Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11](=[O:19])[C:10]=1[C:20]([F:23])([F:22])[F:21])C1C=CC=CC=1>[Pd].C(O)C>[CH:16]1([CH2:15][N:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:20]([F:21])([F:22])[F:23])[C:11]2=[O:19])[CH2:18][CH2:17]1
Reactant: O=c1c(C(F)(F)F)c(OCc2ccccc2)ccn1CC1CC1
Agent: [Pd]
Solvent: CCO
Product: O=c1c(C(F)(F)F)c(O)ccn1CC1CC1
Yield: 100.5 %

Procedure:
A mixture of intermediate D7 (2.0 g, 6.19 mmol), a catalytic amount of 10% palladium on activated carbon and ethanol (60 ml) was stirred under hydrogen atmosphere for 2 hours. The mixture was filtered through diatomaceous earth and the solvent was evaporated in vacuo to yield crude intermediate D8 (1.45 g, 100%) that was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[CH:11]=[C:12]([OH:25])[CH:13]=[C:14]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)[CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][O:29][CH2:30][C@H:31](O)[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C.O>[CH3:28][O:29][CH2:30][C@H:31]([CH3:32])[O:25][C:12]1[CH:13]=[C:14]([B:16]2[O:17][C:18]([CH3:23])([CH3:24])[C:19]([CH3:21])([CH3:22])[O:20]2)[CH:15]=[C:10]([O:9][C:8]2[CH:26]=[CH:27][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:11]=1
Reactant: COC[C@@H](C)O
Reactant: CC1(C)OB(c2cc(O)cc(Oc3ccc(S(C)(=O)=O)cc3)c2)OC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
3-[4-(Methylsulfonyl)phenoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13.20 g, 33.8 mmol) synthesized in Example (1d) was dissolved in tetrahydrofuran (300 mL), and (R)-(−)-1-methoxy-2-propanol (3.70 mL, 37.8 mmol) and triphenylphosphine (9.78 g, 37.3 mmol) were added, and subsequently cooled to 0° C. Diethyl azodicarboxylate (40% toluene solution, 16.2 mL, 37.2 mmol) was added dropwise over 10 minutes under nitrogen atmosphere and stirring was carried out at 0° C. for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (300 mL) and ethyl acetate (300 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (11.94 g, yield 76%) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-n2nc(-c3ccc(C(C)C)cc3)sc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1ccc(-c2nn(-c3ccc(C(=O)O)cc3)c(=O)s2)cc1
Yield: 99.7 %

Procedure:
Methyl 4-[5-(4-isopropylphenyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl]benzoate (0.20 g, 0.56 mmol) in dichloromethane (10 mL) is then treated with boron tribromide (1M in dichloromethane, 1.7 mL, 1.7 mmol) at room temperature overnight. The volatiles are removed in vacuum and the residue is treated with water. The precipitate is collected and washed thoroughly with water to furnish the desired product, 4-[5-(4-isopropylphenyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl]benzoic acid (0.19 g, 100%), m.p. 205-208° C. 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.30 (d, 6H) 2.92-3.06 (m, 1H), 7.35 (d, 2H), 7.70 (d, 2H), 8.11-8.23 (m, 4H). (ES+) m/z: 341.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[F:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([F:9])[CH3:8]
Reactant: CC(F)(F)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(F)(F)c1cc(N)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 31.5 %

Procedure:
A stirred mixture of 4,4-difluoro-3-oxopentanenitrile (prepared as described in Example 152A Step 1) (1 g, 7.52 mmol) and phenyl hydrazine hydrochloride (1.08 g, 7.52 mmol) in ethanol (30 mL) was heated at 70° C. for 8 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (200 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL). The organic layer was separated and dried over magnesium sulfate and filtered. Concentration under reduced pressure gave an oil, which was purified via silica gel column chromatography (eluting with a gradient of 5% to 65% ethyl acetate in hexanes) to afford 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-amine (528 mg, 31%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.57 (m, 5H), 5.81 (s, 1H), 3.84 (brs, 2H), 2.01 (t, J=18 Hz, 3H); LC-MS (ESI) m/z 224 (M+H)+.
Reaction SMILES: CS([CH2:4][CH2:5][S:6]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1)(=[O:8])=[O:7])=O>C(O)CO>[CH:5]([S:6]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1)(=[O:7])=[O:8])=[CH2:4]
Reactant: CS(=O)CCS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Solvent: OCCO
Product: C=CS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
An ethylene glycol solution (25 ml) containing 2.48 g of 6-[4-(3-(2-methylsulfinylethyl)sulfonylaminopropyl)phenyl]pyridazin-3(2H)-one was stirred at 180° C. for 1 hour. The reaction mixture was poured into ice water, and precipitated crystal was collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 1.60 g of 6-[4-(3-vinylsulfonylaminopropyl)phenyl]-pyridazin-3(2H)-one.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:8][N:7]([C:9]([NH:11][CH2:12][CH3:13])=[NH:10])[N:6]=[CH:5]1)[CH3:3].CCN(C(C)C)C(C)C.[N:23]1[S:27][N:26]=[C:25]2[C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:24]=12>C(Cl)Cl>[CH2:12]([NH:11][C:9]([N:7]1[CH2:8][CH:4]([CH2:2][CH3:3])[CH:5]=[N:6]1)=[N:10][S:32]([C:28]1[C:25]2=[N:26][S:27][N:23]=[C:24]2[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])[CH3:13]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: CCNC(=N)N1CC(CC)C=N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc2nsnc12)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
300 mg 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspended in 10 mL. DCM. 0.53 mL DiPEA and 310 mg benzo[1,2,5]thiadiazole-4-sulfonylchloride were added and the mixture was stirred overnight at room temperature. The mixture was washed with 5% NaHCO3 and 2 M NaOH, the organic layer dried over Na2SO4 and the solvent evaporated in vacuo to yield 410 mg of a red/brown oil. The crude product was purified by flash chromatography (DCM:aceton=98:2, Rf=0.18) to yield 350 mg (65%) of an orange oil. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.5 Hz, 3H), 1.16 (br t, J=7 Hz, 3H), 1.41-1.66 (m, 2H), 3.01-3.16 (m, 1H), 3.39-3.55 (m, 2H), 3.59-3.74 (m, 1H), 3.95-4.15 (m, 1H), 6.94 (br s, 1H), 6.95 (br s, 1H), 7.68 (dd, J=9 and 7 Hz, 1H), 8.15 (br d, J=9 Hz, 1H), 8.31 (br d, J=7 Hz, 1H).
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[SiH](Cl)(Cl)Cl.[CH2:12]([Cl:15])[CH:13]=[CH2:14]>>[Si:1]([CH2:14][CH2:13][CH2:12][Cl:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C=CCCl
Reactant: CC[SiH](CC)CC
Agent: Cl[SiH](Cl)Cl
Product: CC[Si](CC)(CC)CCCCl
Temperature: 65 °C
Reaction time: 0.52 h
Yield: 40.9 %

Procedure:
In a 100 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH, 1.7 g (0.0125 mol) of Cl3SiH and 0.05 ml of Pt catalyst solution. The mixture was heated to 65° C. and addition of 7.7 g (0.1 mol) of allyl chloride begun. There was an exothermic reaction to 108.5° C. over 16 min, followed by a temperature drop. Addition of allyl chloride was complete in 31 min, with heat then applied at reflux (up to 114° C.) over 170 min. Vacuum distillation yielded 7.88 g (40.9%) of Et3SiCH2CH2CH2Cl with a Et3SiCH2CH2CH2Cl/Et3SiCl selectivity ratio of 1.13. This example shows that this sequence of combination of reactants allows the Cl3SiH promoter to be consumed, at which point the reaction of Et3SiH with allyl chloride proceeds at the low rate and selectivity exhibited in Comparative Example DD.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH3:9])=[O:6])[CH2:3][OH:4].C(O)(C(F)(F)F)=O.[NH:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl.CCOCC.CCCCCC.O>[NH:21]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C@H:22]([C:27]([NH:1][C@H:2]([C:5]([NH:7][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH3:9])=[O:6])[CH2:3][OH:4])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
40 g of H-Ser-Ala-OMe, TFA and 32.9 g of Boc-Leu-OH, H2O are dissolved in 400 ml of DMF. The product is cooled with an ice bath with magnetic stirring and 14.4 ml of NEM then 65.8 g of BOP and enough NEM to maintain the pH at 6.5-7 are added. The product is stirred for 2 hrs. at ambient temperature. After monitoring by TLC, the product is evaporated to dryness (13.33 Pa 35° C.) and the oil obtained is dissolved in 1500 ml of chloroform, washed twice with a saturated NaCl solution, three times with 5% potassium sulfate/bisulfate, 3 times with saturated sodium bicarbonate, dried over Na2SO4, evaporated to dryness (30°-water-jet pump). The oil obtained is solidified in ether: Fraction A=29 g. A second jet B is obtained by addition of hexane, identical in TLC: B=13.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([O-])(=O)C.[NH4+:33]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:33]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: [NH4+]
Reactant: COc1cc(/C=C/C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nc(-c3ccccc3)c[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxo-2-phenylethyl)acrylic acid amide (100 mg) and ammonium acetate (410 mg) in acetic acid (5 mL) was heated under reflux for 10 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=5:1) to obtain 34 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.C([OH:23])C.CN(C)C=O>[OH-].[Na+]>[CH2:14]([S:13][CH2:12][C:4]1[NH:3][C:2](=[O:23])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(CSCc2ccccc2)nc2nccnc12
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CSCc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 5.4 g (0.019 mole) of 4-amino-2-(benzylthiomethyl)pteridine in 400 ml of 5% aqueous sodium hydroxide. Reaction time: 7 hours at 85° C. Yld: 1.7 g (31%), m.p. 224°-226° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[CH3:10][C:11]1[S:12][C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH3:16])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][C:11]1[S:12][C:13]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[C:14]([CH3:16])[N:15]=1
Reactant: CSc1nccc(I)n1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1nccc(-c2sc(C)nc2C)n1
Yield: 76 %

Procedure:
To a solution of 4-iodo-2-methylsulfanyl-pyrimidine (390 mg, 1.56 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (633 mg, 2.65 mmol added portionwise), Na2CO3 (215 mg, 2.02 mmol), triphenylphosphine (42 mg, 0.15 mmol) in nPrOH (25 ml), Pd(OAc)2 (11 mg, 0.047 mmol) was added and the mixture was refluxed for 2 hour. The solvent was evaporated under vacuum, and the crude was dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and evaporated. A second batch of this compound was prepared according to the same protocol starting from 0.39 mmol of 4-iodo-2-methylsulfanyl-pyrimidine. The residues, deriving from the two batches, were purified by flash chromatography with hexane-ethyl acetate to give the title compound (352, 76% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(N[C@@H](Cc1cccc2ccccc12)[C@@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-naphthyl-2-butanone (190.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (1.01ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, purification by silica gel column chromatography afforded a desired compound, (2R,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-naphthylbutane (190.1 mg; yield: 99.1%). As a result of HPLC analysis, the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 9.5:1. The results of elementary analysis were as follows.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11]C)=[O:9])=[C:5](C)[N:6]=1.NC1SC(C(OC)=O)=CN=1.Cl[CH2:24][CH2:25][N:26]=[C:27]=[O:28]>>[O:28]=[C:27]1[NH:26][CH2:25][CH2:24][N:1]1[C:2]1[S:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C=NCCCl
Agent: COC(=O)c1cnc(N)s1
Product: COC(=O)c1cnc(N2CCNC2=O)s1
Yield: 44 %

Procedure:
Following the procedure as described in Example 3, making variations as required to replace ethyl 2-amino-4-methylthiazole-5-carboxylate with methyl 2-aminothiazole-5-carboxylate to react with 2-chloroethyl isocyanate, the title compound was obtained as a colorless solid in 44% yield: mp 205-208° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 5.55 (s, 1H), 4.25-4.19 (m, 2H), 3.84 (s, 3H), 3.72-3.67 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.8, 162.5, 157.0, 145.1, 122.2, 52.1, 44.4, 38.1; MS (ES+) m/z 228.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
41.0 mg (0.12 mmol) of the compound from Example 14A are provided in 3 ml of tetrahydrofuran, and 28.4 mg (1.19 mmol) of lithium hydroxide and 0.8 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous HCl solution is subsequently added until an acidic pH is obtained, the mixture is extracted three times with dichloromethane and the extracts are dried over sodium sulfate, filtered and concentrated. 35.0 mg (83% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O1CCCC1.O>[CH3:11][C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=1
Reactant: CCOC(=O)c1cc(C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.5 %

Procedure:
A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5-carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18-20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×35 mL) and the combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 3-methyl-isoxazole-5-carboxylic acid as a white solid (660 mg, 90%). The solid was used without purification in the next reaction.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:24])=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:26]1[N:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[C:10]([F:24])=[C:11]([C:26]2[N:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(C2CCCCC2)ccc(B(O)O)c1F
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1c(C2CCCCC2)ccc(-c2cnc(N)cn2)c1F
Temperature: 80 °C
Yield: 101.3 %

Procedure:
A mixture of (3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronic acid (0.821 g, 2.33 mmol), 5-bromopyrazin-2-amine (0.40 g, 2.3 mmol), K2CO3 (0.659 g, 4.77 mmol), Pd(dppf)Cl2.CH2Cl2 (0.086 g, 0.12 mmol), deoxygenated toluene (10 mL), and deoxygenated deionized water (10 mL) was heated for 16 hours at 80° Celsius. The reaction mixture was then cooled to rt, diluted with dichloromethane (25 mL), and washed with brine (2×25 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness to yield the title compound (0.936 g, 100%) which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:20][C:21]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[N:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]3=[C:35](Br)[N:34]=2)=[O:32])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].Cl.CI.C(=O)([O-])[O-].[Cs+].[Cs+]>O.COCCOC.CN(C=O)C.CO.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>[NH2:20][C:21]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[N:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]3=[C:35]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[N:34]=2)=[O:32])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1N
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
0.248 g (1.38 mmol) of [4-(methoxycarbonyl)phenyl]boronic acid, 0.57 g (2.30 mmol) of potassium carbonate in 2 ml of water, and 0.027 g (0.02 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 0.43 g (1.15 mmol) of methyl 2-amino-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 10 ml of DME, under an inert argon atmosphere. The reaction medium is heated at 90° C. for 2 hours. The reaction medium is acidified with a 1N aqueous solution of hydrochloric acid, and extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The solid obtained is dissolved in 5 ml of DMF. 30 μl (0.5 mmol) of methyl iodide and 0.052 g (0.16 mmol) of caesium carbonate are added. After stirring for 24 hours at ambient temperature, the reaction medium is hydrolysed with water and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is taken up in methanol. After filtration and drying overnight at 50° C. under reduced pressure, 0.379 g of a yellow powder is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@@H:39]([CH2:52][CH:53]([CH3:55])[CH3:54])[NH:40][C:41](=[O:51])[C@@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N[C@H](C(NCC(N[C@H](C(O)=O)C)=O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C.C(OC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)N)C1C=CC=CC=1>>[CH2:30]([O:37][C:38](=[O:56])[C@@H:39]([CH2:52][CH:53]([CH3:54])[CH3:55])[NH:40][C:41](=[O:51])[C@@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH:43][C:27](=[O:28])[C@@H:25]([CH3:26])[NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)C[C@@H](NC(=O)[C@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)CNC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)CNC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-D-tyrosylglycyl-D-alanine and D-phenylalanyl-D-leucine benzyl ester are substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and L-phenylalanyl-L-leucine benzyl ester, respectively in Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-D-tyrosylglycyl-D-alanyl-D-phenylalanyl-D-leucine benzyl ester.