Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14].OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:3]2)([O-:23])=[O:22]
Reactant: CCC(=O)NCC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)NCC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
N-Indan-2-ylmethyl-propionamide (4.00 g, 19.7 mmol) was dissolved in nitromethane (60 mL) and added to a mixture of concentrated H2SO4 (19 mL), concentrated nitric acid (1.4 mL) and water (3.2 mL) cooled to 5° C. After stirring for 45 min, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (4.67 g, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A degassed mixture of tert-butyl 4-bromo-2-nitrophenylcarbamate (5.4 g, 17 mmol), 1-ethylpiperazine (2.91 g, 25.5 mmol), Pd2(dba)3 (2.1 g, 3.4 mmol), xantphos (3.92 g, 6.8 mmol) and Cs2CO3 (11.1 g, 34 mmol) in toluene (85 mL) was heated at 100° C. for 4 hours. The reaction was concentrated, and the residue was purified by flash chromatography on silica eluting with MeOH:DCM=1:50-1:20 to obtain the title compound (3.3 g, yield: 55%). MS (ESI): 351 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.[Cl:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]2[N:20]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:22]=[C:14]2[CH:13]=1.[NH2:27][C:28]1[C:32]([Br:33])=[CH:31][N:30]([CH3:34])[N:29]=1>C(#N)C>[Br:33][C:32]1[C:28]([NH:27][S:23]([C:21]2[N:22]=[C:14]3[N:15]([C:16]([O:18][CH3:19])=[N:17][C:12]([Cl:11])=[CH:13]3)[N:20]=2)(=[O:25])=[O:24])=[N:29][N:30]([CH3:34])[CH:31]=1
Reactant: COc1nc(Cl)cc2nc(S(=O)(=O)Cl)nn12
Reactant: Cn1cc(Br)c(N)n1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1nc(Cl)cc2nc(S(=O)(=O)Nc3nn(C)cc3Br)nn12
Temperature: 25 °C

Procedure:
Pyridine (1.08 g, 8.0 mmol) and dimethyl sulfoxide (0.2 g) were added to a solution of 7-chloro-5-methoxy-1,2,4-triazolo[1,5-c]pyrimidine-2-sulfonyl chloride (1.0 g, 4.0 mmol) and 3-amino-4-bromo-1-methylpyrazole (0.70 g, 4.0 mmol) in 10 mL of acetonitrile with stirring at ambient temperature and the mixture was allowed to react overnight. The mixture was then concentrated by evaporation under reduced pressure and the residue was taken up in methylene chloride. The resulting solution was extracted with water and dried over magnesium sulfate. The volatile materials were then removed by evaporation under reduced pressure and the solid residue was extracted with diethyl ether and with water, recovered by filtration, and dried under reduced pressure to obtain 0.38 g (25 percent of theory) of the title compound as a white solid melting at 230°-232° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Cl:31]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.75 mmol) in dry CHCl3 (20 mL), NCS (0.08 g, 0.6 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.15 g) as thick syrup.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@H](CC(=O)O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H](CC(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20 mg, 0.06 mmol), (R)-3-amino-3-phenyl-propionic acid (62 mg, 0.38 mmol, PepTech) and sodium methoxide (19 mg, 0.35 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 17 mg. MS: (−) m/z 451.93 (M−1).
Reaction SMILES: [O-]Cl=O.[Na+].[Cl:5][C:6]1[N:7]=[C:8]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[CH:11]=[O:12].CC(=CC)C.CC([OH:39])(C)C>O.C1COCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[C:11]([OH:39])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of NaClO2 (1.55 g, 17 mmol) and NaH2PO4 H2O (1.42 g, 10.3 mmol) in H2O was added to a mixture of 4-chloro-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carbaldehyde (694 mg, 1.7 mmol), 2-methyl-2-butene (10.8 mL, 21.5 mmol, 2 M in THF), and tBuOH (1.33 mL) in THF (5.5 mL) at room temperature. The mixture was stirred overnight and separated and the aqueous layer was extracted with EtOAc. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-80% 0.1%) formic acid solution of EtOAc in DCM) to give the title compound (740 mg, >99%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.83 (2H, s) 4.80 (2H, s) 3.56 (2H, t, J=8.1 Hz) 0.83-0.91 (11H, m) 0.08 (6H, s) −0.04 (9H, s). LCMS: m/z 421 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15]([C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)=[O:16])=[N:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].CC(O)=O>O1CCCC1.C(O)C>[Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([CH:15]([C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)[OH:16])=[N:12][N:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1nnc(C(=O)c2cnc(Cl)c(Cl)c2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCc1nnc(C(O)c2cnc(Cl)c(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a solution of (5-((tert-butyldimethylsilyloxy)methyl)-1,3,4-oxadiazol-2-yl)(5,6-dichloropyridin-3-yl)methanone (70) (1.75 g, 4.51 mmol) in tetrahydrofuran (8.8 mL) and ethanol (8.8 mL) was added sodium tetrahydroborate (0.085 g, 2.25 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 15 min. AcOH was added to the reaction flask and the mixture was extracted with ethyl acetate (50 mL×2). The resulting organic layer was washed with H2O, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 1.79 g of the product (71) as a pale yellow oil (quant.).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])[CH2:2][CH3:3].[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: CCCOc1cccc(CN)c1
Reactant: O=C(Cl)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCOc1cccc(CNC(=O)Cc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 3-propoxy-benzylamine in 50 mL of dichloromethane and add dropwise to a mixture of 3-bromophenylacetyl chloride (4.90 gm; 21.0 mmol) and triethylamine (3.60 gm; 35.9 mmol) in 250 mL of dichloromethane at 0° C. Allow the reaction to warm to room temperature and stir for 18 h. Pour the reaction into 100 mL of saturated brine, separate the layers and extract the aqueous layer with 100 mL of dichloromethane. Combine organic layers, wash with brine, dry (MgSO4), and concentrate. Purification by chromatography on silica gel with 40% EtOAc in hexanes gives the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:8][C:4]1[CH:3]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:7]=[CH:6][N:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#C[Si](C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-2-methyl-pyridine (9.5 g, 41.8 mmol) was dissolved in 150 mL dry THF and 18 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (341 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at RT for 1 h. Copper(I)iodide (248 mg, 1.3 mmol) and trimethylsilylacetylen (6.39 g, 6.50 mmol) were added. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate gradient 100:0→0:100). The desired product was obtained as a light brown liquid (8.18 g, 99%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CC
Yield: 79.5 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110c) (0.35 g, 1.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.38 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 3/2, 2/1) to obtain 0.23 g of the title compound as a colorless solid (80%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][C:3]=1[O:20][CH3:21].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:27][C:28]=1C>>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])[CH:4]=[C:3]([O:20][CH3:21])[C:2]=1[O:1][CH2:23][C:24]1[N:25]=[C:26](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:27][CH:28]=1
Reactant: Cc1oc(/C=C/c2ccccc2)nc1CCl
Reactant: COc1cc(CCCC2OC(=O)NC2=O)cc(OC)c1O
Product: COc1cc(CCCC2OC(=O)NC2=O)cc(OC)c1OCc1coc(/C=C/c2ccccc2)n1

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-[(E)-styryl]oxazole to obtain 5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.94-95° C.
Reaction SMILES: [N+:1]([CH:4]([CH3:9])[CH:5]([OH:8])[CH2:6][CH3:7])([O-:3])=[O:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:8][CH:5]([CH2:6][CH3:7])[CH:4]([N+:1]([O-:3])=[O:2])[CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)C(C)[N+](=O)[O-]
Product: CCC(OC(C)=O)C(C)[N+](=O)[O-]

Procedure:
reacting 4-nitro-3-pentanol with acetic anhydride to form 3-acetoxy-2-nitropentane;
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([NH2:10])=[O:9])[N:5]=[CH:4]1.Br[CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>CN(C=O)C>[C:8]([C:6]1[N:5]=[CH:4][N:3]([CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)(=[O:9])[NH2:10]
Reactant: CCCC(Br)C(=O)OCC
Reactant: NC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)n1cnc(C(N)=O)c1
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
NaH (60% in mineral oil, 60 mg) was added to a stirred solution of 4-imidazolecarboxamide (obtained in Preparation 1) (167 mg) in DMF (3.5 ml), and the reaction mixture was stirred for 1.5 hours at 55° C. Ethyl 2-bromovalerate (0.153 ml) was added to this mixture, and the reaction mixture was stirred for 3 hours at 55-60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel (12 g) chromatography eluting with chloroform/methanol (25:1) to give ethyl 2-(4-carbamoyl-1-imidazolyl)valerate (150 mg).
Reaction SMILES: C(OCC)C.[OH:6][CH:7]([CH2:19][C:20]([CH2:23][Si](C)(C)C)=[C:21]=[CH2:22])[CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.O>C(OCC)(=O)C>[CH2:22]=[C:21]1[C:20](=[CH2:23])[CH2:19][CH:7]2[O:6][C:11]1([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: C=C=C(CC(O)CCC(=O)Cc1ccccc1)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: C=C1CC2CCCC(c3ccccc3)(O2)C1=C
Temperature: -78 °C
Yield: 97.9 %

Procedure:
1.50 mL of diethyl ether was added to 5-hydroxy-1-phenyl-7-trimethylsilanylmethyl-nona-7,8-diene-2-one (117 mg, 0.37 mmol) under nitrogen atmosphere. While stirring at −78° C., trimethylsilyl trifluoromethanesulfonate (TMSOTf; 67 μL, 0.37 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane={fraction (1/7)}) to obtain 82 mg of the product (98%). 1H NMR(300 MHz, CDCl3) δ 7.43 (d, 2H, J=1.5 Hz), 7.21 (m, 3H), 5.17 (s, 1H), 5.07 (s, 1H), 4.72 (s, 1H), 4.33 (s, 1H), 4.13 (s, 1H), 3.00 (m, 1H), 2.40 (d, 1H, J=14.8 Hz), 2.19 (m, 2H), 1.94 (m, 2H), 1.60 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 152.5, 147.0, 146.0, 128.2, 127.4, 126.4, 111.7, 109.4, 77.7, 69.5, 38.7, 36.7, 30.6, 17.8 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[C:8]([CH3:20])[C:9]([CH:12]3[CH2:17][C:16](=[O:18])[CH:15]=[C:14]([OH:19])[CH2:13]3)=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:23](O)(=[O:26])[CH2:24][CH3:25].CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[C:8]([CH3:20])[C:9]([CH:12]3[CH2:17][C:16](=[O:18])[C:15]([C:23](=[O:26])[CH2:24][CH3:25])=[C:14]([OH:19])[CH2:13]3)=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(C)c2c1CC(C)(C)O2
Reactant: CCC(=O)O
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CCC(=O)C1=C(O)CC(c2c(C)c(C)c3c(c2C)OC(C)(C)C3)CC1=O
Temperature: 25 °C

Procedure:
To a solution of 12 g of the 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one in 100 ml of absolute toluene was added 20.5 ml of anhydrous propionic acid and refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a residue. To a solution of the residue in 100 ml of absolute toluene was added 0.98 g of dimethylaminopyridine, After refluxing 20 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 3.9 g of 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-2-propionyl-3-hydroxycyclohex-2-en-1-one as a yellow solid.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:61]2[N:62]=[C:63]([NH:66]C(OC(C)(C)C)=O)[S:64][CH:65]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][CH2:44][CH2:45][NH:46]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:46][CH2:45][CH2:44][CH2:43][NH:42][CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]3)/[C:61]3[N:62]=[C:63]([NH2:66])[S:64][CH:65]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 43.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (0.5 g, 0.48 mmol), DCM (2.5 mL), and TFA (1 mL, 13 mmol) for 1.5 h. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (123 mg, 42%). LCMS: Rt=0.31 min, m/z=587.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6): δ 9.39 (br s, 1H), 7.76 (s, 1H), 7.22 (s, 2H), 6.73 (s, 1H), 5.33 (dd, J=9.0, 5.5 Hz, 1H), 4.84 (dd, J=14.3, 4.5 Hz, 1H), 4.73-4.61 (m, 1H), 4.61-4.48 (m, 1H), 4.27-4.14 (m, 2H), 3.02-2.89 (m, 3H), 2.85 (t, J=7.4 Hz, 3H), 1.85 (p, J=7.5 Hz, 3H) 1.32-1.04 (m, 6H); 1H NMR (400 MHz, D2O) δ 7.90 (s, 1H), 7.15 (s, 1H), 5.67 (d, J=5.5 Hz, 1H), 5.12-5.04 (m, 1H), 5.04-4.88 (m, 2H), 4.45 (s, 2H), 3.30-3.22 (m, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.24-2.08 (m, 2H), 1.37-1.26 (m, 2H), 1.26-1.08 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[NH:3]1.[H-].[Na+].Br[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[O:1]=[C:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:3]1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NC2c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C2(CCN(C(=O)OC(C)(C)C)CC2)C1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
In a dry 100 mL 3-necked flask, add 1,1-dimethylethyl 1-oxo-3-(4-chlorophenyl) -2,7-diazaspiro[3.5]nonane-7-carboxylate (7.0 g) and dry DMF (50 mL) and cool to ˜2 C. Add portionwise sodium hydride in 60% oil dispersion (1.10 g) keeping temperature at 2-5 C. After 5 min., add portionwise 2-bromopropane (2.6 mL) keeping temperature 3 to 8° C. Warm mixture to 50° C. After 4.5 h, cool to ˜20° C. and add ice water (400 mL). Extract with EtOAc (2×499 mL). Extract EtOAc with brine (50 mL). Concentrate the dried (MgSO4) EtOAc in vacuo to give the title compound as an amber oil (8.80 g). Add EtOAc:hexane (1:2, 20 mL) and keep overnight at RT to give the title compound as a yellow solid (5.75 g).