Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[C:14]([CH3:41])[CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Agent: Cl
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2nccn2)C1
Yield: 34 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 7, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (106.7 mg, 34%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 7.72 (s, 2H), 7.43-7.38 (m, 2H), 7.09-6.81 (m, 9H), 5.29 (d, 2H), 4.84 (d, 1H), 3.59-3.53 (m, 1H), 3.19 (t, 1H), 2.96-2.87 (m, 1H), 2.82 (dd, 1H), 2.72-2.59 (m, 2H), 2.32 (s, 3H). MS (EI) for C29H28F2N5O3 found 532 (MH+).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Si:1]([O:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(Br)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyldiphenylsilyl chloride (10.4 mL, 40.1 mmol) was added to a solution of 4-bromobenzyl alcohol ( 5.0 g, 26.7 mmol) and 50 mL of dichloromethane. The solution was treated with triethylamine (3.72 mL, 26.7 mmol) and (dimethylamino)pyridine (163 mg, 1.34 mmol) and stirred overnight at room temperature. The solution was diluted with 300 mL of dichloromethane and washed with 50 mL of 10% aqueous HCl. The layers were separated and the aqueous layer was extracted with 50 mL of dichloromethane. The combined organic extracts were washed with brine, and dried (MgSO4), and filtered, and the solvents were removed in vacuo. The residue was filtered through a plug (6@X 2@) of silica gel using a solution of 97% hexane/ethyl acetate. After removal of the solvent the residue was heated under vacuum (3 torr) to 170° C. for 1 hour to remove a low-boiling impurity. The remaining material is the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=1[NH:1][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccc(N)c(C(N)=O)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(OC)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of 2-amino-5-methoxybenzamide (1.50 g, 9.03 mmol) and triethylamine (1.00 g, 9.93 mmol) in THF (40 mL) was added dropwise ethyl chloroglyoxylate (1.36 g, 9.93 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the precipitated insoluble material was collected by filtration. The filtered cake was washed with water and ethanol to give ethyl ((2-(aminocarbonyl)-4-methoxyphenyl)amino)(oxo)acetate as a pale-yellow powder (2.42 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10](NC(=O)C2C=CC=CC=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[N:33]1[CH:38]=CC=CC=1.[ClH:39].CO[NH2:42]>C(O)C>[ClH:39].[NH2:42][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:18]=[CH:19][C:20]([F:23])=[CH:21][N:22]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:38]#[N:33])[N:9]=1
Reactant: O=C(NC1=NC2(c3cccc(Br)c3)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Reactant: CON
Reactant: c1ccncc1
Agent: Cl
Solvent: CCO
Product: N#Cc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(N)=N3)c1
Temperature: 60 °C

Procedure:
To a solution of racemic N-[7a-(3-bromophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (180 mg, 393 μmol) in ethanol (8.0 mL) is added sequentially pyridine (0.5 mL, 6.2 mmol) and O-methylhydroxylamine hydrochloride (350 mg, 4.19 mmol). The mixture is heated at 60° C. for 16 hours, cooled to ambient temperature, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with a gradient of 0 to 10% of dichloromethane/2 M ammonia in methanol to give the free base form of the title compound as a colorless oil. The racemic material is separated chirally by SFC (Column: Chiralpak AS-H, 5 p; eluent: 35% isopropyl alcohol with 0.2% isopropylamine) in CO2; flow: 70 mL/minute at 225 nm). The first eluting isomer is the free base of the title compound, (Rt=0.92 minutes). EI/MS (m/e): 355 (M+H). This isomer is dissolved in dichloromethane (1 mL) and hydrogen chloride gas is bubbled through this solution for approximately 10 seconds. The solution is then concentrated to give the title compound as a white solid (55 mg, 36%, >99% ee).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]([Cl:30])=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[ClH:30].[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](=[O:29])[O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:9]2)[CH3:26]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1cccc2c1CN(Nc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1cccc2c1CN(Nc1ccncc1)C2
Product: Cl
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-4-ol (1.50 g), triethylamine (1.47 g) and chloroform (15 ml), diethylcarbamyl chloride (1.07 g) in chloroform (10 ml) was added dropwise, with stirring at ambient temperature, under nitrogen. The reaction mixture was stirred under reflux for 5 hrs, at ambient temperature overnight, and poured into dilute sodium bicarbonate solution (100 ml). The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was flash chromatographed (silica), eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with excess ethereal hydrogen chloride. The precipitate was recrystallized from ethanol-ether to give 1.20 g (50%) of product, mp 213-215° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](O)=[O:9])[S:4][N:3]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][OH:9])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: OCc1snc(Cl)c1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
A mixture of 3,4-dichloroisothiazole-5-carboxylic acid (2.0 g) and toluene (20 mL) was treated with thionyl chloride (5.0 mL) and N,N-dimethylformamide (0.5 mL), and the resulting mixture was heated at 100° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (5.0 mL). The mixture was cooled to −78° C. and treated dropwise over a period of 1 hour with a 2.0 M solution of sodium borohydride in N,N-dimethylformamide (8.5 mL). The mixture was stirred at −78° C. for 5 minutes, diluted with 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:0 to 0:1 by volume) to afford the title compound as a pale yellow solid (1.1 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=O)=[CH:10][CH:9]=1)([CH3:5])[CH3:4].Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:1][CH2:2][C:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15]/[C:16](=[N:35]\[OH:36])/[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:10][CH:9]=1)([CH3:5])[CH3:4]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(C)(C)CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(C)(C)CO)cc1

Procedure:
In analogy to example 151, step 3, N-(1-hydroxy-2-methylpropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=462.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[S:9](=[O:11])(=[O:10])[NH:8][C:7]2[N:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]1=[O:16])[CH3:3].[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>COCCOCCOC>[CH3:23][N:8]1[C:7]2[N:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5](=[O:16])[N:4]([CH:2]([CH3:1])[CH3:3])[S:9]1(=[O:10])=[O:11]
Reactant: CC(C)N1C(=O)c2cccnc2NS1(=O)=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CC(C)N1C(=O)c2cccnc2N(C)S1(=O)=O

Procedure:
3-(1Methylethyl)pyrido(2,3-c) (1,2,6)thiadiazin-4(3H)-one-2,2-dioxide (5.0 grams; 0.0208 mole) was mixed with 50 ml of diethylene glycol dimethyl ether. The system was flushed with nitrogen and sodium hydride (1.0 gram; 0.02 mole), previously washed with n-hexane, was added portionwise to the reaction mixture. After the effervescence of hydrogen ceased, 2.2 ml of dimethyl sulfate (0.023 mole, 1.33g/ml) was added and the reaction mixture heated at reflux temperatures for a period of 4 hours. During the reaction, the color of the reaction mixture changed from light yellow to deep red and gradually back to yellow.
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.O=[CH:22][C:23]([OH:25])=[O:24]>CC#N>[S:1]1[CH:5]=[C:4]([CH:22]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:23]([OH:25])=[O:24])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=CC(=O)O
Reactant: OB(O)c1csc2ccccc12
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Benzo[b]thiophen-3-ylboronic acid (387 mg, 2.17 mmol), aniline (202 mg, 2.17 mmol), and 2-oxoacetic acid hydrate (200 mg, 2.17 mmol) were dissolved in CH3CN (12 ml) and stirred in a microwave reactor at 100° C. for 1 hour. The solvent was evaporated, and the residue was dissolved in EtOAc and washed with sat. NaHCO3. The pH of aqueous phase was adjusted with 2N HCl to about 7, and the product was extracted with EtOAc. The organic phase was dried with Na2SO4, filtered and evaporated to obtain 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (295 mg, 47.9% yield), which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31](OCC)=[O:32])[CH2:28][N:29]=1)=[CH:9]2.O1CCCC1.CO.[BH4-].[Li+]>O>[OH:32][CH2:31][CH2:30][CH:27]1[S:26][C:25]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:24])[S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])=[N:29][CH2:28]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CCO)S3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a mixture of ethyl (2-{5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (200 mg), tetrahydrofuran (5 mL) and methanol (1 mL) was added lithium borohydride (16 mg), and the mixture was stirred at room temperature for 1 hr. Lithium borohydride (16 mg) was added to the mixture, and the mixture was further stirred at room temperature for 1 hr. Lithium borohydride (16 mg) was added to the mixture, and the mixture was further stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:9, volume ratio) to give yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (100 mg, yield 56%) as a pale-yellow powder. melting point 122-123° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH2:17]>>[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:17][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: Brc1cccc(-c2ccncc2)n1
Product: N[C@H](CNc1cccc(-c2ccncc2)n1)Cc1ccccc1
Temperature: 190 °C

Procedure:
A neat mixture of 6-bromo-[2,4′]bipyridine (2.35 gm, 10 mmole) and (S)-2-amino-3-phenylpropylamine (3 gm, 20 mmole) was heated to 190° C. for 4 hr. The reaction was cooled to rt and purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give the step 1 compound. (This reaction provides major products wherein the less hindered amine functionality displaces the bromide,when the nucleophile is an alkyldiamine) MS (m/z): Calcd. C19H20N4 (M+): 304, found (M+H)+: 305.2.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[CH:8][CH:9]=1
Reactant: Cc1ccc(N(C)S(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(c1ccc(CBr)cc1)S(C)(=O)=O
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of N-methyl-N-(4-tolyl)methanesulphonamide (0.31 g, 1.54 mmol), N-bromosuccinimide (0.28 g, 1.55 mmol) and 2,2'-azobisisobutyronitrile (20 mg) in carbon tetrachloride (20 ml) was refluxed for 2 hours. The mixture was then cooled to ambient temperature and filtered. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (50 ml), washed with brine (50 ml) and dried (MgSO4). The solvent was evaporated yielding N-(4-bromomethylphenyl)-N-methylmethanesulphonamide (0.24 g, 54%) which was used without further purification.
Reaction SMILES: [OH:1][C@:2]([CH3:33])([CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:3][CH2:4][C:5]1[C:6]([CH2:14][CH2:15][CH3:16])=[C:7]([OH:13])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11].C(#N)C.C(Cl)Cl.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[OH:1][C@:2]([CH3:33])([CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][C:7](=[O:13])[C:6]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1c(O)cc(C)c(O)c1CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
A 50 mL RBF flask was charged with (R,R,R)-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-2-propyl-benzene-1,4-diol (Ex-1E-5) (110 mg, 0.24 mmol), ACN (15 mL) and DCM (2 mL), then cooled to 0° C. A solution of CAN (269 mg, 0.49 mmol) in water (1 mL) was added dropwise over 1 min to the reaction resulting in a bright orange solution. The reaction was stirred for 15 min then was diluted with water (5 mL). The aqueous layer was washed with DCM (3×30 mL). The combined DCM layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield an orange oil. The oil was purified by column chromatography (gradient—hept to 20:1 hept.:EtOAc) to yield (R,R,R)-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-2-propyl-[1,4]benzoquinone (Ex-1E-6) as an orange oil (50 mg, 44%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.56 (s, 1H), 2.58-2.54 (m, 2H), 2.45 (t, J=7.9 Hz, 2H), 2.04 (s, 3H), 1.55-1.04 (m, 26H), 1.00 (t, J=7.4 Hz, 3H), 0.89-0.85 (m, 15H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].C(N(C(C)C)CC)(C)C.N1C=CC=CC=1O[C:54](=[S:62])OC1C=CC=CN=1>C(Cl)Cl>[CH:23]1([C:15]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C@H:9]([N:8]=[C:54]=[S:62])[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:13][CH2:14]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)N=C=S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To 1 g (1.88 mmol) of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate trifluoroacetate dissolved in 10 ml of CH2Cl2 and 1 ml (5.66 mmol) of diisopropylethylamine are added 438 mg (1.88 mmol) of thiocarbonic acid O,O-bis(2-pyridyl) ester. After stirring the reaction medium for 2 hours at room temperature, the solvents are evaporated off and the crude product obtained is chromatographed on silica gel (eluent: 6/4 heptane/EtOAc). 763 mg of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 88%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=2)[N:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-methylbenzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[F:24][C:25]([F:31])([F:30])[C:26]([CH3:29])([NH2:28])[CH3:27].C(#N)C.[OH2:35]>CC(N(C)C)=O.C(Cl)Cl>[C:26]([OH:21])([C:25]([F:31])([F:30])[F:24])=[O:35].[CH3:22][C:3]1[C:2]([NH:28][C:26]([CH3:29])([CH3:27])[C:25]([F:31])([F:30])[F:24])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: O
Reactant: CC(C)(N)C(F)(F)F
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 120 °C
Reaction time: 5 h
Yield: 0.1 %
Yield: 2 %

Procedure:
A mixture of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (254c, 85 mg, 0.272 mmol), 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride (178 mg, 1.087 mmol, Oakwood Products, West Columbia, S.C.), Pd(tBu3P)2 (Strem, Newburyport, Mass.; 13.89 mg, 0.027 mmol), and K2PO4 (346 mg, 1.631 mmol) in DMA (2718 μl) was stirred at 120° C. for 5 h; the reaction was then heated to 145° C. for 2.5 d. The mixture was diluted with DCM (100 ml), and washed with saturated aq. NaHCO3 (2×75 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% DCM to 5% 2 M NH3 in MeOH/DCM) then by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(2-methyl-3-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (254, 2% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 404.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.81 (s, 6H) 2.63 (s, 3H) 2.97 (t, J=6.94 Hz, 2H) 3.66 (td, J=6.85, 2.54 Hz, 2H) 4.77 (s, 1H) 5.29 (br. s., 1H) 7.10 (d, J=2.15 Hz, 1H) 7.46 (t, J=7.92 Hz, 1H) 7.70 (dd, J=8.12, 1.27 Hz, 1H) 7.95 (dd, J=7.63, 1.37 Hz, 1H) 11.79 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −78.37 (3F, s).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[CH3:41][C:42]1[S:43][C:44]([CH:48]=O)=[C:45]([CH3:47])[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:48]/[C:44]1[S:43][C:42]([CH3:41])=[N:46][C:45]=1[CH3:47]
Reactant: Cc1nc(C)c(C=O)s1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 133; 116 mg, 0.24 mmol) in tetrahydrofuran (6 mL) at −20° C. After 15 min, 2,4-dimethylthiazole-5-carboxaldehyde (Example 43; 37 mg, 0.26 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (15 mL) was added. The resulting solution was washed with saturated sodium bicarbonate solution (15 mL) and brine. The organic layer was dried (MgSO4), filtered, evaporated, chromatographed over silica gel (60% ethyl acetate/hexanes) and crystallized from diethyl ether/hexanes to (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (98 mg, 82% yield) as a colorless solid.