mg, 69%). MS (ISP) 355.0 [(M+H)+]; mp 196° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N=C=NC2CCCCC2)CCCCC1.[F:38][C:39]1[C:44](O)=[C:43]([F:46])[C:42]([F:47])=[C:41]([F:48])[C:40]=1[F:49]>C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][C:44]1[C:43]([F:46])=[C:42]([F:47])[C:41]([F:48])=[C:40]([F:49])[C:39]=1[F:38])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.3 %

Procedure:
To a suspension of 6-octyloxy-2-naphthoic acid (3.15 g, 10.5 mmol) and dicyclohexylcarbodiimide in ethyl acetate (25 ml) at 0° C. was added pentafluorophenol (2.12 g, 11.5 mmol). The mixture was stirred at 25° C. for a period of 18 h. The precipitate was removed by s filtration. The filtrate was washed with water (2×150 ml) and brine and dried with magnesium sulfate. Removal of the ethyl acetate in vacuo gave 5.4 g of pentafluorphenyl 6-octyloxy-2-naphthoate as a solid: 1H NMR (400 MHz, CH3OD) δ 0.88 (t, 3, J=6.9 Hz), 4.10 (t, 2, J=6.6 Hz), 7.16 (d, 1), 7.21 (d, 1), 7.80 (d, 1), 7.87 (d,1), 8.08 (dd, 1), 8.69 (d, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3COC3)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC3COC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(oxetan-3-yl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 7% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=484.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:29])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[O:29]=[C:7]([CH2:8][S:9][C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: NCCCCCC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCNC(=O)Nc1ccccc1)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 7-amino-1-tritylsulfanyl-heptan-2-one (0.36 g, 0.86 mmol) in dichloromethane (10 mL) was added phenylisocyanate (0.10 mL, 0.92 mmol). The mixture was stirred at room temperature for 2 h. Solvent was then removed in vacuo and the crude product was purified by column chromatography (dichloromethane/MeOH=100/1 to 40/1) to provide 1-(6-Oxo-7-tritylsulfanyl-heptyl)-3-phenyl-urea (0.43 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[Cl:18][C:19]1[CH:23]=[N:22][N:21]([CH3:24])[C:20]=1[NH2:25]>>[Cl:18][C:19]1[CH:23]=[N:22][N:21]([CH3:24])[C:20]=1[NH:25][C:15]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]2[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=12)=[O:17]
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Reactant: Cn1ncc(Cl)c1N
Product: COCc1cc2c(C(=O)Nc3c(Cl)cnn3C)ccc(OC)c2o1

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.14 g) and 4-chloro-2-methyl-2H-pyrazol-3-ylamine (78 mg). Purification by column chromatography on silica eluting with 50%-75% ethyl acetate in hexane afforded the title compound as an off white solid (34 mg).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:10]([OH:13])[CH:11]=[CH2:12])=O)(C)(C)C.[H-].[Na+].CCCCCC>CN(C)C=O>[CH:15]1([CH2:14][C@H:9]2[CH:10]([CH:11]=[CH2:12])[O:13][C:6](=[O:5])[NH:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CC1OC(=O)N[C@H]1CC1CCCCC1
Reaction time: 3 h

Procedure:
The resultant product of Example 118 (2.80 g, 9.88 mmol) in dry dimethylformamide (DMF) (50 ml) was added to a stirred suspension of NaH (593 mg of a 60% dispersion in oil, 14.8 mmol, hexane washed) in dry DMF (50 ml). After 3 h, the mixture was quenched (750 ml water+100 m brine) and extracted with ether (5×100 ml). The combined organic phase was washed with brine (3×50 ml), dried (MgSO4), filtered and evaporated to an oil (2.33 g). The NMR spectrum of the crude product revealed an 82:18 mixture of 5S:5R diastereomers. Silica gel chromatography gave 80% recovery of pure diastereomers. 5S:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:46]=[CH:47][CH:48]=4)[C:28]([NH:30][CH2:31][CH2:32][C:33]4[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41]CC)=[O:40])=[CH:35][CH:34]=4)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:50]>CO.O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:46]=[CH:47][CH:48]=4)[C:28]([NH:30][CH2:31][CH2:32][C:33]4[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O-:41])=[O:40])=[CH:35][CH:34]=4)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:50]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cccc(CC3CCCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])COc1ccc(CCNC(=O)c2cccc(CC3CCCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of ethyl (±)-4-{2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}ethyl}phenoxyacetate (115 mg, 0.18 mmol) in MeOH-1,4-dioxane (1:1, 4 ml) was added 1N sodium hydroxide solution (0.18 ml, 0.18 mmol) at 5° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated and Et2O was added thereto. The resulting solid was collected by filtration to give sodium (±)-4-{2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}ethyl}phenoxyacetate (105.0 mg, 92%).
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1.[CH3:11]SC>>[CH3:11][CH:2]1[CH:3]([C:8]([OH:10])=[O:9])[C:4](=[O:7])[CH2:5][CH2:6][S:1]1
Reactant: O=C(O)C1CSC=CC1=O
Reactant: CSC
Product: CC1SCCC(=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of methyl cuprate in dimethylsulfide (prepared from 1.05 g copper (I) iodide/4.0 mL dimethylsulfide and 4.0 mL methyllithium/ether at -78° C.) at -78° C. was added a solution of 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.910 g, 4.6 mmol) in dimethylsulfide (5 mL). The resulting yellow-colored solution was stirred for 30 min. at the same temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride and ammonia solution and then warmed to room temperature for and 1 h. The reaction mixture was added to ether (100 mL) and the etheral layer washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the product purified by flash column chromatography on silica gel eluted with hexane:ether (4:1) to give 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.794 g) as a 7:3 mixture of enol:keto tautomers.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([N:16]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])[C:13]2[C:8](=[CH:9][C:10]([O:38][CH3:39])=[C:11]([O:36][CH3:37])[CH:12]=2)[N:7]1[C:40](OC(CC)C)=[O:41])=O)C.[BH4-].[Na+].O>CO>[CH3:20][O:19][C:17](=[O:18])[N:16]([CH2:21][C:22]1[CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH:14]1[C:13]2[C:8](=[CH:9][C:10]([O:38][CH3:39])=[C:11]([O:36][CH3:37])[CH:12]=2)[N:7]2[C:40](=[O:41])[O:3][CH2:4][CH:6]2[CH2:15]1
Reactant: CCOC(=O)[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC2COC(=O)N2c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of cis 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 5) (100 mg, 0.15 mmol) in 8.5 mL methanol at 0° C. was added sodium borohydride (57 mg, 1.5 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using 80% ethyl acetate/hexanes to afford the title product (70 mg). 1H NMR (CDCl3) δ 1.8 (br, 1H), 2.4 (br, 1H), 3.6 (s, 3H), 6.5 (br, 1H), 7.6 (br, 2H), 7.9 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]([OH:11])=O)[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:35][N:36]([C@H:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][CH2:51]1)[C:37]([C:39]1[N:40]=[C:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[S:42][CH:43]=1)=[O:38].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]([N:47]2[CH2:48][CH2:49][CH:44]([C:41]3[S:42][CH:43]=[C:39]([C:37]([N:36]([CH3:35])[C@H:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH2:53][CH2:52][CH2:51]4)=[O:38])[N:40]=3)[CH2:45][CH2:46]2)=[O:11])[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (170 mg, 0.76 mmol) (i.e. the product of Example 16, Step C) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6 Step C) (219 mg, 0.56 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by silica gel MPLC using ethyl acetate/hexanes as eluant to give 200 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][O:19][C:20]([CH3:22])=[O:21].[C:25](O)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40]CC>C1(C)C=CC=CC=1>[CH3:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:22][C:20]([O:19][CH2:18]/[CH:17]=[C:16](\[CH:15]=[CH:14]\[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:24])/[CH3:23])=[O:21]
Reactant: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC/C=C(C)\C=C\C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 6 h

Procedure:
Retinyl acetate (22.0 g; 80% in oil; 53.6 mmol) and linoleic acid (Pamolyn 200; 15.0 g; 53.6 mmol; 1.0 equiv) were dissolved in 160 mL of toluene in a 500 mL flask. A dip tube in the flask was connected through a peristaltic pump to a column containing 6.0 g of Novozyme 435 which was connected in sequence to a second column containing 6.0 g of dried Amberlyst A-21. A tube from this second column returned to the original flask. The pump was started (flow rate 6 mL/min) sending the reaction mixture through the two columns and then back to the pot. After 6 h conversion had reached 71%, and the pump was stopped and the Amberlyst resin was regenerated by removing the column and washing the contents with 100 mL of 10% triethylamine in toluene (with 100 mL of toluene chaser). The apparatus was reassembled and the pump re-started. After 3 more hours conversion had reached 75% and the pump was stopped. Approximately 50% of the contents of the pot (80 mL) was removed and a mixture of 11.0 g of 80% retinyl acetate and 7.5 g of linoleic acid in 80 mL of toluene was added to the pot to serve as a first reactant replenishment. The Amberlyst resin was regenerated as above, the apparatus reassembled, and the pump started. After 9 h 73.6% conversion had been achieved and the pump was stopped. Approximately 50% of the contents of the pot (80 mL) was removed and a mixture of 11.0 g of 80% retinyl acetate and 7.5 g of linoleic acid in 80 mL of toluene was added to the pot to serve as a second replenishment. The Amberlyst resin was regenerated as above, the apparatus reassembled, and the pump started. After 12 h 75.0% conversion had been achieved and the reaction was stopped.
Reaction SMILES: [C:1]1([C:7](=[O:11])[C@H:8](O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46]>C(Cl)Cl>[C:1]1([C@:7]2([OH:11])[O:46][CH2:45][C:44]([CH3:48])([CH3:47])[NH:43][C@H:8]2[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](O)C(=O)c1ccccc1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccccc1
Yield: 68.3 %

Procedure:
Compound 4b was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-phenyl-2-hydroxypropan-1-one (10b, 3.49 g, 0.0233 mol), Proton sponge (5.9 g), triflic anhydride (4.2 mL, 26 mmol), and 2-amino-2-methyl-1-propanol (4.6 g, 0.052 mol) in CH2Cl2 (50 mL). After purification by chromatography on silica gel, 3.52 g (68%) of the free base 4b was isolated, and converted to 1.19 g of the hemi-D-tartrate salt, which had >99% ee: mp 112-113° C.; [α]20D +15.8° (c 1.1, CH3OH); 1H NMR (methanol-d4) δ 7.61-7.59 (m, 2H), 7.44-7.36 (m, 3H), 4.32 (s, 1H), 4.24 (d, 1H, J=12.3 Hz), 3.58-3.48 (m, 2H), 1.64 (s, 3H), 1.39 (s, 3H), 1.09 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 179.1, 142.4, 130.3, 129.6 (2C), 127.9 (2C), 97.3, 75.4, 67.4, 55.47, 55.27, 24.1, 21.3, 14.3; LCMS (ESI) m/z 222.4 (M-tartrate)+; Anal. (C15H22NO5.0.5H2O) calcd: C, 59.00; H, 7.59; N, 4.59. found: C, 58.77; H, 7.46; N, 4.64.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17]O.BrC1C(C)=CC(C)=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O1CCCC1>[C:1]1([CH:7]2[CH2:8][C:9]3[NH:15][CH:16]=[CH:17][C:10]=3[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: NCCO
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 0.7 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (15.0 g), 2-aminoethanol (6.3 g), molecular sieves 4A (100 g) and tetrahydrofuran (200 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated to give oil, which was dissolved in dimethylformamide (5 ml). To the solution were added 2-bromomesitylene (0.20 g), tetrakistriphenylphosphine palladium (30 mg) and potassium carbonate (0.28 g), and the mixture was stirred at 150° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g).