Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[C:13](#[N:16])[CH:14]=[CH2:15].CC(C)([O-])C.[K+]>>[C:13]([CH2:14][CH2:15][O:1][CH2:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[N:16]
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Reactant: C=CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cccc(COCCC#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of 10 grams (g) [60 millimoles (mMol)] of 3-hydroxymethyl-2-nitrotoluene (1) (Aldrich Chemical Co., Milwaukee, WI) and 7.9 milliliters (ml) of acrylonitrile was stirred under argon at room temperature. Potassium tert-butoxide [10 milligrams (mg)] was added, followed 90 minutes later by an additional 10 mg portion. After a total of 3 hours, the reaction was quenched by the addition of 0.2 ml of acetic acid. Volatile material was removed under reduced pressure, and the residue chromatographed on 300 g of silica gel eluting with methylene chloride (CH2Cl2). Fractions of approximately 17 ml were collected. Fractions 155-200 were combined and the solvent evaporated to give 12.5 grams (g) (90% yield) of 3-(2-cyanoethoxymethyl)-2-nitrotoluene (2) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].OS(O)(=O)=O>O>[OH:4][CH:3]([CH:5]1[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][O:12]1)[CH2:2][OH:1]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: OCC(O)C1OCC(O)C1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This was prepared by modification of the method of S. Soltzberg (J. Am. Chem. Soc., 68, 919 (1946)). In a 2L round bottom flask, D-Sorbitol (130 g) was added to a solution of 1.43 g of concentrated H2SO4 in 19.5 ml of H2O. The flask was warmed in a 100° oil bath until the solid began to melt. The flask was then evacuated, maintained at approximately 20-25 mm Hg, and placed in a 140° oil bath. The reaction was stirred at 125°-145° for 30 minutes at reduced pressure. The reaction flask was then cooled to room temperature and 500 ml of H2O and approximately 25 g of Norit were added. The flask was warmed in a 80° oil bath for several minutes and the mixture was filtered. After cooling to room temperature, the filtrate was neutralized with barium acetate to pH 6.5, and allowed to stand for one hour. The precipitate was then removed by filtration and the solvent was removed to provide a colorless, oily solid. Chromatography on silica gel (750 g 0-30% CH3OH in CHCl3) yielded 30.0 g of impure [2R-2α(S*),3α,4β]]-tetrahydro-β,3,4-trihydroxy-2-furanethanol, which was used as such in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[C:20](C)[C:21]=2[Br:22])=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(N1CCC(C(C2SC(C)=CC=2Br)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][C:19]([CH3:24])=[CH:20][C:21]=2[Br:22])=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: Cc1csc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Product: Cc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Prepared essentially as 29b except that 4-[1-(3-Bromo-5-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material and the reaction mixture was stirred at 70° C. for 6 hours. LC/MS (ESI), m/e 347 (M−56) and 403 (MH+), retention time 2.03 minutes. Condition II.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[I:28]N1C(=O)CCC1=O>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:28])=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)cnn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 5-6 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and N-iodosuccinimide. LCMS (M+H)+=418.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH3:20].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 95 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
1.97 g (6.67 mmol) of 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) was dissolved in 20 ml of CCl4 and treated with 1.781 g (10.0 mmol) of N-bromosuccinimide and 0.126 g (0.669 mmol) of dibenzoyl peroxide. The mixture was refluxed (oilbath temperature 95° C.) and the course of the bromination followed by GC. After 5 h, the reaction mixture was poured onto crashed ice, extracted twice with AcOEt, washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvents i. V., followed by careful flash chromatography (SiO2, hexane/AcOEt=92/8), afforded 1.39 g of the title compound as white crystals, contaminated with roughly 5% of the dibromo-analogue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])[CH3:2].[K+].[F:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1.ClC1C=CC(NN)=CN=1>>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[CH2:12][C@H:11]3[CH2:10][C@H:9]3[C:8]=2[N:23]([C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][N:21]=2)[N:24]=1)=[O:14])[CH3:2]
Reactant: NNc1ccc(F)cn1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Agent: NNc1ccc(Cl)nc1
Agent: [K+]
Product: CCOC(=O)c1nn(-c2ccc(F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method C using potassium 2-ethoxy-2-oxo-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate and mixture of 5-fluoro-2-hydrazinylpyridine and 2-chloro-5-hydrazinylpyridine. LCMS m/z=288.2 [M+H]+.
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:6].C(N(CC)CC)C.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[NH2:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@@H]1CCC[C@H]1N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
(±)-trans-1,2-Cyclopentanediamine (WO98/30574) (692 mg) was dissolved in methylene chloride (10 mL), and to the solution were added triethylamine (1.1 mL) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) at 0° C., followed by stirring at 0° C. for 1 hour. Subsequently, additional 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) was added thereto, and the thus-obtained mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture to partition the mixture. The organic layer was washed with saturated brine, and was dried over sodium sulfate anhydrate. The residue was purified by silica gel flash column chromatography (methylene chloride:methanol=9:1), to thereby give the title compound (395 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[CH3:15][N:16](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:15]#[N:16])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1cc(F)cc2cc[nH]c12
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 7-bromo-5-fluoro-1H-indole (D131) (15 g) in DMF (150 mL) under N2 atmosphere were added Zn(CN)2 (24.0 g) and then Pd(PPh3)4 (15.8 g), the reaction mixture was heated to 120° C. and stirred overnight. After cooling, DCM (300 mL) was added to the resulting mixture which was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to afford 7 g (64% yield) of 5-fluoro-1H-indole-7-carbonitrile (D132) as a white solid. δH (CDCl3, 400 MHz): 6.51 (1H, t), 7.20 (1H, dd), 7.30 (1H, t), 7.52 (1H, dd), 8.82 (1H, br s).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:21]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:11]([O:10][C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][CH:7]=2)=[C:12]1[CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(Oc2c(C)n(Cc3ccccc3)c3cc(Cl)ccc23)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(Oc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-benzoic acid methyl ester (0.100 g, 0.25 mmol) was dissolved in THF (3 mL) and the solution was cooled to 0° C. Diisobutylaluminum hydride (0.750 mL, 1.0M in hexanes, 0.75 mmol) was added dropwise and the reaction was stirred for 20 minutes then an additional amount of diisobutylaluminum hydride (0.100 mL, 1.0M in hexanes, 0.10 mmol) was added. The reaction was allowed to stir for 20 minutes then quenched with aq. HCl (2 mL, 1M). The reaction was submitted to a standard workup procedure to give the title compound.
Reaction SMILES: [Br:1][C:2]([Br:13])([Br:12])[CH2:3][C:4]1(Cl)[C:7]([CH3:9])([CH3:8])[CH2:6][C:5]1=[O:10].[ClH:14]>C(O)C>[Br:1][C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6]([Cl:14])[C:5]1=[O:10]
Reactant: Cl
Reactant: CC1(C)CC(=O)C1(Cl)CC(Br)(Br)Br
Solvent: CCO
Product: CC1(C)C(Cl)C(=O)C1CC(Br)(Br)Br
Temperature: 80 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
22.8 g (0.054 mole) of 2-(2',2',2'-tribromoethyl)-2-chloro-3,3-dimethylcyclobutan-1-on is dissolved in 220 ml of absolute ethanol saturated with hydrogen chloride and the solution is stirred for 5 hours at 80° C. Then solvent is evaporated until the volume of the reaction mixture is reduced to one third of the starting volume and, after addition of water, the mixture is extracted with ether. The etheral extract is washed at first with saturated sodium chloride solution and subsequently with sodium bicarbonate solution and thereafter dried over sodium sulphate. The residue obtained after evaporation of the ether is purified by chromatography on silica gel using toluene as eluent. After combination of the pure fractions and evaporation of the solvent there is obtained 17.1 g (75% of theory) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-chloro-cyclobutane-1-one, melting point 87°-89° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]1[CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:30]1[CH2:31][CH2:32][CH2:33][CH:28]([N:3]2[C:4]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:5]([C:7]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[O:8])[NH:6][C:2]2=[O:1])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2[nH]c(=O)n(C3CCCNC3)c2-c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCCC(n2c(-c3ccccc3)c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
16G (0.39 g, 0.85 mmol) prepared in the previous step was dissolved in 3 mL of anhydrous DCM. TEA (0.36 mL, 2.54 mmol) was added and the mixture was chilled to 0° C. To this chilled mixture, acetic anhydride (0.08 mL, 0.85 mmol) was added slowly. After about 30 minutes, TLC and LC/MS showed no signs of 16G. At this point, the mixture was concentrated to give tert-butyl 4-(1-(1-acetylpiperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate (16H) as an oil (0.42 g, quantitative yield). ESI-MS: m/z 498.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]3[C:17]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:16][C:15]([CH3:23])=[N:14][C:13]=23)=[C:6]([CH3:25])[CH:5]=1)([O-])=O.[C:26](Cl)(=[O:28])[CH3:27].ClCCl>C1COCC1.[Pd]>[CH2:19]([CH:18]([C:17]1[N:12]2[N:11]=[C:10]([CH3:24])[C:9]([C:7]3[S:8][C:4]([NH:1][C:26](=[O:28])[CH3:27])=[CH:5][C:6]=3[CH3:25])=[C:13]2[N:14]=[C:15]([CH3:23])[CH:16]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc([N+](=O)[O-])cc3C)c(C)nn12
Reactant: CC(=O)Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc(NC(C)=O)cc3C)c(C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
Dissolve 3-(5-nitro-3-methyl-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.33 g, 0.92 mmol) in THF (10 mL) with 10% palladium on carbon (0.10 g), degas with vacuum/hydrogen atmosphere flush (3×) and stir under a hydrogen atmosphere (55 psi) at room temperature for 3 h. Confirm the reaction is complete using TLC. Dilute the reaction with THF (50 mL) and filter through diatomaceous earth, followed by concentration to a crude orange oil (0.328 g). Dissolve the oil in dichloromethane (4 mL) and 1.0 M NaOH (1 mL). Add acetyl chloride (0.038 mL, 0.52 mmol) to the reaction and stir in a sealed reaction vessel at room temperature over the weekend. Dilute the reaction with dichloromethane (100 mL) and wash with water. Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate to a red oil under reduced pressure. Purify the oil using flash chromatography, eluting with 100% hexane/0% (15% ethyl acetate/10% 7 N ammoniated methanol/75% hexane) to 0% hexane/100% (15% ethyl acetate/10% 7 N ammoniated methanol/75% hexane) in a step gradient of 10% increments to give a brown foam (0.048 g, 26%). ES/MS m/z 371.0 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]3[N:4]=[C:5]([CH3:8])[S:6][CH:7]=3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1nc(CCl)cs1
Product: Cc1nc(COc2ccn(-c3nc(C)c(C(=O)NCc4ccccc4)s3)c(=O)c2)cs1
Yield: 20 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 4-(chloromethyl)-2-methylthiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 7.34-7.26 (m, 5H), 7.20 (s, 1H), 6.24 (dd, J=8.1, 2.7 Hz, 1H), 6.13-6.07 (m, 2H), 5.10 (s, 2H), 4.59 (d, J=5.6 Hz, 2H), 2.73 (s, 3H), 2.67 (s, 3H); MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9]/[C:10](/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)\[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.ClCCl>[C:30]([O:13][CH2:12]/[C:11](/[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1)=[C:10](/[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)\[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 46 g of (2Z)-4{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-ol with 120 mmol of DMAP in 1 L of dichloromethane, 120 mmol of acetic anhydride was added dropwise. The resulted mixture was stirred at rt for 1 h. The reaction mixture was loaded on a silica gel column and eluted with EtOAc to afford 50.5 g of the titled compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.68 (d, 2H), 7.33 (d, 2H), 7.15-7.04 (m, 5H), 5.16 (s, 2H), 4.75 (s, 2H), 3.02 (s, 3H), 1.92 (s, 3H), 0.81 (s, 9H), −0.03 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:6]=1[C:15]([F:18])([F:17])[F:16])[OH:4].[CH:19](OCC)=[O:20]>>[CH3:14][O:13][C:7]1[C:6]([C:15]([F:16])([F:17])[F:18])=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:19]=[O:20])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc([C@H](O)CN)c(C(F)(F)F)c1OC
Reactant: CCOC=O
Product: COc1ccc(C(O)CNC=O)c(C(F)(F)F)c1OC
Temperature: 25 °C

Procedure:
3.4-dimethoxy-2-(trifluoromethyl)-(N-methylamino)ethanol (12) was made according to methods known in the art. See Kirk et al. (2000). Specifically, a solution of (1S or 1R)-2-amino-1-(3,4-dimethoxy-2-trifluoromethylphenyl)ethanol (10) (MW=265.23, 3.00 g, 11.3 mmol) in ethyl formate (140 ml) was heated to reflux under an atmosphere of Ar for 3 hours with stirring. The suspension eventually goes into solution during the first hour of reflux. Upon completion, the reaction was allowed to cool to room temperature. Volatiles were removed in vacuo to afford 1-N-[2-(3,4-dimethoxy-2-trifluoromethylphenyl)-2-hydroxyethyl]formamide (11) as a low melting yellowish solid. To a cold (0° C.) suspension of LiAlH4 (MW=37.95, 95%, 2.4 g, 63.2 mmol) in THF (30 ml) under Ar a solution of formamide (11) (MW=293.24, 13.0 mmol, 3.81 g) in THF (70 ml) was added dropwise. The mixture was heated to reflux for 3 hours and then cooled to 0° C. and quenched by the addition of 2.4 ml H2O, 2.4 ml 15% NaOH and 7.2 ml H2O. The mixture was stirred at room temperature until all of the unreacted LAH has reacted. The solid was filtered and washed 5 times with 50 ml of hot EtOAc. The filtrate was concentrated and the residue was recrystallized from hex/EtOAc. For S isomer: mp=121-128° C. 1H NMR for S in CDCl3 (300 MHz) δ 7.53 (m, 1H, J=8.8), 7.06 (m, 1H, J=8.8), 5.16 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.80 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H). 13C NMR in CDCl3 (75 MHz) 152.5, 148.1, 133.8, 124.5 (q, J=274 Hz), 122.8, 121.3, 115.5, 66.8, 61.5, 59.2, 55.9, 35.5. 19F (282.8 Mz) −53.4. For R isomer: mp=125-127° C. 1H NMR for R in CDCl3 (300 MHz) δ 7.55 (m, 1H, J=8.8), 7.06 (m, 1H, J=8.8), 5.22 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.83 (m, 1H), 2.62 (m, 1H), 2.47 (s, 3H). 13C NMR in CDCl3 (75 MHz) 152.3, 148.1, 133.6, 124.5 (q, J=274 Hz), 122.9, 121.3, 115.5, 66.6, 61.6, 58.9, 56.0, 35.2. 19F (282.8 Mz) −53.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:40][C:35]2C=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][CH2:50][O:51]C(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([C:13]([NH:40][CH2:35][CH2:34][N:39]2[CH2:38][CH2:37][O:51][CH2:50][CH2:49]2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: CCOC(C)=O
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate C) (250 mg, 0.874 mmol) in NMP (8 ml) was added 4-(2-aminoethyl)morphonline (138 ul, 1.049 mmol) followed by DIPEA (763 ul, 4.37 mmol). To this solution was then added HATU (499 mg, 1.311 mmol) in portions and the reaction mixture was left to stir at RT for 1 hour. A further 1 equiv. of 4-(2-aminoethyl)morphonline was added. After a further 1.5 hr, 0.5 equiv. HATU (166 mg, 0.425 mmol) was added and the RM was left to stir for a further 30 min. The mixture was added to EtOAc (50 ml) and washed with 0.1M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (50 ml). The combined organics were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate and evaporated under reduced pressure to give a brown oil (418 mg). The crude product was purified by chromatography (Biotage-silica 20 g/70 ml column, 3:1 EtOAc/iso-hexane). The resulting yellow residue was loaded onto an SCX-2 cartridge (10 g) that had been pre-wetted with MeOH. The cartridge was washed with MeOH (140 ml) and eluted with 3.5M ammonia in methanol solution (70 ml). The appropriate fractions were evaporated under reduced pressure to give a solid. This solid was dissolved in EtOAc and filtered under vacuum. The filtrate was evaporated under reduced pressure and then dried in vacuo to afford the title compound as a yellow solid;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[C:12]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:28]=[C:27]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)CCc1ccc(Sc2ccccc2)cc1
Reactant: c1ccc(-c2cnco2)nc1
Product: O=C(CCc1ccc(Sc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 33 %

Procedure:
The title compound was prepared from 5-(2-pyridyl)oxazole and 3-(4-(phenylthio)phenyl)propanoic acid (S44) using General Procedure B. PTLC (SiO2, 50% EtOAc-hexanes) afforded 11i (50 mg, 0.13 mmol, 33%) as an orange solid: 1H NMR (CDCl3, 500 MHz) 8.68-8.66 (m, 1H), 7.88 (s, 1H), 7.88-7.85 (m, 1H), 7.82 (td, 1H, J=7.7, 1.8 Hz), 7.34-7.28 (m, 7H), 7.24-7.20 (m, 2H), 3.46 (t, 2H, J=7.4 Hz), 3.10 (t, 2H, J=7.4 Hz); 13C NMR (CDCl3, 125 MHz) 187.1, 157.1, 153.4, 150.1, 146.2, 139.7, 137.1, 136.3, 132.9, 131.8, 130.4, 129.4, 129.1, 126.9, 126.7, 124.2, 120.4, 40.4, 29.2; IR (film) νmax 3054, 2925, 2855, 1698, 1601, 1581, 1505, 1470, 1427, 1381, 1282, 1083, 990, 963, 913, 818, 784, 740, 691 cm−1; ESI-TOF m/z 387.1170 (C23H18N2O2S+H+ requires 387.1162).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Br)=[CH2:12].Cl.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 mL) was cooled to 0° C. and vinylmagnesium bromide (1M in THF, 48 mL, 48 mmol) was added dropwise. The reaction was warmed to room temperature and was stirred overnight. Aqueous HCl (1N) and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated. The residue was used in the next step without further purification.