Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[O:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(O)C3C4)nc2n(CCC)c1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(=O)C3C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
8-(4-Hydroxy-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (140 mg) from step 1 was taken in CH2Cl2 (5 ml). Celite (2 g) was added, followed by PCC (90 mg) and stirred at room temperature for 1 hr. Additional PCC (90 mg) was added and stirred for 2 hrs at room temperature. The reaction mixture was diluted with ether (100 ml) and filtered through celite and concentrated. Purified on silica column eluted with ethyl acetate:hexane (25:75) to yield 65 mg of the desired product. Mass (ES+ 369).
Reaction SMILES: Br[C:2]1[C:3]([O:13]C(C)(C)C)=[N:4][C:5]([O:8]C(C)(C)C)=[N:6][CH:7]=1.[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1>>[CH:29]1[C:25]2[CH2:26][CH2:27][C:28]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([C:2]3[C:3](=[O:13])[NH:4][C:5](=[O:8])[NH:6][CH:7]=3)[C:24]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: O=C1c2ccccc2CCc2ccccc21
Product: O=c1[nH]cc(C2c3ccccc3CCc3ccccc32)c(=O)[nH]1

Procedure:
The subtitle compound was prepared from 5-bromo-2,4-bis(1,1-dimethylethoxy)pyrimidine (example step(i)) (3.5 g) and 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (2.41 g) according to the method of example 1 step (iii). Purification was by chromatography eluting with 2% ethanol in dichloromethane. Yield 2.17 g. Used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17][C:18](C)(C)C)=[O:16])[CH:6]=[C:5]([CH2:22][OH:23])[N:4]=1.C(O)(C(F)(F)F)=O.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(Cl)Cl.CO.CCCCCC.O.CCOC(C)=O>[OH:23][CH2:22][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: CC(C)(C)OC(=O)CCNCCOc1cc(CO)nc(CO)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CCNCCOc1cc(CO)nc(CO)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 26.6 %

Procedure:
To a solution of 670 mg of tert-butyl 3-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-propanoate in 20 ml of DCM was added 2 ml of TFA. The mixture was stirred for 6 hours at room temperature and then concentrated under reduced pressure, taken up in DCM and concentrated again under reduced pressure. To the residue obtained, dissolved in 10 ml of MeOH, was added, at 5° C., 7 ml of a 2M solution of (trimethylsilyl)diazomethane in hexane. The mixture was stirred for 1 hour 30 minutes at 5° C. and then 200 μl of acetic acid were added. The mixture was taken up in 30 ml of water and 30 ml of EtOAc. The aqueous phase was extracted 2× with 30 ml of EtOAc. The organic phases were combined, washed with saturated NaCl solution, concentrated under reduced pressure and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF15-24g), using a gradient of 0 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 155 mg of methyl 3-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-propanoate were obtained. LC/MS (C): tr=2.56 min; [M+H]+: m/z 470.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:29])[CH:17]([NH:18][C:19](=[O:28])[C:20](=[N:25][O:26][CH3:27])[C:21](=O)[CH2:22]Br)[C@H:4]2[S:3]1.[NH2:30][C:31]([NH2:33])=[S:32]>C(O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:29])[CH:17]([NH:18][C:19](=[O:28])[C:20](=[N:25][O:26][CH3:27])[C:21]3[N:30]=[C:31]([NH2:33])[S:32][CH:22]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Reactant: NC(N)=S
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 2,2,2-trichloroethyl 2-methyl-7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (0.94 g.) and ethanol (10 ml.) was added thiourea (0.12 g.), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was separated, and the remaining aqueous layer was neutralized with sodium bicarbonate and then extracted with ethyl acetate. Thus obtained ethyl acetate layers were combined together, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (0.6 g.). This compound was subjected to column chromatography on silica gel using a mixed solvent of benzene, ethyl acetate and acetic acid (10:10:1) as a developer, and the eluates containing the object compound were collected, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give pale brown powder of the purified object compound (syn isomer) (0.16 g.), mp 128° to 149° C. (dec.).
Reaction SMILES: OC1C=CC(CC(NC2C=CC=C(C#CC3C=CC=CC=3)C=2)=O)=CC=1OC.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[C:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:37])=[CH:31][C:30]=1[O:53][CH3:54]>>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2/[CH:45]=[CH:46]\[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:37])=[CH:31][C:30]=1[O:53][CH3:54]
Reactant: COc1cc(CC(=O)Nc2ccccc2C#Cc2ccccc2)ccc1O
Agent: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Product: COc1cc(CC(=O)Nc2ccccc2/C=C\c2ccccc2)ccc1O

Procedure:
Instead of 4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]-phenylacetamide (the compound of Example 36) in Example 56, 4-hydroxy-3-methoxy-N-[2-(2-phenylethynyl)phenyl]phenylacetamide (the compound of Example 107) is treated in a similar manner to Example 56 to give the desired compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH:7]([N:20]1[CH2:23][CH:22](O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([CH2:3][C:4]([O:6][CH:22]1[CH2:23][N:20]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21]1)=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: N#CCC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
4.25 g (0.05 mole) of cyanoacetic acid and 11.95 g (0.05 mole) of 1-benzhydryl-3-hydroxyazetidine were dissolved in 400 ml of tetrahydrofuran. 12.38 g (0.06 mole) of 1,3-dicyclohexylcarbodiimide were then added to the solution, whilst stirring, after which the mixture was stirred at 55° C. for 11 hours. At the end of this time, the mixture was cooled, precipitated crystals were removed and the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and then dried over anhydrous sodium sulfate.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:14]([O:15][C@@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:29].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.N1C=CC=CC=1>[N:18]1([CH2:17][C@H:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][C:14]2[CH:13]=[CH:12][C:11]3[C:10](=[O:29])[CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH2:4][NH:3][S:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 5-aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one bis-hydrochloride (40 mg, 0.092 mmole) in CH2Cl2 (1 mL) and pyridine (1 mL) was added 4-methoxybenzenesulfonyl chloride (0.75 mL, 0.4 M solution in trifluorotoluene, 3 equiv). The reaction was shaken overnight. A polyamine resin was added to quench the excess sulfonyl chloride. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed with 1 M NaOH and brine, dried over Na2SO4 and concentrated to give a light brown oil. Purification by chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title compound as an off-white foam (32 mg, 0.060 mmol, 66%). The structure was confirmed by NMR and mass spectrometry. MS m/z 532 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][C:8]=1[N:9]1[CH2:14][CH:13]=[C:12]([O:15][Si](C)(C)C)[CH2:11][CH2:10]1)([O-:3])=[O:2].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:21][CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:9]([C:8]2[NH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:10]1
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)OC1=CCN(c2[nH]ncc2[N+](=O)[O-])CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(c2[nH]ncc2[N+](=O)[O-])CC1F

Procedure:
FIG. 10 shows an exemplary synthesis of 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 52 from 5-chloro-4-nitro-1H-pyrazole 3. Heating 3 with piperidin-4-one hydrochloride hydrate and potassium fluoride in a suitable solvent such as dimethylsulfoxide or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 46. Heating 46 with trimethylsilyl chloride and triethylamine in a suitable solvent such as DMF or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine 47. Fluorination of 47 using SelectFluor® in acetonitrile at a suitable temperature or using methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 48. Ring expansion of 48 to ethyl 6-fluoro-1-(4-nitro-1H-pyrazol-5-yl)-5-oxoazepane-4-carboxylate 49 may be achieved using ethyl diazoacetate and boron trifluoride diethyl etherate in a suitable solvent such as dichloromethane at suitable temperatures or using methods described in the literature. Decarboxylation of 49 by heating with hydrochloric acid at a suitable temperature or by methods described in the literature to give 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-one 50. Reductive amination of 50 by methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 51. The amine of 51 can be protected with a suitable protecting group such as trifluoroacetamide using trifluoroacetic anhydride with diisopropylethylamine in a suitable solvent such as dichloromethane, or using other methods described in the literature, to give amine-protected 52.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=2[CH3:46])=[C:32]([CH2:34]O)[CH:33]=1>ClCCl>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=2[CH3:46])=[C:32]([CH2:34][I:20])[CH:33]=1
Reactant: COc1cccc(CCc2ccc(Br)cc2CO)c1C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCc2ccc(Br)cc2CI)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To polymer-supported triphenylphosphine (9.2 g; ˜27.5 mmol) in dichloromethane (40 mL) was added iodine (6.98 g; 27.5 mmol). The mixture was stirred for 30 minutes and then imidazole (1.87 g; 27.5 mmol) was added to the mixture. After stirring for 15 minutes a solution of 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-ethyl]-phenylmethanol 8 (4.19 g; 12.5 mmol) in dichloromethane (100 mL) was added. The mixture was heated at reflux for 2 hours, cooled to room temperature and filtered. The filtrate was washed sequentially with sodium thiosulfate solution, water, and brine, dried over MgSO4, and concentrated to dryness at ambient temperature under high vacuum to give compound 9 as a yellow oil, 5.56 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6](C)[C:7](C1C=CC(OCCCCl)=CC=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl.[Na+].[I-]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)CCC=O
Temperature: 80 °C
Yield: 293 %

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (7 g, 22 mmol), K2CO3 (9.3 g, 67 mmol), NaI (330 mg, 2.2 mmol), and (R)-methyl-pyrrolidinium benzenesulfonate (11 g, 47 mmol) in CH3CN (160 mL) was heated under argon at 80° C. for 36 h. The reaction mixture was concentrated at reduced pressure and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material. The crude material was purified by ISCO (80 g silica gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 2.5 mL ammonium hydroxide in methylene chloride to afford a pure product. The pure product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to give 3-methyl-4-{4-R-2methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (8.39 g, quantitative yield), MS m/z 362 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#N.[OH2:13]>C(O)=O>[CH3:12][NH:11][C:4]1[C:3]([CH:1]=[O:13])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: O
Reactant: CNc1nc(SC)ncc1C#N
Solvent: O=CO
Product: CNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4.00 g (0.022 mol) of 5-cyano-4-methylamino-2-methylsulfanyl-pyrimidine (from Example 3) in 150 mL of 50% aqueous formic acid was reacted with 6.0 g of water-wet Raney Nickel. The mixture was stirred at 25° C. for 12 hours. The solids were filtered and washed with 40 mL of 50% aqueous formic acid. With ice bath cooling, a cold saturated solution of potassium carbonate was added slowly to the green filtrate until complete precipitation of a solid was achieved (pH is still acidic; pH about 5). The solid was extracted into 200 mL of ethyl acetate, and the solution was dried (potassium carbonate), filtered, and concentrated; wt 2.30 g (57%); mp 98°-100° C.; tlc (1:1 hexane:ethyl acetate) one spot Rf 0.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: Cc1ccc(-c2cc[nH]c2)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cc[nH]c2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following a standard procedure (Balasubramanian, T. et al, J. Org. Chem. 2000, 65, 7919-7929), a solution of 7 (472 mg, 3.00 mmol) in DMF (0.96 mL) and CH2Cl2 (30 mL) under argon was cooled to 0° C. and then POCl3 (340 μL, 3.60 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight (˜18 h). The reaction was quenched at 0° C. with 2.5 M NaOH (25 mL). The mixture was poured into water (50 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (NaSO4), and concentrated. The residue was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to give a brown solid. 1H NMR spectroscopy showed two regioisomers in ˜13:1 ratio. Cooling of the solution (ethyl acetate/hexanes) at ˜−16° C. resulted in precipitation of an orange solid, which proved to be a single regioisomer (354 mg, 64%): mp 149-150° C.; 1H NMR δ 2.41 (s, 3H), 6.42-6.44 (m, 1H), 7.10-7.13 (m, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 9.63-9.64 (m, 1H), 9.52-9.78 (br, 1H); 13C NMR δ 21.4, 111.6, 126.2, 128.9, 129.3, 129.7, 130.9, 137.7, 137.9, 180.2; FAB-MS obsd 186.0907, calcd 186.0919 (C12H11NO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:17])[C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:17])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(O)C#CC(C)(C)O)cc1Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1Cl
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 2.716 mmol) in DCM (20 mL) was added DMP (2.36 g, 5.430 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(3-chloro-4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-one (0.45 g, 65%) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCNCC4)cc3)oc12
Yield: 3.3 %

Procedure:
2-(4-(Pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (135 mg, 0.43 mmol) and platinum (IV) oxide monohydrate (70 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichloromethane:methanol=8:1) to give the solid. The solid was acidified by hydrochloride acid. 4.6 mg of 2-(4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 3%. 1H-NMR (400 MHz, CD3OD-d4) δ 1.89 (m, 2H), 2.03 (m, 2H), 2.95 (m, 1H), 3.09-3.12 (m, 2H), 3.43-3.46 (m, 2H), 7.40-7.46 (m, 3H), 7.81 (t, J=8.4 Hz, 2H), 8.21 (d, J=8.0 Hz, 2H). LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].[CH3:13][C:14](=[CH2:16])[CH3:15].OS(C(F)(F)F)(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:14]([CH3:16])([CH3:15])[CH3:13])[CH:6]=1)[CH3:2]
Reactant: C=C(C)C
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OC(C)(C)C)c1
Temperature: -20 °C
Yield: 95 %

Procedure:
Into a solution of 3-hydroxy-benzoic acid ethyl ester (10.14 g, 0.061 mol) in CH2Cl2 (200 mL) cooled to −78° C. was condensed isobutylene (150 mL) followed by addition of triflic acid (1.08 mL, 0.061 mol). The reaction mixture was allowed to warm to −20° C. When a solution was obtained and tlc indicated loss of starting material, the reaction was quenched with Et3N (6.8 mL, 0.049 mol) and left to warm to ambient temperature. The solution was concentrated and the residue chromatographed on an ISCO combiflash eluting with 0-10% EtoAc/hexane to give 12.91 g (95%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.[NH2:28][C@@H:29]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:56][CH:55]=1)[C:30]([N:32]([C@@H:44]([CH3:52])[CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:28][C@@H:29]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:56][CH:55]=1)[C:30]([N:32]([C@@H:44]([CH3:52])[CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 182 mg (0.77 mmol), hydroxybenzotriazole 104 mg (0.77 mmol) and 1-ethyl-3-(3-s dimethylaminopropyl)carbodiimide 148 mg (0.77 mmol) in dichloromethane 3 ml, a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 260 mg (0.51 mmol) and 4-dimethylaminopyridine 31 mg (0.26 mmol) in dichloromethane 3 ml was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound 333 mg (90%).