Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1cncc(F)c1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cncc(F)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and 5-fluoropyridine-3-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.84 min, m/z=435 (M+1); 1H NMR (CDCl3) 8.58 (t, 1H, J=1.5, 1.5 Hz), 8.44 (d, 1H, J=3 Hz), 7.51-7.48 (ddd, 1H, J=9, 4, 2 Hz), 7.33-7.262 (m, 4H), 7.04 (at, J=9, 9 Hz), 6.98 (d, 2H, 8 Hz), 5.76-5.66 (m, 2H), 5.11-5.00 (m, 2H), 3.00-2.95 (m, 1H), 2.65-2.5 (m, 2H), 2.41-2.33 (m, 1H) 2.31-2.18 (m, 2H), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:24]([OH:26])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8][S:9]([C:12]1[C:21]([CH3:22])=[C:19]([CH3:20])[C:16]([O:17][CH3:18])=[CH:15][C:13]=1[CH3:14])(=[O:11])=[O:10].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1F>C(Cl)Cl>[C:30]([O:29][C:27](=[O:28])[NH:1][CH:2]1[CH2:3][CH2:4][CH2:5][N:6]([C:7](=[NH:23])[NH:8][S:9]([C:12]2[C:13]([CH3:14])=[CH:15][C:16]([O:17][CH3:18])=[C:19]([CH3:20])[C:21]=2[CH3:22])(=[O:11])=[O:10])[C:24]1=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)NC(=N)N2CCCC(NC(=O)OC(C)(C)C)C2=O)c(C)c1C
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a solution of Boc-Arg(Mtr)-OH (6.81 g, 14 mmol) and pyridine (1.11 g, 14 mmol) in CH2Cl2 (50 mL) at −20° C. was added cyanuric fluoride (9.45 g, 70 mmol). After addition, the reaction mixture was stirred at −10° C. for 1.5 hours. The reaction mixture was quenched with an ice-H2O mixture and CH2Cl2 (50 mL), the resulting suspension was filtered through a pad of Celite and the two clear layers were separated. The aqueous layer was extracted with CH2Cl2 (50 mL)). The combined organic layer was washed with H2O (50 mL), and dried over MgSO4. After filtration and concentration, the crude oil was dissolved in CH2Cl2 and triturated in hexane. The title product was obtained as a white solid by vacuum filtration.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(C(N)=O)c1
Yield: 95 %

Procedure:
3-((Trimethylsilyl)ethynyl)benzamide (I143) (0.565 g, 2.60 mmol) was dissolved in THF (33 mL), and 1 M TBAF in THF (3.25 mL, 3.25 mmol) was added. After two hours the reaction was poured into water (200 mL) and the resulting solution was extracted with diethyl ether (3×200 mL). The combined ether phases were washed with brine (200 mL), dried over sodium sulfate then evaporated to give the title compound (I144) (0.357 g, 95% yield) as a tan solid; 1H NMR (400 MHz, CDCl3) δ 7.92 (t, J=1.5 Hz, 1H), 7.83-7.79 (m, 1H), 7.64 (dt, J=7.7, 1.4 Hz, 1H), 7.42 (td, J=7.8, 0.5 Hz, 1H), 6.07 (br s, 1H), 5.77 (br s, 1H), 3.13 (s, 1H). LCMS Method C: rt 4.74 min, m/z 146.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][C:16]2([CH2:23][O:22][CH:21]([CH2:24][CH2:25][CH2:26][N:27]([CH2:32][CH2:33][C:34]#[N:35])[CH2:28][CH2:29][C:30]#[N:31])[O:20][CH2:19]2)[CH2:15][O:14]1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][C:16]2([CH2:23][O:22][CH:21]([CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:32][CH2:33][CH2:34][NH2:35])[O:20][CH2:19]2)[CH2:15][O:14]1)[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: N#CCCN(CCC#N)CCCC1OCC2(CO1)COC(CCCN(CCC#N)CCC#N)OC2
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCC1OCC2(CO1)COC(CCCN(CCCN)CCCN)OC2
Yield: 97 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-3,9-bis(aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane, 0.50 g of Raney Co and 50 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 5.01 g of the title compound as a pale red oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.O1CCOCC1.C1COCC1.[Al]>O=[Mn]=O.CCOCC>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (745 mg, 1.61 mmol, Intermediate 50: step b) was added 1,4-dioxane (36 mL) and THF (11 mL) to give a suspension at room temperature. Heating to approximately 45° C. formed a homogeneous solution. Then, activated MnO2 (719 mg, 8.3 mmol) was introduced and the mixture was heated to 80° C. in an aluminum heating mantle under an atmosphere of N2. After 2 hours, the mixture was filtered through a Celite® pad, rinsed with THF and concentrated to give a white solid. Trituration from Et2O gave the title compound as a white solid.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:20]=1[NH2:21])=[O:16])[CH3:19]
Reactant: NNC1CCCCC1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 70 °C
Yield: 92.9 %

Procedure:
Cyclohexylhydrazine hydrochloride (3.057 g, 20.29 mmol, CAS #24214-73-1, purchased from Aldrich) was combined with ethyl (ethoxymethylene)-cyanoacetate (3.390 g, 20.04 mmol) and anhydrous sodium acetate (2.080 g, 25.36 mmol) in 30 mL ethanol. The mixture was heated at 70° C. for 16 hours then cooled to room temperature and concentrated. The residue was partitioned between methylene chloride and water. The separated aqueous phase was extracted with a second portion of methylene chloride. The organic phases were successively washed with water and brine and then combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with a gradient of 25-70% ethyl acetate/hexanes to give 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.42 g, 92%). Mass spectrum: m/z: 238.1 (M+H).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:24]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28]>CCOC(C)=O.[Pd]>[NH:24]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:25]([C:30]([N:1]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A suspension of CBZ-L-Pip-OtBu (0.52 g, 1.6 mmol) and Pd on C (10%, 0.10g) in EtOAc was stirred under a hydrogen atmosphere (balloon) for 1h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The resulting oil was coupled with CBZ-L-Leu (0.43 g, 1.6 mmol) using the procedure described in Example 1 for the preparation of ethyl-3-[BOC-L-N-Me-Phe-L-(Tr-Gln)]-E-propenoate, to provide CBZ-L-Leu-L-Pip-OtBu (0.57 g, 83%) as a colorless oil after column chromatography on silica (20% EtOAc/hexanes): IR (thin film) 3300, 1726, 1642 cm-1 ; 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.5 Hz), 1.03 (d, 3H, J=6.5 Hz), 1.46 (s, 9H), 1.50-1.60 (m, 2H), 1.64-1.83 (m, 2H), 2.23-2.27 (m, 2H), 3.19-3.28 (m, 2H), 3.77-3.81 (m, 2H), 4.76-4.83 (m, 2H), 5.10 (s, 2H), 5.26 (d, 1H, J=4.7 Hz), 5.60 (d, 1H, J=8.7 Hz), 7.27-7.36 (m, 5H); Anal. (C24H36N2O5) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(#N)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])=[CH:17][CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1oncc1C(=O)Cl
Solvent: CC#N
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
A solution of 0.05 mol of 5-methylisoxazole-4-carbonyl chloride (7.3 g) in 20 ml of acetonitrile is added dropwise at room temperature to a solution of 0.1 mol of 4-trifluoromethylaniline (16.1 g) in 150 ml of acetonitrile. After stirring for 20 minutes, the precipitated 4-trifluoromethylaniline hydrochloride is filtered off with suction and washed twice with 20 ml of acetonitrile each time, and the combined filtrates are concentrated under reduced pressure. 12.8 g of white, crystalline N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (compound 1) are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]4[C:36]([N+:37]([O-])=O)=[CH:35][CH:34]=[CH:33][C:28]=4[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]4[C:36]([NH2:37])=[CH:35][CH:34]=[CH:33][C:28]=4[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)=[CH:40][CH:41]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of methyl 2-[({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21a, 2.73 g, 4.96 mmol) and tin(II) chloride dihydrate (4.48 g, 19.9 mmol) in methanol (60 mL) was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and to the concentrated residue were added saturated aqueous sodium hydrogen carbonate and ethyl acetate. The mixture was stirred for 1 hr, and filtered, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and concentrated under reduced pressure. The concentrated solution was extracted with ethyl acetate. The ethyl acetate solution of the resultant product was dried magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column (hexane→hexane:AcOEt=4:1→2:1→3:2) to give methyl 2-[({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-aminobenzoate (compound 22a) (1.96 g, 70%) as a brown amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc([N+](=O)[O-])c2s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a stirred solution of 13.6 g (57.1 mmol) (4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 300 ml acetic acid at room temperature was added 200 ml 65% nitric acid and the mixture heated at 70° C. for 4 h. The mixture was then poured onto stirred ice-water and the resulting slurry was filtered. The filter-cake was dissolved in THF and 5 N sodium hydroxide solution was added until the pH was 8. This mixture was then stirred for 1 h, filtered, and the filter-cake dried in vacuo to afford 7.61 g (47%) (4-methoxy-7-nitro-benzothiazol-2-yl)-carbamic acid methyl ester as a yellow crystalline solid. Meanwhile, the filtrate was separated into its aqueous and organic phases and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in 200 ml THF and 200 ml methanol and heated at 70° C. overnight. The mixture was then cooled to room temperature and the resulting crystals were collected by filtration, washed with THF, and dried in vacuo to afford a further 1.50 g (9%) of product as a yellow crystalline solid. ES-MS m/e (%): 306 (M+Na+, 28), 2,S4 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH:22]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([CH:27]2[CH2:28][CH2:29][C:30]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)[CH:8]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: OC1CCc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cn(C2CCc3ccccc3C2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a mixture of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (0.10 g), 1,2,3,4-tetrahydronaphthalen-2-ol (0.17 g), triphenylphosphine (0.29 g) and toluene was added DIAD toluene solution (1.9M, 0.59 mL) at 50° C., and the mixture was stirred at 50° C. for 1 hr and at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/n-heptane to give the title compound (27 mg).
Reaction SMILES: CC(C)[O-:3].[Sm+3].CC(C)[O-].CC(C)[O-].C1([As](=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OO)(C)(C)C.[CH:59]1([NH:62][C:63](=[O:69])/[CH:64]=[CH:65]/[CH2:66][CH2:67][CH3:68])[CH2:61][CH2:60]1>C1COCC1>[CH:59]1([NH:62][C:63]([CH:64]2[CH:65]([CH2:66][CH2:67][CH3:68])[O:3]2)=[O:69])[CH2:61][CH2:60]1
Reactant: CCC/C=C/C(=O)NC1CC1
Reactant: CC(C)[O-]
Agent: CC(C)(C)OO
Agent: O=[As](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Sm+3]
Solvent: C1CCOC1
Product: CCCC1OC1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with samarium (III) isopropoxide (Sm(O-i-Pr)3, 430 mg, 1.3 mmol), triphenyl arsine oxide (Ph3As═O; 420 mg, 1.3 mmol), S-(−)1,1′-bi-2-naphthol ((S)-BINOL), 370 mg, 1.3 mmol), 4 Å molecular sieves (13 g) and THF (20 mL) then stirred for 30 min at 25±5° C. Tert-butyl hydroperoxide (2.8 mL, 5.5 M, 16 mmol) was then added. The mixture stirred for 30 minutes at 25±5° C., the amide of Example 4 (2.0 g, 13 mmol) in THF (2.0 mL) was then added. The reaction was stirred for 14 hours after which time the reaction had reached 95% completion as determined by HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([N:16]1[CH2:22][CH2:21][CH:20]([C@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:19]([OH:34])[CH:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:42])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([N:16]1[CH2:22][CH2:21][CH:20]([C@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:24])[CH:19]([O:34][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:42])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)N1CCC([C@@H](C)COCc2ccccc2)C(O)C(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)N1CCC([C@@H](C)COCc2ccccc2)C(O[Si](C)(C)C(C)(C)C)C(Cc2ccccc2)C1=O

Procedure:
A single isomer of the alcohol (62) is dissolved in DMF and treated with imidazole (2 equivalents) and t-butyldimethylsilyl chloride (1.05 equivalents) at room temperature overnight. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic extracts are dried over MgSO4 and evaporated at reduced pressure. The residue is purified by flash chromatography to give (63).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][OH:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].CC1(C)N([O])C(C)(C)CCC1.[Br-].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:9]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]1)=[O:10]
Reactant: CCOC(=O)C1(CO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCOC(=O)C1(C=O)CC1
Reaction time: 0.08 h
Yield: 100.5 %

Procedure:
To a solution of Preparation 232 1-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (3.00 g, 21.00 mmol) in dichloromethane (50 ml), at 0° C., was added saturated sodium hydrogen carbonate solution (50 ml), followed by TEMPO (659 mg, 4.00 mmol) and sodium bromide (400 mg, 4.00 mmol). After stirring for 5 min, sodium hypochlorite solution (10%, 14.00 mmol) was added slowly, followed by saturated sodium thiosulphate solution (50 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the titled compound (3.00 g).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23]N)=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.O1CCOCC1.N(OCCC(C)C)=O.N[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].Cl>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a solution of Boc-Leu-DTrp-NHNH2 (39 mg) obtained in Example 1-(2) in DMF (0.5 ml) was added 3.1 M HCl/1,4-dioxane (81 μl) at -60° C. The temperature of the solution was raised to -20° C. and isoamyl nitrite (15 μl) was added. The reaction mixture was stirred at -20° C. to -15° C. for 1.5 h and cooled at -60° C. A solution of βAla-OEt.HCl (17 mg) in DMF (0.5 ml) and TEA (50 μl) were added. The reaction mixture was stirred at 5° C. overnight and concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (41 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]#[C:27][C:28]([OH:31])([CH3:30])[CH3:29])=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][C:8]=1[F:32])(=O)=O.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:22]1[O:23][CH2:24][C@:18]2([N:21]=1)[C:19]1[CH:20]=[C:7]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)[C:8]([F:32])=[CH:9][C:10]=1[O:11][C:12]1[C:17]2=[CH:16][C:15]([C:26]#[C:27][C:28]([CH3:29])([OH:31])[CH3:30])=[CH:14][CH:13]=1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)c(F)cc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)c(F)cc1O2
Temperature: 100 °C

Procedure:
A solution of (R)-2-amino-6′-fluoro-2′-(3-hydroxy-3-methylbut-1-ynyl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.317 g, 0.633 mmol), pyrimidin-5-ylboronic acid (0.157 g, 1.267 mmol), Pd(PPh3)4 (0.037 g, 0.032 mmol), and potassium carbonate (0.438 g, 3.17 mmol) in 1.5 mL dioxane was treated with 0.5 mL water and was heated to 100° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc. The layers were separated and the organic layer was dried over MgSO4 filtered and concentrated. Purification of the crude residue by column chromatography [0-80% (9:1:0.1—CH2Cl2:MeOH:NH4OH)/CH2Cl2] gave (R)-4-(2-amino-3′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol. MS m/z=431.0 [M+H].
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
1.10 (1), Leu; 5.17 (5), Tyr; 1.14 (1),