Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:22]1[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](CCCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS No. 183890-36-0, 7.5 g) in THF (200 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether, 100 mL) was added dropwise at −40° C., and the reaction solution was stirred at room temperature for six hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 4.0 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[C:24]([O:27][CH2:28][C:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH3:33])[C:30]([OH:32])=[O:31])(=[O:26])[CH3:25]>>[C:36]([O:35][CH2:34][C:29]([CH3:33])([C:30]([O:32][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:31])[CH2:28][O:27][C:24](=[O:26])[CH3:25])(=[O:38])[CH3:37]
Reactant: ON=C1CCOCC1
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC(=O)OCC(C)(COC(C)=O)C(=O)OC1(N=O)CCOCC1

Procedure:
2-Methyl-2-((4-nitrosotetrahydro-2H-pyran-4-yloxy)carbonyl)propane-1,3-diyl diacetate was prepared from tetrahydro-pyran-4-one oxime and bis(3-acetoxy-2-acetoxymethyl-2-methyl-propionate)iodobenzene (synthesized from iodobenzene diacetate and 3-acetoxy-2-acetoxymethyl-2-methyl-propionic acid which was in turn synthesized using the reported method J. Am. Chem. Soc., 118, 1996, 6388-6395) using conditions of General Method 4. 1H NMR (250 MHz, CHLOROFORM-d) δ 4.32 (4H, s), 3.98-4.17 (2H, m), 3.54-3.74 (2H, m), 2.28-2.46 (2H, m), 2.13 (6H, s), 1.77-1.94 (2H, m), 1.40 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@:11]1([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCN(CC)CC.[NH2:45][CH2:46][CH2:47][OH:48].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[NH2:1][C@H:2]([C:7]([O:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@:11]1([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](=[O:34])[NH:45][CH2:46][CH2:47][OH:48])=[CH:31][CH:30]=1)[C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)NCCO)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of 4-{[(1′R,2′R)-1′-(L-leucyloxy)-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}benzoic acid (24, 130 mg, 0.26 mmol), Et3N (78 mg, 0.78 mmol) and 2-amino ethanol (24 mg, 0.39 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The separated organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 70 mg (54%) of the title compound as an off white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 9.37 g (69.3 mM) of 3-phenylpropylamine and 14 ml (100.4 mM) of triethylamine in acetonitrile (70 ml) was added 16.4 ml (122.7 mM) of ethyl trifluoroacetate at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. The solvent was then distilled off and the residue was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[N:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1([C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([O:2][CH3:1])=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cncc(N2CCOCC2)c1
Temperature: 110 °C
Yield: 42 %

Procedure:
To a mixture of methyl-5-bromonicotinate (10 g, 0.045 mol) and morpholine (4.6 g, 0.054 mol) in dry toluene (100 mL) was added fused CsCO3 (30 g, 0.09 mol) with stirring under argon. To this mixture was added BINAP (0.45 g, 0.0005 mol), Pd2(dba)3 (0.22 g, 0.00015 mol) and then the reaction mixture was refluxed at 110° C. for 50 h. The reaction mixture was cooled down to r.t. and diluted with diethyl ether (400 ml) and filtered through celite. The filtrate was concentrated under vacuum and purified by flash column chromatography (CHCl3/MeOH, 4:1) to give 4.2 g (41%) of methyl 5-morpholin-4-ylnicotinate as a liquid. TLC—Chloroform/Methanol (8/2): Rf=0.7.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): δ 0.73-0.83 (m, 3 H), 1.10-1.40 (14 H), 1.91 (m, 2 H), 3.93 (m, 2 H), 4.39 (d, J=5.0 Hz, 2 H), 5.25-5.45 (m, 1 H), 5.98 (m, 1 H), 7.11 (m, 2 H), 7.35 (m, 2 H). Rf=0.36 (10% ethyl acetate/n-hexane).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH3:32].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:2]1([N:1]([CH2:30][CH2:31][CH3:32])[C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(c1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 0 °C
Yield: 48.7 %

Procedure:
To a solution of methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate (0.20 g, 0.58 mmol) in N,N-dimethylformamide (4 mL) was added 60% sodium hydride (0.035 g, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. n-Propylbromide (0.063 mL, 0.69 mmol) and sodium iodide (0.10 g, 0.69 mmol) were added to this mixture with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. Then the residue was dissolved in a mixed solution of methanol (3 mL) and tetrahydrofuran (6 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid, separated and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-1/2) to give the title compound (0.11 g, yield 47%) as colorless crystals. MS (APCI−): 388 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH2:14][NH2:15].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([C:26](OCC)=[O:27])[N:25]=2)[CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([C:26]([NH:15][CH2:14][C:4]3[CH:5]=[C:6]([O:9][C:10]([F:12])([F:11])[F:13])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:27])[N:25]=2)[CH:22]=1
Reactant: COc1ccc(OC(F)(F)F)cc1CN
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: COc1ccc(OC(F)(F)F)cc1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-methoxy-5-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20].CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=1
Reactant: N#Cc1cc(Br)c[nH]c1=O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(Br)cc(C#N)c1=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 74.8 %

Procedure:
To 5-bromo-3-cyano-2(1H)-pyridinone (1.4 g, 7.0 mmol) and potassium carbonate (1.9 g, 1.3 mL, 14.1 mmol), THF (26.4 mL) and methyl chloroacetate (1.53 g, 1.2 mL, 14.1 mmol) were added. The reaction was stirred at 80° C. The starting material didn't dissolve well in THF. After 3.5 hours, mainly staring material was observed. DMF (18 mL) was added and the starting material went into solution. The reaction was heated at 80° C. for 45 minutes. The desired mass was observed by LCMS. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure. The crude product was separated by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(5-bromo-3-cyano-2-oxopyridin-1(2H)-yl)acetate as a yellow solid (1.42 g, 74%). ESI-MS m/z calc. 271.07. found 271.3 (M+1)+. Retention time 0.59 minutes.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:9][C:10]=1[C:11]([CH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1)=[O:12].ClC1C=CC=C(C(OO)=[O:35])C=1.O>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[S:9][C:10]=1[C:11]([CH:13]1[CH2:14][CH2:15][S:16](=[O:35])[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCS(=O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Compound 587 (500 mg, 1.27 mmol) was dissolved in chloroform (13 mL), and m-chloroperbenzoic acid (219 mg, 1.27 mmol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 591 (359 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:6]#[N:7].C(N(CC)CC)C.C[Si]([N:42]=[N+:43]=[N-:44])(C)C.[OH-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6]1[N:42]=[N:43][NH:44][N:7]=1
Reactant: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2Br)c2nn[nH]n2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To the product of step C (909 g, 1.80 mol) in methyl tert-butyl ether (9 L) was added triethylamine (2.5 L, 18 mol) followed by trimethylsilylazide (415 g, 3.60 mol). The resulting mixture was heated to 50° C. for 8 hours. An aliquot was checked by HPLC and starting material was still present. The mixture was cooled and trimethylsilylazide (50 g) was added. The mixture was again heated to 50° C. and stirred 3 hours. After cooling, 1N sodium hydroxide (9 L) was added. The layers were separated (added 150 ml ethanol to facilitate separation). The organics were washed with aqueous 10% citric acid solution (8 L, then 2 L) until washings were acidic. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid turned white upon standing (976 g, 99% yield). 1H-NMR (CD3OD) δ 7.47 (m, 3H), 7.64 (d, 8.3 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.38 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.88 (s, 2H), 4.86 (s, 2H). Mass Spec (ESI): M+1=548.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@@H:12]([NH:18][C:19](=[O:35])[C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:14][C:15](O)=[O:16])[CH2:6][CH2:5]2.O1CCOCC1.N.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C>[C:15]([CH2:14][CH2:13][C@H:12]([NH:18][C:19]([C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:35])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)(=[O:16])[NH2:44]
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)CN2CCc3cc(F)ccc32)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)CN2CCc3cc(F)ccc32)c1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
The title compound of Example 43 (30 mg, 61 μmol) was treated with dioxane (2 mL) and concentrated ammonia (0.2 mL). HATU (35 mg, 92 μmol) was added and the reaction was stirred overnight. Another portion of HATU (80 mg, 210 μmol) was added and the reaction was stirred for an additional 3 hours. The reaction was then diluted with ethyl acetate and extracted once with 1 M NaOH solution. The organics were dried over MgSO4 and the solvent was removed. The residue was purified by silica gel column chromatography using DCM and methanol as solvents to afford the title compound (25 mg, 84%); 1H NMR (CDCl3, 400 MHz) δ 0.90 (s, 3H), 0.91 (s, 3H), 0.88-0.99 (m, 1H), 1.58-1.80 (m, 4H), 1.97-2.12 (m, 2H), 2.23-2.30 (m, 2H), 2.37 (s, 3H), 2.82 (s, 2H), 2.85-3.04 (m, 3H), 3.15 (dd, 1H, J1=6.5, J2=13.6), 3.34 (dd, 1H, J1=8.4, J2=16.9), 3.48 (dd, 1H, J1=8.1, J2=16.0), 4.12-4.21 (m, 1H), 4.40-4.72 (m, 1H), 5.86 (s, 1H), 6.32-6.47 (m, 2H), 6.72 (dd, 1H, J1=J2=8.4), 6.79 (d, 1H, J=7.4), 6.94 (d, 1H, J=7.6), 7.06 (d, 1H, J=8.4), 7.23-7.36 (m, 2H), 7.52-7.61 (m, 2H); HPLC-MS calcd. for C27H35FN4O3 (M+H+) 483.3, found 483.5.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2)(=[O:26])=[O:25]
Reactant: O=C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(=O)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a solution of 4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexan-1-one (450 mg, 1.41 mmol, 1.00 equiv) in DCM (10 mL) was added methanesulfonyl chloride (242 mg, 2.11 mmol, 1.50 equiv) and triethylamine (430 mg, 4.25 mmol, 3.00 equiv) via syringe under nitrogen. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was diluted with 50 mL of DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated to give 500 mg (89%) of [(3S)-12-[(4-oxocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:14])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.6 %

Procedure:
To a solution of 2,4-difluorocinnamic acid (20 g, 135 mmol) in N,N-dimethylformamide (500 mL) at room temperature under dry nitrogen was added potassium carbonate (90 g, 675 mmol) then iodomethane (21 mL, 337.5 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 7 hours before being quenched by the addition of water (1 L) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 120 g column) eluting with 2% ethyl acetate in pentane increasing polarity in a linear gradient to 10% ethyl acetate in pentane over 1 hour to afford the title compound as a white solid (20.5 g, 77%). 1H NMR (400 MHz, CDCl3) δH 3.80 (3H, s), 6.50 (1H, d), 6.85 (1H, m), 7.50 (1H, m), 7.75 (1H, d); LRMS (APCI) 216 [MNH4+], 199 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([NH2:31])[CH:23]=[C:24]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:31][C:22]2[CH:23]=[C:24]([C:26]3[NH:30][N:29]=[N:28][N:27]=3)[CH:25]=[C:20]([Br:19])[CH:21]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(Br)cc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (250 mg, 1.1 mmol) in CH2Cl2 (6 mL) was added 3-bromo-5-(1H-tetrazol-5-yl)-phenylamine dihydrochloride (prepared as described in Part C, 365 mg, 1.32 mmol), HBTU (626 mg, 1.65 mmol) and DIPEA (0.576 ml, 3.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH2Cl2 and successively washed with 1M aqueous HCl solution (30 mL) and a saturated aqueous NaHCO3 solution. The organic phase was dried (phase separator) and evaporated under vacuum. The crude mixture was purified by preparative HPLC (C18 Nucleosil 100-10, flow: 40 ml/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA). After combination of the purified fractions, CH3CN was removed under vacuum and lyophilization gave the desired compound. MS (LC/MS): 447.1 [M−H]−; tR (HPLC conditions k): 4.62 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=C)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:31]1CCCC1>O=[Os](=O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=[O:31])[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: C=Cc1c(C(F)(F)F)ccc2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)OC
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
NaIO4 (1.80 g) and OsO4 (4% in water, 50 μL) are added to a mixture of {(S)-6-[(R)-5-trifluoromethyl-4-vinyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (1.25 g), tetrahydrofuran (16 mL), and water (4 mL) at room temperature. The mixture is stirred at 50° C. overnight. After cooling to room temperature, water is added and the mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 4): tR=1.19 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8]
Reactant: CC(C)N
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Product: CC(C)NC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Yield: 23.9 %

Procedure:
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid and isopropylamine as the raw materials, the same operation as the example 212(2) gave the title compound.