Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[NH:16][CH2:17][CH2:18][CH3:19].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([NH:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:20])=[O:2])[CH2:18][CH3:19]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 85.9 %

Procedure:
3-(2-Propylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (67.3 mg, 0.234 mmol) was reacted with aqueous 1N LiOH solution (5 ml) in THF/CH3OH (10 ml/5 ml) for 1 hr. The reaction solvent removed in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1N HCl solution, an then extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield title compound (55 mg, 0.201 mmol, 86%).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]2=[O:13])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(OC)(O[C:24](SC)([S:27][CH3:28])[S:25][CH3:26])(=O)=O>O1CCOCC1>[CH3:26][S:25][C:24]([S:27][CH3:28])=[C:8]1[C:9](=[O:12])[CH:10]=[CH:11][N:6]([CH2:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:7]1=[O:13]
Reactant: O=c1cc(O)ccn1CC1CCC1
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)C=CN(CC2CCC2)C1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A solution of the product of Example 468B (0.244 g, 1.36 mmol) and pyridine (0.88 mL, 10.89 mmol) in dioxane (6 mL) was treated with excess tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi), stirred at 90° C. for 1.5 hours, and cooled to about 25° C. The reaction solution was decanted from the resulting solids and the solvent was removed under a stream of warm nitrogen. The residue was dissolved in hexanes and loaded onto a 2 g Alltech Seppack and eluted with hexanes followed by dichloromethane followed by 25% ethyl acetate in dichloromethane to provide the title compound (0.192 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].[C:14](Cl)(=O)[CH3:15].[Cl-].[NH4+]>C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Br:12][C:7]1[C:8]([F:11])=[C:9]2[O:10][C:14]([CH3:15])=[N:1][C:2]2=[C:3]([C:4]#[N:5])[C:6]=1[CH3:13]
Reactant: CC(=O)Cl
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
Diisopropylethylamine (22 ml, 0.126 mmol) was added to an ethyl acetate (400 ml) solution of 2-amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (8.85 g, 36.1 mmol), cooled with ice, then acetyl chloride (3.85 ml, 54.2 mmol) was dropwise added, followed by stirring as such for 14 hours with gradually heating up to room temperature. With cooling with ice, aqueous saturated ammonium chloride solution was added, and the organic layer was collected. This was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was suspended in toluene (500 ml), a catalytic amount of p-toluenesulfonic acid was added, followed by heating under reflux for 3 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, the resulting residue was dissolved in ethyl acetate, washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, the precipitated crystal was washed with isopropyl ether, then collected by filtration to obtain the entitled compound (7.07 g, 73%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([I:12])[C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:10]([I:12])[CH:11]=1
Reactant: COC(=O)c1cnc(Br)cc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1cnc(Br)cc1I
Reaction time: 0.5 h
Yield: 137 %

Procedure:
To a solution of methyl 6-bromo-4-iodonicotinate (500 mg, 1.0 mmol) in methylene chloride (6 mL) cooled at 0° C. was added a 1.0M solution of diisobutylaluminum hydride in tetrahydrofuran (5.85 mL) dropwise over 5 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then quenched by dropwise addition of a 1.0M solution of citric acid in water (1 mL). The reaction mixture was diluted with dichloromethane (20 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a white solid (430 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:29][CH3:30])=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C)C=O.CC(O)=O.O.C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:29][CH3:30])=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCBr
Reactant: CCc1c(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)cccc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)cccc1C1CCN(CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a solution of 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]piperidine (D122) (108 mg, 0.244 mmol) and ethyl 4-bromobutanoate (95 mg, 0.489 mmol) in N,N-Dimethylformamide (DMF) (8 mL) was added K2CO3 (223 mg, 1.614 mmol). This solution was sealed and stirred for overnight at room temperature. To the above solution was added Isopropanol (10.00 mL) and Water (2 mL) and sodium hydroxide (0.5 mL, 3.05 mmol). The solution was sealed and stirred for 5 h at 40° C. The reaction was neutrolized by AcOH, dried and purified by Mass Directed AutoPrep to afford 4-{4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]-1-piperidinyl}butanoic acid (E102) (62 mg) as a TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:25][O:24][C:20](=[O:23])[CH2:21][O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: COC(=O)CO
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (prepared as in Example 1, 150 mg, 0.535 mmol) in THF (2 mL) was added methyl glycolate (82.5 μL, 1.07 mmol) followed by DBU (160 μL, 1.07 mmol). The reaction was stirred for 5 h, diluted with 3/6/1 ethyl acetate/hexane/dichloromethane, and passed through a plug of SiO2 using 4/5/1 ethyl acetate/hexane/dichloromethane. The filtrate was concentrated, and the resulting solids triturated with dichloromethane/hexane to afford 95.1 mg (58% yield) of the titled ester as a white solid. ESI-MS m/z 306 (MH+), 304 (M−H)−.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C@H:26]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[C@@H:27]([NH2:29])[CH3:28])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[CH:12][CH:11]=1>ClCCl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C@H:26]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[C@@H:27]([NH:29][C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:8])[CH3:28])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[CH:14][CH:15]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)C1CCCC1
Solvent: ClCCl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,1-carbonyldiimidazole (12 mg, 70 μmol) in dichloromethane (1 ml) was added cyclopentanecarboxylic acid (11 μl, 100 μmol) to give a colorless solution. The reaction mixture was stirred for 1 h at r.t. Then a solution of (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 19 mg, 50 μmol) in dichloromethane (0.5 ml) was added, and the stirring was continued at r.t. overnight. The solvent was removed in vacuo, the residue dissolved in acetonitrile/water mixture, and the crude product purified by preparative HPLC. Yield 18 mg (76%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)C#N>C(#N)C1C=CC=CC=1>[NH2:15][C:16]1[CH:17]=[CH:18][CH:21]=[C:22]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:23]=1
Reactant: C#CC(C)(C)C
Reactant: N#Cc1cccc(N)c1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CC(C)(C)C#Cc1cccc(N)c1
Reaction time: 45 h
Yield: 48 %

Procedure:
The procedure was identical to Example 2, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-aminobenzonitrile (0.236 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 45 h at 65° C. showed the presence of 0.96 mmol (48% yield) of 1-amino-3-(3,3-dimethyl-1-butynyl)benzene and 1.00 mmol of 3-aminobenzonitrile remaining in the reaction mixture.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(O[CH:16]1[CH2:20][CH2:19][CH:18](OCC)O1)C>C(O)(=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:16]=[CH:20][CH:19]=[CH:18]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC1CCC(OCC)O1
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(-n2cccc2)cc1
Yield: 81 %

Procedure:
The compound was prepared according to Colotta et al. J. Med. Chem. 2006, 49, 6015. A solution of 4-trifluoromethoxyphenyl amine (500 milligrams (mg), 2.82 millimoles (mmol), 1.00 equivalent (eq)) and 2,5-diethoxy tetrahydrofuran (452 mg, 2.82 mmol, 1.00 eq) in glacial acetic acid (20 milliliters (mL)) was heated at 90° C. for 1 hour (h) before being dried onto silica gel. The residue was then slurried in refluxing hexane, filtered hot, and concentrated to dryness affording the desired intermediate (519 mg, 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][C:11]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Product: COc1cc(C(=O)CSc2ccc(F)cc2)cc(OC)c1OC
Yield: 125 %

Procedure:
Substantially the same procedure as in Reference Example 13 was repeated using 4-fluorothiophenol (0.82 g) and 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 1.54 g) obtained in Reference Example 1 to give 2-(4-fluorophenylthio)-3',4',5'-trimethoxyacetophenone (Compound IX-11, 2.24 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCS(=O)(=O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 3-(1,1-dioxo-1-thiomorpholin-4-yl)-azetidine-1-carboxylic acid tert-butyl ester (3.35 g, 11.5 mmol) and TFA (15 mL) in DCM (30 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-thiomorpholine 1,1-dioxide as a white solid (2.0 g, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.64-3.53 (m, 4 H); 3.49-3.39 (m, 1 H); 3.08 (m, 4 H); 2.86-2.79 (m, 4 H); 1.83 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[C:10](=[O:24])[CH:9]([N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[N:20]([C:36]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:21]=[N:22][N:23]=3)[C:10](=[O:24])[CH:9]([N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.2 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (100 g) and trityl chloride (61.96 g) in N,N-dimethylformamide (1.8 #) was added dropwise triethylamine (36.1 ml) under stirring and cooling in an ice-bath. The mixture was stirred for 10 minutes at the same temperature and for 20 hours at ambient temperature. The reaction mixture was poured into water (18 l) under stirring and the resultant precipitate was collected by filtration, washed with water several times and dried in vacuo at 60° C. for 8 hours to give (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1-trityl-1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (128.2 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=3[Cl:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1c(F)cccc1Cl
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cccc3Cl)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 284. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.66 (s, 1H), 7.72 (s, 1H), 7.64 (td, J=8.3, 6.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.50-7.40 (m, 1H), 4.77 (dd, J=10.9, 3.7 Hz, 1H), 4.38-4.17 (m, 1H), 4.17-4.03 (m, 1H), 4.02-3.83 (m, 1H), 3.78 (s, 3H), 3.23-3.09 (m, 1H), 2.10-1.98 (m, 1H), 1.91-1.76 (m, 1H), 1.70-1.56 (m, 4H). LCMS (ES+) m/z 468 (M+1).
Reaction SMILES: [CH2:1]([N:17]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1C=CC=CC=1>[CH2:1]([N:17]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)C(=O)COc1ccc(CN)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)CCOc1ccc(CN)cc1
Yield: 28.1 %

Procedure:
N,N-Dihexadecyl-4-(aminomethyl)phenoxy acetamide (2.8 g, 0.0042 mole) was dissolved in benzene (30 ml) and treated with sodium bis-(2-methoxyethoxy)-aluminum hydride (5.94 g of a 70% solution in benzene). The mixture was refluxed for 16 hours, cooled and quenched with 10% sodium hydroxide solution (10.2 ml). The organic phase was separated, washed with saturated sodium chloride solution (3×50 ml), dried over sodium sulfate, filtered and concentrated under vacuum to an oil (2.27 g). The product was purified by silica gel chromatography (eluted with a chloroform/ethanol gradient mixture), converted to the hydrochloride salt, and recrystallized from ethanol/acetonitrile (1:1) to give the desired ethyl amine (0.725 g, 25% yield), mp 231°-238° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([S:36](Cl)(=[O:38])=[O:37])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([S:36]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)(=[O:37])=[O:38])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-methoxybenzyl)thiazol-2-amine (1 g, 4.577 mmol) in THF (30 mL) was added LiHMDS (1.58 g, 9.09 mmol, Aldrich) at −78° C. and the reaction mixture was stirred at 25° C. for 15 min. Afterward, 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (2.17 g, 9.09 mmol) dissolved in THF was added to the above mixture at −78° C. and reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was cooled to 0° C. and quenched with ice water (70 mL). The organic compound was extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated to get the crude material which was purified by silica gel column chromatography using a gradient of 0-40% EtOAc in hexanes as the eluent to afford 1.1 g of 3-fluoro-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide as light yellow solid in 57.8% yield. 1H-NMR (400 MHz, DMSO): δ 8.12 (t, J=18.8 Hz, 1H), 8.09-8.07 (m, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.49-7.53 (dd, 2H), 7.22-7.32 (m, 2H), 6.88-6.98 (m, 2H), 5.07 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:17][CH2:16][C:15]2=[O:29])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO>[CH3:28][O:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=1[CH:18]1[N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:31][CH:30]=2)[C:15](=[O:29])[CH2:16][CH2:17]1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-(benzyloxy)benzyl)-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one (316 mg; 0.75 mmol), and 10% Pd(C) (90 mg) in anh. MeOH (4 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 24 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and additional drying under HV afforded 5-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)pyrrolidin-2-one as a colorless solid (120 mg; 48%). LC-MS (conditions A): tR=0.67 min.; [M+H]+: 328.10 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[C:14]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2
Reactant: Nc1ccc(F)cc1C=O
Reactant: COc1cccc(OC)c1CCC#N
Product: COc1cccc(OC)c1Cc1cc2cc(F)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-fluorobenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([O:34]CC)=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)OCC)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenate (1.00 g, 2 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N sodium hydroxide (4 mL). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.92 g, 97.9%) as crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14][CH2:13]2)[O:10][C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[CH2:1]([N:8]1[CH2:12][C:11]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:10][C:9]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CN(Cc1ccccc1)C(=O)O2
Agent: [Pd]
Solvent: CCO
Product: O=C1OC2(CCNCC2)CN1Cc1ccccc1
Reaction time: 1.5 h
Yield: 107.1 %

Procedure:
A mixture of 22.2 g 3-benzyl-8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 150 ml ethanol and 5 g, 5% palladium on barium sulfate is hydrogenated at 60 psi at room temperature for 90 minutes. After filtration and removal of solvent there is obtained 15.4 g of 3-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 69°-71°.