Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (155 mg, 1.126 mmol) and 4-bromomethyl-benzenesulfonamide (84 mg, 0.337 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 15.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:13]([O:14]C(=O)C(C)(C)C)[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C@@H:13]([OH:14])[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@@H](O)C1

Procedure:
To a 1,4-dioxane (500 μL)-water (100 μL) solution of tert-butyl (R)-4-(4-fluorophenyl)-5-(pivaloyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 0.132 mmol) synthesized in Reference Synthesis Example 131, lithium hydroxide monohydrate (17.0 mg, 0.405 mmol) was added and the resultant mixture was stirred at 115° C. for 10 hours. After completion of the reaction, the reaction solution was analyzed with chiral column chromatography to measure optical purity.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([OH:10])=O.C1N=C[N:13](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([NH2:13])=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(C(=O)O)c(Br)s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(C(N)=O)c(Br)s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-methyl-thiazole-4-carboxylic acid (14.4 g, 64.8 mmol) was dissolved in 100 ml DMF and CDI (11.6 g, 71.3 mmol) was added. The solution was stirred for 2 hrs at 60° C., cooled and NH4OH (150 ml, 973 mmol) was added. The reaction mixture was stirred over night at room temperature and extracted two times with ethyl acetate and water. The organic extracts were washed four times with water, dried with sodium sulfate, filtered and evaporated. The crude product (11.3 g, 79%) [MS: m/e=222.8 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and aniline (CAN 62-53-3) as starting materials, MS (EI) m/e: 309.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2].O1CCCC1.[H][H]>[C].[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(N)cc1
Yield: 73.8 %

Procedure:
Ethyl(4-nitrophenoxy)acetate (10.0 g, 44.4 mmol) and 10% palladium-carbon (50% water-containing product, 3.0 g) were added to a mixed solution of tetrahydrofuran (50 mL) and ethanol (50 mL), and the mixture was stirred at room temperature for 18 hr in a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2-2:3-1:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (6.4 g, yield 74%) as pale-pink prism crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Reaction time: 4 h

Procedure:
0.489 g (2 mmol) of 5-chloro-2-methylsulfonylindan-1-one and 0.095 g (2.5 mmol) of sodium borohydride are suspended in 10 ml of ethanol and placed in an ultrasonic bath for 4 h. The reaction mixture is then acidified with 2N HCl and stirred. The ethanol is distilled off, water and dichloromethane are added to the residue and the mixture is extracted with dichloromethane. The organic phase is separated off, dried over MgSO4, filtered and concentrated and the residue is purified chromatographically on silica gel using dichloromethane/methanol 20/1. This gives 5-chloro-2-methylsulfonylindan-1-ol of melting point 163° C.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CO)c1ccccc1
Reaction time: 2.5 h

Procedure:
Ethyl 2-methyl-2-phenylpropionate (XXXVIII, 4.50 g, 23.5 mmol) is added to lithium aluminum hydride (0.908 g, 23.5 mmol) in dry ether (100 ml) cooled at 0°. After stirring for 2.5 hr, the mixture is quenched by adding, successively, water (1 ml), aqueous sodium hydroxide (15%, 1 ml) and water (3 ml). After stirring for several minutes, the solids are filtered off and washed well with ether. The filtrate is washed twice with saline and the organic phase is separated, dried over magnesium sulfate and concentrated to give 2-methyl-2-phenylpropanol (XLV), NMR (CDCl3) 1.34, 3.62, 3.71, 7.22 and 7.31-7.41 δ.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28].C(Cl)Cl>C(C(C)=O)C>[CH3:1][N:2]1[C:6]([O:7][CH2:26][C:27](=[O:28])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: Cc1nn(C)c(OCC(=O)C(C)(C)C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 82.7 %

Procedure:
Into a four necked flask was charged 0.45 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole, and the contents were dissolved in 15 ml of methyl ethyl ketone. To the solution were added 0.5 g of anhydrous potassium carbonate and then 0.3 g of tert-butyl bromomethyl ketone while stirring, and the mixture was reacted for 2 hours under the reflux condition (80° C.). After completion of the reaction, the reaction product was collected by filtration, and the solvent (methyl ethyl ketone) was distilled off to obtain a crude product. The crude product was passed through a silica gel column (eluent: methylene chloride), and the eluent was distilled off to obtain 0.5 g of the titled compound having a melting point of 104° to 105° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[OH:16].[Br:17][CH2:18][CH:19](OC)OC.OS(O)(=O)=O>C1COCC1>[Br:17][CH2:18][CH:19]1[O:16][C:4]2[CH:5]=[C:6]([S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: COC(CBr)OC
Reactant: O=S(=O)(c1ccc(CO)c(O)c1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Temperature: 50 °C
Yield: 87 %

Procedure:
Preparation according to Preparation 9. 2-(hydroxymethyl)-5-[(trifluoromethyl)sulfonyl]phenol (2.7 g, 10.5 mmol), 2-bromo-1,1-dimethoxyethane (3.0 ml, 25.4 mmol), conc. H2SO4 (1.0 ml), THF (20 ml). Heating at 50° C. for 6 h. Additional 2-bromo-1,1-dimethoxyethane (5×0.5 ml, 21.1 mmol) and conc. H2SO4 (3×1.0 ml) were added during the reaction. Purification by flash column chromatography gave the title compound (3.3 g). MS m/z (rel. intensity, 70 eV) 362 (M+, 5), 360 (M+, 5), 267 (bp), 238 (64), 141 (52), 77 (55).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]#[C:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][Cl:9].[CH2:13]([Mg]Br)[C:14]#[CH:15]>>[Cl:9][CH2:8][CH2:7][CH2:6][C:5]([OH:10])([C:4]#[C:3][Si:2]([CH3:1])([CH3:11])[CH3:12])[CH2:15][C:14]#[CH:13]
Reactant: C#CC[Mg]Br
Reactant: C[Si](C)(C)C#CC(=O)CCCCl
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCCl

Procedure:
In the manner described hereinabove in Reference Example 11, 1-trimethylsilyl-3-oxo-6-chloro-1-hexyne is reacted with propargyl magnesium bromide to give 7-chloro-4-hydroxy-4-trimethylsilylethynyl-1-heptyne.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[C:16]([CH3:22])[CH:17]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(N)ccc1F
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Product: Cc1cc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)ccc1F

Procedure:
A mixture of the product from Example 86A was reacted with 4-Fluoro-3-methyl-phenylamine to produce 4-Fluoro-N-(4-fluoro-3-methyl-phenyl)-3-nitro-benzamide according to the procedure of Example 86B, which was treated sequentially using the procedures from Examples 86C and 395D to provide the title product.
Reaction SMILES: FC1C=C(C=CC=1)C[O:6][C:7](=[O:25])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:12][CH:11]=1.[OH-].[Na+].Cl>C1COCC1>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]=[CH:8][C:7]([OH:25])=[O:6])=[CH:15][CH:14]=1
Reactant: O=C(C=Cc1ccc(OCc2cccc(F)c2)cc1)OCc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 50 °C
Yield: 95.7 %

Procedure:
6.48 g (17 mmol) 3-[4-(3-fluoro-benzyloxy)-phenyl]-acrylic acid 3-fluoro-benzyl ester is dissolved in 100 ml THF and 1.36 g (34 mmol) solid sodium hydroxide is added. The reaction mixture is heated overnight at 50° C., cooled and acidified with 1N hydrochloric acid. The precipitate is filtered off and washed with cold water to give 4.43 g (96%) of a colorless solid. MS: m/e=271.2 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=3)[C@@H:21]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:20]2)[CH2:15][CH2:14]1>>[CH3:32][C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([CH3:33])[CH:29]=1)[C:25]([N:22]1[CH2:23][CH2:24][C@@H:19]([N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:5](=[O:6])[C:4]3[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=3)[CH2:14][CH2:15]2)[CH2:20][C@@H:21]1[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34]
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(N)CC3)C[C@@H]2Cc2ccccc2)c1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: Cc1cc(C)cc(C(=O)NC2CCN([C@@H]3CCN(C(=O)c4cc(C)cc(C)c4)[C@@H](Cc4ccccc4)C3)CC2)c1

Procedure:
Using the same reaction procedure as described in example B6, 3,5-dimethylbenzoyl chloride was reacted with compound 22 to form (±)-trans-N-[1-[1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-3,5-dimethylbenzamide (compound 21, mp. 120.1° C.).
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH3:6][S:7]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:8]>CCOCC>[CH3:6][S:7]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:3])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
To 600 ml of thionyl chloride at 0° C. is added 150 g (0.63 mole) of 4-[(methylsulfonyl)amino]benzoic acid sodium salt under a nitrogen atmosphere and the reaction is refluxed for 40 hours. The excess thionyl chloride is removed in vacuo and the crude product triturated with toluene and evaporated. After dissolving the solid in tetrahydrofuran, charcoal is added, and the mixture filtered through Celite. Concentration in vacuo provides a solid which is then slurried with cold ether and collected by filtration. Drying for 18 hours in vacuo provides 133 g of the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][CH:7]=2)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>ClCCl.Cl[Ti](Cl)(Cl)Cl>[N:13]1([CH2:12][CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:6]([C:5]3[S:1][C:2]4[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=4[C:4]=3[C:29]([C:28]3[CH:32]=[CH:33][C:25]([Br:24])=[CH:26][CH:27]=3)=[O:30])=[CH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a solution of 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (650 mg, 2.0 mmol) and 4-bromobenzoyl chloride (657 mg, 1.5 equiv) in dichloromethane (25 mL) at 0° C. in dark was added TiCl4 (1.0 mL, neat) slowly under argon. The resulting mixture was stirred at ambient temperature for 4 h before being transferred carefully to a stirring solution of saturated aqueous NaHCO3 (100 mL). After stirring for 30 min, the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (4:4:92) afforded the product (940 mg, 92%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][CH:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]#[N:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([CH:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[N:36]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: N#CC(N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CC(Cc1ccccc1)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-3-phenylpropanenitrile hydrochloride (8.47 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to provide (R/S)-N-(1-cyano-2-phenylethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.012 mmol, 26.2% yield) as a mixture of diastereomers: LCMS=546.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.05-8.17 (2 H, m), 7.18-7.72 (12 H, m), 5.08-5.15 (1 H, m), 5.02 (1 H, t, J=7.70 Hz), 3.11-3.27 (2 H, m); HPLC peak RT=11.0 min (Method A).
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:23]N1C(=O)CCC1=O>ClCCCl>[Cl:23][C:21]1[CH:22]=[C:16]([S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:17]=[CH:18][C:19]=1[NH2:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)cc1
Solvent: ClCCCl
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Reaction time: 0.75 h
Yield: 173 %

Procedure:
A stirred mixture of 4-dodecylsulfonylaniline (519.6 g 1.6 moles), 1,2-dichloroethane (2.5 liters) and N-chlorosuccinimide (110 g 0.825 moles) was heated under reflux for 45 minutes. A further 60 g (0.45 moles) of N-chlorosuccinimide was added and heating was continued for 45 minutes. A further 53 g of N-chlorosuccinimide (0.40 moles) was added and heating was maintained for another hour. The total amount of N-chlorosuccinimide was used 223 g (1.67 moles). TLC showed no starting material. The solvent was removed on the rotovapor and the residue was dissolved in ethyl acetate (2 liters). The solution was washed with 3×15 liters of hot water, then it was dried over magnesium sulfate and the solvent was removed. The product was recrystalized twice from petroleum ether (bp 60°-80° C.) containing a little ethyl acetate to give 513.6 g (89%) of pure material.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:2].[CH3:13][N:14](C=O)C>>[CH2:1]([S:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Product: CCSc1ccc2c(C#N)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a mixture of 6-ethylsulfanyl-1H-indole (2.75 g, 15.54 mmol) in DMF (20 mL) was added chlorosulfonyl isocyante dropwise at −30° C. The temperature was raised to 0° C. after addition and stirred for 30 minutes. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (CH2Cl2) to provide 6-ethylsulfanyl-1H-indole-3-carbonitrile (3.25 g, 84%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:37]([O:36][C:35]([NH:34][CH2:33][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(OC(F)(F)F)cc1
Yield: 56.1 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-trifluoromethoxyphenoxy)propionate (2.93 g), t-butyl 2-methanesulfonyloxyethylcarbamate (4.73 g) and potassium carbonate (5.46 g) and the reaction mixture was treated to afford the title compound (2.28 g) as a colorless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[Br:14][CH2:15][Si:16](Cl)([CH3:18])[CH3:17].O>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:15]([Br:14])[SiH:16]([CH3:18])[CH3:17])=[CH:8][CH:9]=1
Reactant: C[Si](C)(Cl)CBr
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[SiH](C)C(Br)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
A solution of n-butyllithium (2.5M, 53 mL, 0.133 mole) was added dropwise over 30 minutes under argon to a solution of 1,4-dibromobenzene (30.0 g, 0.127 mole) in dry THF (575 mL) at -78° C. After stirring for 1.5 h, bromomethylchlorodimethylsilane (25.0 g, 0.133 mole) was added to the reaction mixture through a canula and the solution was stirred for 1.5 h at -78° C. The reaction was poured into water (325 mL) and extracted with ether. The combined extracts were washed with water and brine, and then dried (Na2SO4) and concentrated in vacuo to an oil. The oil was distilled (Kugelrohr, 110°-125° C., 0.05 mm Hg) to afford the compound as a clear, colorless oil (22.6 g, 58%). 1H NMR (400 MHz, CDCl3) 7.45 (dd, 4H), 2.60 (s, 2H), 0.45 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:10]1
Reactant: COC(=O)CC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-methoxycarbonyl-1-oxoethyl)pyrrolidine (3.17 g, 7.9 mmol) was added a 3N hydrogen chloride--dioxane solution (30 ml). The mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. Chloroform (20 ml) and methanol (20 ml) were added thereto, and the solvent was removed in vacuo. This operation was repeated twice, followed by being left overnight to obtain crude (2S,4R)-4-hydroxy-2-(2-methoxycarbonyl-1-oxoethyl)pyrrolidine monohydrochloride (1.76 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C@H:7]([CH2:19][OH:20])[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:31].[H][H]>CO>[ClH:31].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C@H:7]([CH2:19][OH:20])[NH2:8]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
To a mixture consisting of 4.16 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosine methyl ester [for the preparation of this compound see J. Am. Chem. Soc., 76, 5076 (1954)], 30 ml. of methanol, and 416 mg. of 5% palladium-on-barium sulfate is added 8.7 ml. of methanol containing 400 mg. of hydrogen chloride, and hydrogen is passed over the stirred mixture for 75 minutes. The mixture is then filtered to remove the catalyst, and the filtrate is evaporated to dryness under reduced pressure to give a solid residue of L-seryl-L-tyrosine methyl ester hydrochloride, which is suitable for use without further purification.