Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:18])=[C:10]([CH3:17])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:18])=[C:10]([CH2:17][Br:19])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(C)c(C)c(=O)oc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc2c(C)c(CBr)c(=O)oc2c1C
Temperature: 25 °C

Procedure:
A mixture of 7-acetoxy-3,4,8-trimethylcoumarin (6.22 g, 25.3 mmol), N-bromosuccinimide (4.61 g, 25.9 mmol) and benzoyl peroxide (390 mg) were refluxed in carbon tetrachloride for 3.5 hours. The mixture was cooled to room temperature and partitioned between CH2Cl2 and water. The organic layer was separated and washed with water several times, then washed with brine. The organic layer was then dried with anhydrous sodium sulfate and evaporated to give crude product (11.8 g) which was recrystallized twice in toluene to give 7-acetoxy-3-bromomethyl-4,8-dimethylcoumarin, a white crystalline solid (4.86 g, 59%). 1H NMR (CDCl3): δ7.54 (d; J=8.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 4.57 (s, 2H), 2.50 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1I)([CH3:4])[CH3:3].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.CCOC(C)=O>[CH3:1][C:2]([O:5][C:6]([N:7]1[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH:21]=[C:20]1[CH:19]([O:22][CH2:23][CH3:24])[O:18][CH2:16][CH3:17])=[O:15])([CH3:4])[CH3:3]
Reactant: C#CC(OCC)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(OCC)c1cc2cnccc2n1C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
Heat a solution of (3-iodo-pyridin-4-yl)carbamic acid 1,1-dimethylethyl ester (13.3 g, 41.56 mmol, Darnbrough, Shelley; Mervic, Milijenko; Condon, Stephen M.; Burns, Christopher J. Synthetic Communications (2001) 31(21), 3273-3280), 3,3-diethoxy-1-propyne (5.96 ml, 41.56 mmole), triethylamine (23 ml, 166 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (1.46 g, 2.08 mmol) and copper iodide (237 mg, 1.25 mmol) in dry DMF under argon to 90° C. for 3 h. Allow the reaction mixture to cool to 70° C. and add DBU (12.5 ml, 83.12 mmol). Stir the reaction at 70° C. for 3 h and then stir at room temperature overnight. Pour the reaction mixture into EtOAc, wash with water (2×) and brine, dry over MgSO4, filter and concentrate to give the title compound as an oil. Purify the oil by flash chromatography (silica, elute with 10-20% EtOAc/n-heptane) to provide 9.8 g of the title compound as a clear oil, tlc (silica, 30% EtOAc/heptane, Rf=0.30).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([C:24](=[O:30])[CH2:25][C:26](OC)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CO>[C:1]1([NH:7][C:8]([NH:10][C:11]([CH2:12][O:13][C:26](=[O:27])[CH2:25][C:24]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:30])([CH2:16][O:17][C:26](=[O:27])[CH2:25][C:24](=[O:30])[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:14][O:15][C:26](=[O:27])[CH2:25][C:24]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:30])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)NC(CO)(CO)CO
Reactant: COC(=O)CC(=O)C1CCCCC1
Solvent: CO
Product: O=C(Nc1ccccc1)NC(COC(=O)CC(=O)C1CCCCC1)(COC(=O)CC(=O)C1CCCCC1)COC(=O)CC(=O)C1CCCCC1

Procedure:
8.4 g (35 mmol) of the compound (11) and 22.0 g (119 mmol) of methyl 3-cyclohexyl-3-oxo-propionate are heated at 130° C. in a Claisen apparatus for 4 hours under application of a weak vacuum, the methyl alcohol formed being distilled off. The excess methyl 3-cyclohexyl-3-oxo-propionate (boiling point 75°-76° C./0.05 mm Hg) is then distilled off from the mixture. A brownish highly viscous oil of N-phenyl-N'-[1,1-bis-(5-cyclohexyl-3,5-dioxo-2-oxa-pentyl)-6-cyclohexyl-4,6-dioxo-3-oxa-hexyl]-urea (12) remains and can be further used without additional purification.
Reaction SMILES: C([N:8]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])C1C=CC=CC=1.C(#N)C.O.FC(F)(F)C(O)=O>CO.O.[Pd].[H][H]>[OH:13][CH:10]([CH2:11][CH3:12])[CH2:9][NH:8][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCC(O)CN(CC(=O)O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCC(O)CNCC(=O)O

Procedure:
4.60 g of [N-benzyl-N-(2-hydroxybutyl)amino]acetic acid are dissolved in a mixture of methanol and water (7:1) and hydrogenated in the presence of palladium (10% on activated charcoal) as catalyst for about 2.5 hours at ambient temperature until the calculated amount of hydrogen has been taken up. For working up, the catalyst is filtered off and the filtrate evaporated down in vacuo, leaving a white solid. Yield: 2.77 g (97% of theory); Rf value: 0.86 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid=50:50:1); mass spectrum (ESI−): m/z=146 [M−H]−.
Reaction SMILES: C([Mg]Br)C.[CH:5]1([CH2:8][CH3:9])[CH2:7][CH2:6]1.[N:10]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=[N+:11]=[N-:12]>C1COCC1>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([N:10]4[C:8]([CH:5]5[CH2:7][CH2:6]5)=[CH:9][N:12]=[N:11]4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: CCC1CC1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-n3nncc3C3CC3)nc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a 1M solution of ethylmagnesium bromide in THF (1.3 mL, 1.3 mmol) under a nitrogen atmosphere, was added dropwise cyclopropylethane (70% in toluene, 0.154 mL, 1.3 mmol). The reaction mixture was heated at 50° C. for 15 mins then allowed to cool down to RT. A solution of 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (425 mg, 1.3 mmol) in THF (1.5 mL) was then added dropwise. The reaction mixture was stirred at RT for 2 h, quenched with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as a pale yellow solid (373 mg, 64%). LCMS 110142391 (Method B): RT=4.40 min, [M+H]+=390. 1H NMR (DMSO-d6): 8.20 (1 H, d, J=8.6 Hz), 7.71 (1 H, d, J=0.7 Hz), 7.36 (1 H, dd, J=8.6, 2.1 Hz), 7.30 (1 H, d, J=2.1 Hz), 4.40 (2 H, t, J=5.0 Hz), 3.41 (2 H, t, J=5.0 Hz), 2.70-2.63 (1 H, m), 1.21-1.15 (2 H, m), 0.91-0.86 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 46.9 %

Procedure:
1 g (2.5 mmole) 5-(4-[2-(4-methoxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was mixed with Pd/C (5%) and hydrogenated in ethyl acetate for 4 hours at room temperature. The catalyst was filtered off through celite and the solvent was evaporated in vacuo. All of the starting material was not consumed so the hydrogenation was restarted as above. The catalyst was filtered off through celite and the solvent was evaporated in vacuo. The crude product was purified by crystallization in diethyl ether to give 0.47 g (yield 47%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[OH:24])[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1nccs1)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCCC1CC(C(=O)Nc1nccs1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 25, 162.5 mg, 0.42 mmol) in methylene chloride (4.2 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 545 mg, 0.50 mmol). The reaction mixture was stirred at 25° C. for 2 h. At this time, the reaction was filtered through a plug of celite (ethyl acetate as eluent). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (64.8 mg, 40.1%) as a light tan solid: mp 79–81° C.; EI-HRMS m/e calcd for C17H16Cl2N2O2S (M+H)+ 383.0383, found 383.0384.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)O)=[O:4].[OH-].[Na+].Cl[C:20]([O:22]CC)=[O:21]>O1CCOCC1>[N+:14]([C:9]1[CH:8]=[C:7]([N:5]2[C:3](=[O:4])[N:2]([CH3:1])[C:20](=[O:21])[O:22]2)[CH:12]=[CH:11][C:10]=1[CH3:13])([O-:16])=[O:15]
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)N(O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-n2oc(=O)n(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
1-Methyl-3-(3'-nitro-4'-methylphenyl)-3-hydroxyurea (11 g; 0.049 mole) was dissolved in dioxane (80 ml.) and mixed with a 2 N aqueous sodium hydroxide (28.5 ml; 0.057 mole). Ethyl chloroformate (5.2 ml; 0.054 mole) was added dropwise at 10°-15° C. with stirring and the stirring continued for about 1/2 hour after the addition was completed. The product which precipitated as formed was removed by filtration, washed with water and dried. This product was recrystallized from methanol and dried under vacuum to yield 2-(3'-nitro-4'-methylphenyl)-4-methyl-1,2,4-oxadiazolidine-3,5-dione as yellow crystals melting 80°-81° C. and having the following elemental analysis as calculated for C10H9N3O5 :
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[C:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[C:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC#CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
In THF (5.0 ml)/methanol (5.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-butynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution was added 2N potassium hydroxide (5.0 ml), and the mixture was stirred at 50° C. for 3 hours. pH was adjusted to approximate 4 with 6N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-butynyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.40 g).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>>[OH:4][CH2:3][CH2:2][S:1][C:10]1[C:5](=[O:12])[CH:6]=[C:7]([S:1][CH2:2][CH2:3][OH:4])[C:8](=[O:11])[CH:9]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: OCCS
Product: O=C1C=C(SCCO)C(=O)C=C1SCCO
Reaction time: 0.5 h

Procedure:
2-Mercaptoethanol (3.5 ml, 0.05 mole) is added in a single amount to an ethanolic solution of p-benzoquinone (10.81 g, 0.1 mole) and the mixture is allowed to stand, with stirring, for 1/2 hour. Further 2-mercaptoethanol (1.75 ml, 0.025 mole) is added and the mixture is allowed to stand, with stirring, for 2 hours. The mixture is filtered and the precipitate is washed with absolute ethanol. Dark red crystals of the expected derivative are obtained:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:33][C:34]#[N:35])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCC#N)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
The o-alkylation procedure described for 10 (example 5, step 2) was employed. To a stirred suspension of 4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene) methyl]phenol 9 (0.508 g, 1.5 mmol), K2CO3 (0.414 g, 3.0 mmol), and acetone (50 mL) was added, under N2 at RT, bromoacetonitrile (0.21 mL, 3.0 mmol). The reaction mixture was refluxed for 4 h, cooled to RT, and filtered. Standard work-up followed by purification afforded 0.410 g (72%) of the title compound 14 as a white foam. mp 100-101° C. 1H NMR (300 MHz, CDCl3): δ 7.18-7.11 (m, 4H), 6.99 and 6.97 (dd, J1=8.7 Hz, J2=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.76 (s, 2H), 1.98 (s, 2H), 1.97 (s, 2H), 1.32 (s, 2H), 0.96 (s, 12H). LCMS (ESI): m/z 376 (M−H)−. Anal. Calcd for C25H28FNO, C, 79.54, H, 7.48; N, 3.71. Found: C, 79.21, H, 7.46; N, 3.73.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C(=O)=O.CC(C)=O.C([Li])CCC.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.Cl.[Cl-].[Na+]>[CH3:1][N:2]1[C:6]([CH2:7][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5][N:4]=[N:3]1
Reactant: Cc1nnnn1C
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C=O
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nnnn1C
Reaction time: 0.67 h

Procedure:
To a solution of 1,5-dimethyltetrazole (10 g) in 100 mL of dry tetrahydrofuran and 20 mL of hexamethylphosphoramide at -78° C. (dry ice-acetone) under an argon atmosphere was added dropwise 50 mL (1.2 equivalent) of n-butyllithium (2.5M in hexane). The deprotonation of 1,5-dimethyltetrazole was allowed to proceed at -78° C. for 40 minutes, then at -20° C. for 30 minutes. The anion solution was rechilled to -78° C. and transferred via a cannula over a period of 45 minutes into a cold (-78° C.) solution containing 12 mL of ethyl chloroformate in 50 mL of tetrahydrofuran. The reaction mixture was diluted with aqueous 2N HCl and saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The residue from the organic extract was purified by silica gel flash chromatography. The appropriate fractions were combined and evaporated to give 4 g of product. The product was further purified by crystallization from ethyl acetate-hexanes to yield 3.52 g (21%) of the title compound; m.p.=64°-66° C.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][O:24][C:25](=[O:45])[CH:26]([NH2:44])[CH2:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:43])[C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:32][CH:31]=1.[Cl:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49](O)=[O:50].Cl>ClCCl>[CH3:23][O:24][C:25](=[O:45])[CH:26]([NH:44][C:49](=[O:50])[C:48]1[C:52]([F:56])=[CH:53][CH:54]=[CH:55][C:47]=1[Cl:46])[CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:31]=[CH:32][C:33]([N:36]([CH3:43])[C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:34][CH:35]=1
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: COC(=O)C(N)CC=Cc1ccc(N(C)c2ncccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Under an argon atmosphere, EDC hydrochloride (39 mg) and HOBT (3 mg) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (51 mg) and 2-chloro-6-fluorobenzoic acid in dichloromethane (1.5 ml), and the resulting mixture was stirred at room temperature for 28 hours. To the reaction solution, 1N hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, developing solvent:hexane/ethyl acetate=1/2) to obtain (E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (39 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[N:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][N:6]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][N:6]=1
Reactant: Clc1ncc(C=Nc2ncccc2-c2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ncc(CNc2ncccc2-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-[(2-chloro-5-thiazolyl)methylene]-3-phenyl-2-pyridinamine (i.e. the product of Step B) was added portionwise to a stirred excess of sodium borohydride (0.379 g, 10.0 mmol) in methanol (8 mL). After addition was complete, the reaction mixture was allowed to stir for 5 min at ambient temperature. The excess reducing agent was quenched by adding glacial acetic acid until gas evolution ceased. Water (20 mL) was added, and the reaction mixture was concentrated to remove methanol. The resulting aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried (MgSO4) and concentrated to give the title compound as a yellow solid (0.659 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a suspension of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (150 mg, 0.37 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.4 mmol) in dichloromethane (6 mL) was added DIEA (257 μL, 1.48 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 48 h. Then, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed with 0.5 N HCl (50 mL), saturated NaHCO3 solution (50 mL) and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography on a Biotage (40 m) column to give 190 mg (95% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H21Cl2F3N2O4 (M+Na) 563.0724, found 563.0726.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:22])[NH:9][C@@H:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[C:15]=2[F:21])[CH2:11][CH:12]=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C=C.ClC1C(F)=C([C@H](N[S@@](C(C)(C)C)=[O:42])CC=C)C=CN=1.ClC1C(F)=C([C@@H](N[S@@](C(C)(C)C)=O)CC=C)C=CN=1.Cl.O1CCOCC1>C1COCC1.CO>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C@H:10]([NH:9][C:8](=[O:22])[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH:12]=[O:42])[CH:19]=[CH:18][N:17]=1
Reactant: C=CC[C@@H](NC(=O)Oc1ccccc1)c1ccnc(Cl)c1F
Reactant: C=CC[C@@H](N[S@](=O)C(C)(C)C)c1ccnc(Cl)c1F
Agent: C=CC[C@H](N[S@](=O)C(C)(C)C)c1ccnc(Cl)c1F
Agent: C=CC[Mg]Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: O=CC[C@@H](NC(=O)Oc1ccccc1)c1ccnc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
(R)-Phenyl(1-(2-chloro-3-fluoropyridin-4-yl)but-3-en-1-yl)carbamate: To a solution of Intermediate 24A (1.13 g, 4.30 mmol) in THF (50 mL) at was −78° C. was added allylmagnesium bromide (1 M in ether) (8 mL, 8.00 mmol). The reaction was stirred at −78° C. for 0.5 h and warmed up to rt. The mixture was stirred for 1 h at rt and quenched with saturated NH4Cl. The mixture was extracted with EtOAc (3×). The combined organic layer was concentrated to give a 5:1 mixture of (R)-N-((R)-1-(2-chloro-3-fluoropyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide and (R)—N-((5)-1-(2-chloro-3-fluoropyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.56 g, 119%) as an orange oil. The oil was taken up with methanol (10.00 mL) and treated with 4 N HCl in dioxane (3 mL, 99 mmol). The reaction was stirred at rt for 1.5 h and then concentrated to give the desired product (0.55 g, 40%) as an orange oil. MS (ESI) m/z: 321.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[C:9](=[O:14])[NH:10][NH:11][C:12]=2[CH3:13])=[CH:5][CH:4]=1)[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:17]([O:14][C:9]1[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:16][CH:15]=2)=[C:12]([CH3:13])[NH:11][N:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(OCc3ccccc3)n[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 1,2-dihydro-4-(4-ethylbenzyl)-5-methyl-3H-pyrazol-3-one (synthesized as described in WO0116147; 1.0 g, 4.6 mmol), benzyl alcohol (600 mg, 5.5 mmol) and triphenylphosphine (1.46 g, 5.5 mmol) in tetrahydrofuran (30 mL), diethyl azodicarboxylate (40% in toluene, 5.1 mmol) was added dropwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25 to 70:30) to give 3-benzyloxy-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole (550 mg, 39%) as a colorless powder.