Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12](CO)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.O.CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:7][C:6]#[N:3])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(CO)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CC#N)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.04 ml) was added to a solution of the product of step (ii) (3.02 g) in DCM (30 ml) and cooled to 0° C. before adding methane sulfonyl chloride (1.13 ml). The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with water, extracted with DCM then dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was dissolved in DMF (20 ml), sodium cyanide (1.07 g) was added and stirred at 100° C. for 2 h. The reaction mixture was diluted with water, extracted with ether, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent ether) to give the subtitle compound (1.9 g).
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:17]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]([Cl:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=NNC(C)(C)C
Reactant: ClCl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N=NC(C)(C)Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 64 grams (0.5 moles) of acetone t-butylhydrazone and 51 grams (0.504 moles) of triethylamine in 400 ml of pentane in a 1 liter 4 neck flask equipped with a mechanical stirrer, thermometer and gas inlet tube, was added 35.5 grams (0.5 moles) of chlorine gas, holding the temperature at -5° to 0° C. After the chlorine addition was complete, the reaction mixture was stirred an additional 15 minutes and the insoluble triethylamine hydrochloride filtered off. The filter cake was washed with an additional 150 ml pentane and the filtrate used in the subsequent reaction.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:16]1)(=[O:14])=[O:13])=[CH:6]2.C(N(C(C)C)CC)(C)C.[C:50](=O)([O:58]C1C=CC([N+]([O-])=O)=CC=1)[O:51][CH:52]([O:54][C:55](=[O:57])[CH3:56])[CH3:53]>C(O)C>[C:55]([O:54][CH:52]([O:51][C:50]([CH:28]1[NH:27][CH2:26][C:25]2[S:24][C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([C:7]4[NH:8][C:9]5[C:5]([CH:6]=4)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=5)(=[O:13])=[O:14])[CH2:16][CH:17]3[CH2:32][C:33]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[O:34])=[O:22])=[N:31][C:30]=2[CH2:29]1)=[O:58])[CH3:53])(=[O:57])[CH3:56]
Reactant: O=C(CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CNCC2)N1CCOCC1
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In ethanol (6 ml) was dissolved 4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (200 mg), followed by the addition of diisopropylethylamine (83 μl) and 1-acetoxyethyl p-nitrophenyl carbonate (128 mg). The resulting mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure. Methylene chloride and an aqueous solution of sodium bicarbonate were added and the mixture was separated into layers. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (1-2% methanol-methylene chloride). The product was dissolved in ethyl acetate, followed by crystallization from diethyl ether, whereby the title compound (100 mg) was obtained as colorless powder.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][NH2:15]>>[CH3:14][NH:15][C:3](=[O:2])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CN
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Yield: 82 %

Procedure:
Hydrochloride salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methyllimidazolidin-4-one (1): To a solution of ethanolic MeNH2 (8.0 M, 50 ml) was added (S)-phenylalanine methyl ester (23.0 g, 130 mmol). The resulting solution was stirred at room temperature until the amino ester was judged to be consumed by TLC analysis. The resulting solution was then concentrated to provide (S)-phenylalanine N-methyl amide (18 g, 82% yield) as a white solid. To a flask containing (S)-phenylalanine N-methyl amide (8.9 g, 50 mmol) was added THF (100 ml), trimethylacetaldehyde (5.4 g, 50 mmol), FeCl3 (1.7 g, 10 mmol) and 4Å MS (5.0 g). The resulting mixture was stirred at room temperature for 36 h, then washed with H2O (3×100 mL). The combined organics were concentrated and the resulting residue was treated with HCl (27 mL, 1N in ether). The resulting heterogeneous mixture was filtered to removed the undesired trans isomer.HCl salt and the resulting solution was concentrated. The residue was recrystallized (9:1 pentane/CH2Cl2) to provide the product (1) as a crystalline solid (2.88 g, 23% yield, >99% ee). IR (film) 3343, 2958, 1605, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ7.31−7.17 (m, 5H, ArH), 4.04 (s, 1H, NCHN), 3.72−3.65 (m, 1H, CHCH2), 3.13 (dd, J=4.1, 13.7 Hz, 1H, CH2), 2.92 (dd, J=7.7, 13.7 Hz, 1H, CH2), 2.90 (s, 3H, NCH3), 0.82 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ175.3, 138.0, 129.8, 128.7, 126.8, 82.7, 77.8, 77.4, 76.9, 59.7, 38.6, 35.4, 31.0, 25.7; [α]D=−39.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC using a Chiralpak OD-H and OD guard column (3.0% i-PrOH/hexanes, 1 mL/min); (5S) isomer tr=16.7 min, (5R) isomer tr=20.1 min.
Reaction SMILES: Cl.[CH3:2][C:3]([C:7]1[N:11]=[CH:10][N:9]([CH2:12]Cl)[N:8]=1)([CH3:6])[CH2:4][CH3:5].[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:2][C:3]([C:7]1[N:11]=[CH:10][N:9]([CH2:12][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[N:8]=1)([CH3:6])[CH2:4][CH3:5]
Reactant: CCC(C)(C)c1ncn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 23.1 %

Procedure:
0.98 g of 3-(1,1-dimethylpropyl)-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.11 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.29 g of {[3-(1,1-dimethylpropyl)-1H-1,2,4-triazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (30), hereinafter) shown by below formula.
Reaction SMILES: C[O:2][C:3]1[C:4]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:5][C:6]([CH3:14])=[C:7]([CH:13]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11].B(Br)(Br)Br.OS(O)(=O)=O>C(Cl)Cl.CO.CCOC(C)=O>[OH:2][C:3]1[C:4]([S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)=[CH:5][C:6]([CH3:14])=[C:7]([CH:13]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: BrB(Br)Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(O)cc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid, prepared according to Example 4, (1.0 g, 2.2 mmol) in 75 mL DCM at 0° C., was treated with dropwise addition of BBr3 (5.5 mL of a 1.0 M solution in DCM). After 30 minutes, the reaction was carefully quenched with 50% NH4OH. The reaction was then acidified to pH 1 with conc. HCl, and extracted with EtOAC. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then taken up in MeOH, followed by addition of 50 μL H2SO4, and then refluxing for 3 hours. The reaction was then diluted with EtOAc, washed 1×50 mL water, dried (Na2SO4), and the reaction concentrated in vacuo. The resulting ester was purified by recrystallization from EtOAC/Hexanes. The ester was then saponified in the same manner as described for Example 1, to give the title compound in 37% overall yield. IR cm−1:3408, 1752, 1323; 400 MHz 1H NMR (DMSO-d6) δ 9.56 (s, 1H), 7.82 (d, 2H, J=8.4 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.92 (s, 1H), 6.30 (s, 1H), 4.55 (s, 2H), 4.00 (s, 2H), 1.95 (s, 3H). Anal. Calc'd for C23H19F3NO4S.0.1 H2O C, 61.35; H, 4.30. found: C, 61.08; H, 3.92.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[N:16]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[C:26]([O:25][C:23]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([S:12]([C:7]2[C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:11]=3[CH:10]=[CH:9][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:17]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred suspension of isoquinoline-5-sulfonylchloride hydrochloride (3.00 g, 11.4 mmol) in anhydrous methylene chloride (100 mL) was added tert-butyl 1-homopiperazine carboxylate (3.00 g, 15.0 mmol) and triethylamine (4.36 g, 43.1 mmol). The mixture was stirred for 3 h, evaporated to dryness, mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (80 mL×2). The combined extracts were dried, filtered and evaporated to give an oil (4.45 g, 100%). LCMS (+APCI) m/z 392 (M+H).
Reaction SMILES: [CH2:1]([O:8]/[N:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[C:18]\1=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[C:24]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:25][N:26]([CH3:28])[CH:27]=1>C(#N)C.O>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[N:25][N:26]([CH3:28])[CH:27]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Reactant: Cn1cc(Br)c(-c2ccncc2)n1
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCC3=NOCc2ccccc2)c(-c2ccncc2)n1
Yield: 75.4 %

Procedure:
To (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (3.00 g; Example 2, Step 4) in 32 mL acetonitrile and 8.0 mL water was added 4-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (2.00 g; Example 3, Step 3). The solution was deoxygenated by bubbling nitrogen through the solution for 10 min. To the resulting mixture was added 5.62 g potassium carbonate, 10 mL N,N-dimethylformamide, and 290 mg tetrakis(triphenyphosphine)palladium(0). The mixture was then refluxed for 8 hours (over the course of this time a small portion of catalyst was added twice). The cooled reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water, brine, dried over sodium sulfate, filtered, and evaporated under vacuum to yield 5.1 g crude product as an oil. The crude material was purified by chromatography, eluting with ethyl acetate to afford 2.50 g (80% yield) product as a light yellow foam. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 395.2 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])(=[O:30])=[O:29])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.4 g) and 2,4-dichlorobenzenesulfonyl chloride ((0.38 g) were combined to provide the title compound (0.26 g), as a crystalline solid following flash chromatography and trituration with ether. mp 150-151.5° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=1)[NH2:3].C(N(CC)CC)C.C[O:19][C:20](=O)[N:21]=[C:22](SC)[C:23]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH2:46][CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:38]=1[F:56])=[N:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)=[CH:27][CH:26]=1>CN(C=O)C>[Si:49]([O:48][CH2:47][CH2:46][O:45][C:39]1[C:38]([F:56])=[C:37]([CH:23]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:35]=[C:34]([CH3:36])[O:33][N:32]=3)=[CH:29][CH:30]=2)[C:22]2[NH:21][C:20](=[O:19])[N:2]([C:4]3[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=3)[N:3]=2)[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: NNc1ncc[nH]c1=O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
3-Hydrazino-1H-pyrazin-2-one hydrochloride (24 mg) and triethylamine (0.033 ml) were added to 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (200a)). The resulting mixture was stirred at 85° C. for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were further added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (34 mg).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:15][C:14]([C:26](O)=[O:27])=[CH:13]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][O:56][C:57](=[O:64])[C@H:58]([C:60]([CH3:63])([CH3:62])[CH3:61])[NH2:59].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:55][O:56][C:57](=[O:64])[C@@H:58]([NH:59][C:26]([C:14]1[N:15]=[C:16]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:9][C:8]1[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=1)=[CH:19][CH:18]=2)=[O:27])[C:60]([CH3:63])([CH3:62])[CH3:61]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)c1ccc(Oc2ccc3c(CC4CCCC4)nc(C(=O)O)cc3c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2c(CC2CCCC2)n1)C(C)(C)C
Yield: 35 %

Procedure:
To a solution of 6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (50 mg, 0.124 mmol) in dry DMF (1.25 mL) was added HBTU (1.5 eq., 0.19 mmol, 71 mg), tert-butylglycine methyl ester (1.1 eq., 0.14 mmol, 25 mg) and DIEA (3.0 eq., 0.37 mmol, 0.065 mL) according to general procedure A. Purification by chromatography on silica afforded 23 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH2:21]>CN(C=O)C>[C:1]1([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([C@@:9]2([CH3:11])[CH2:10][O:21]2)=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O
Reactant: C=C(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
A solution of (S)-tert-butyl (1-(cyclopent-1-en-1-yl)-4-methyl-3-oxopent-4-en-2-yl)carbamate (10.0 g, 35.6 mmol) in DMF (180 mL) was cooled to −20° C. and bleach (54.0 mL, 71.2 mmol, 10%) was added dropwise under nitrogen. The reaction mixture was warmed to 0° C. and stirred for 1.5 h. Water (200 mL) was added and the mixture was extracted with EtOAc (200 mL×2). The organic phases were combined, washed with brine (200 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)carbamate as viscous oil (5.6 g, 53% yield). 1H NMR (300 MHz, CDCl3): δ 4.62 (s, 1H), 4.91 (d, J=7.5 Hz, 1H), 4.44-4.37 (m, 1H), 3.29 (d, J=4.8 Hz, 1H), 2.89 (d, J=4.8 Hz, 1H), 2.56-2.52 (m, 1H), 2.29-2.26 (m, 5H), 1.92-1.82 (m, 2H), 1.51 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.2 %

Procedure:
Benzyl 3-hydroxypyrrolidine-1-carboxylate (0.30 g, 1.34 mmol) was dissolved in DCM (20 mL) and pyridinium chlorochromate was added (0.44 g, 2.0 mmol). The resulting slurry was stirred at room temperature for 72 h. Benzyl 3-oxopyrrolidine-1-carboxylate (0.080 g, 27%) was isolated as a colorless oil by prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.25 min. LCMS: 1.20 min [M+1] not observed (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][CH2:7][C:8](Cl)=[O:9]>C(Cl)Cl>[Cl:6][CH2:7][C:8]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])=[O:9]
Reactant: C[C@@H](N)CO
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: C[C@H](CO)NC(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)-2-amino-propan-1-ol (2.0 g, 26.6 mmol) in 150 mL of DCM at −40° C. under nitrogen atmosphere was added dropwise chloroacetyl chloride (2.3 mL, 29.2 mmol) in 60 mL of DCM. The mixture was gradually warmed to 0° C. and was stirred for 2 hours. After the removal of the solvents the residue was diluted with 50 mL of 1:1 ethyl acetate/hexane, stirred for 30 min and filtered. The filtrate was concentrated to afford 2-chloro-N—((R)-2-hydroxy-1-methyl-ethyl)-acetamide as a liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:11]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of methyl 3-amino-2,6-dibromoisonicotinate (5.00 g, 16.1 mmol), 4-methoxycarbonylphenylboronic acid (2.90 gm, 16.1 mmol), and tetrakis-(triphenylphosphine)palladium(0) (0.932 g, 0.807 mmol) in a flask was flushed with nitrogen. Toluene (70 mL), MeOH (14 mL), and a 2 N aqueous solution of sodium carbonate (18 mL, 37 mmol) were added and the reaction was heated in a 120° C. oil bath for 4 hr. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)isonicotinate (2.0 gm). MS (ESI) m/z 365.0 and 367.0 (M+H). 1H NMR (CDCl3) δ ppm 8.15 (2H, d, J=8.24 Hz), 7.84 (1H, s), 7.71 (2H, d, J=8.24 Hz), 5.94 (2H, br. s.), 3.94 (6H, d, J=5.19 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>>[NH2:7][C:4]1[S:5][C:6]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: O
Product: Cc1nc(N)sc1C(O)(C(F)(F)F)C(F)(F)F

Procedure:
The title compound was prepared from commercially available of 4-methylthiazol-2-amine (Aldrich) and hexafluoroacetone trihydrate (Aldrich) according to the procedure described in European Journal of Organic Chemistry, (21), 4286-4291; 2003. MS (ESI+) m/z 281 (M+H)+.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:16]([CH3:17])=[CH:15][S:14][CH:13]=1)(=[O:11])=[O:10])=[O:7])CCC.C1(C2CCCCCCC2)CCCCCCC1.C(Cl)(Cl)=O>>[CH3:17][C:16]1[C:12]([S:9]([N:8]=[C:6]=[O:7])(=[O:10])=[O:11])=[CH:13][S:14][CH:15]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1cscc1C
Agent: C1CCCC(C2CCCCCCC2)CCC1
Agent: O=C(Cl)Cl
Product: Cc1cscc1S(=O)(=O)N=C=O

Procedure:
A mixture of 18.8 g of N-butylaminocarbonyl-4-methyl-3-thiophenesulfonamide, 0.3 g of 1,4-diaza-[2.2.2.]bicyclooctane and 100 ml of dry xylenes was heated to reflux (136° C.) and 7.4 g of phosgene was then added at a rate to maintain the temperature at above 125°. The mixture was refluxed for three and one half hours after the addition was completed. It was then cooled, filtered and concentrated in vacuo to yield a dark oil, (15 g) which showed absorption in the infrared spectrum at 2250 cm-1. This intermediate was used without further purification.