Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[F:7])(=O)[CH3:2].[CH2:9]1C[O:12][CH2:11][CH2:10]1.C(OCC(Br)F)(=[O:16])C.C1COCC1.C(OC(C)C)(C)C>O>[F:7][CH:6]([CH:11]([OH:12])[CH2:10][CH3:9])[C:5]([O:4][CH2:1][CH3:2])=[O:16]
Reactant: C1CCOC1
Reactant: CC(=O)OCC(F)Br
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCOC(=O)C(F)C(O)CC
Reaction time: 0.33 h
Yield: 85 %

Procedure:
After a 500 mL reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, and placed in an ice bath, 24.2 g (370 mmol/1.5 equivalent) of activated metal zinc and 300 mL of THF (dehydrated) were added into the reaction vessel. Thereto was added a bromofluoroethyl acetate/THF solution (46.91 g (253.6 mmol/1.0 equivalent) of bromofluoroethyl acetate and 80 mL of THF (dehydrated)) dropwise over 5 min. After the dropwise addition, the temperature of the mixture was elevated to the room temperature, followed by stirring for 20 min. Thereto was added a propionealdehyde/THF solution (17.76 g (305.8 mmol/1.2 equivalent) of propionealdehyde and 80 mL of THF (dehydrated)), and the mixture was stirred for 60 min at a room temperature. Thereafter, water and diisopropyl ether were added thereto, and two-layer separation was carried out. The organic layer thus obtained was washed with diluted hydrochloric acid and water, and the moisture was eliminated using magnesium sulfate, followed by filtration. Then diisopropyl ether was distilled off to give 35.4 g (yield: 85%) of ethyl 2-fluoro-3-hydroxy-pentanoate represented by the following formula.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][N:5]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in 20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonate and 0.85 ml (6.3 mmol) of p-methoxybenzyl chloride were added successively. The reaction mixture was heated at 70° C. under stirring for 5 hours. Water was then added and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. 2.4 g (86%) of the title compound crystallized from a mixture diethylether-diisopropylether.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])CCC)[CH2:8][CH2:7]2.[C:19]([NH2:22])(=[O:21])[CH3:20].[OH-].[NH4+]>>[CH2:16]([NH:12][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([NH:22][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: CC(N)=O
Agent: [NH4+]
Agent: [OH-]
Product: CCCNC1CCc2cccc(NC(C)=O)c2C1
Temperature: 180 °C

Procedure:
To 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (500 mg, 1.6 mMol) were added acetamide (5 gm) and cuprous iodide (340 mg, 1.8 mMol), and the mixture was heated at 180° C. for four hours. The dark reaction mixture was then poured into a slurry of ice and ammonium hydroxide. This mixture was extracted well with dichloromethane, and the combined extracts were washed with water, dried over sodium sulfate and concentrated in vacuo to give a dark viscous residue. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the title compound as a dark, viscous oil (130 mg, 31%). The maleate salt was formed and crystallized (ethanol/diethyl ether) to give tan crystals (m.p.=132°-133° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])=[O:9])=[O:4].[I-].[Na+].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)(=[O:9])=[O:10])[C:28](=[O:29])[N:27]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C1CN1S(=O)(=O)c1cccc(OC)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CN(S(=O)(=O)c2cccc(OC)c2)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of (RS)-1-(3-methoxy-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester (0.098 g) in tetrahydrofuran (3 ml) were added sodium iodide (0.054 g) and phenylisocyanate (0.043 g). The mixture was stirred for 18 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, 1% aqueous Na2S2O3 solution and again with water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 9:1=>1:1) to give (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid methyl ester (0.060 g) as a colorless solid. MS: 391.1 ([M+H]+)
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][CH2:11][CH3:12])[NH:6][C:7]=1[CH:8]=[O:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C>[F:19][C:20]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:6]1[C:7]([CH:8]=[O:9])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]1[CH2:10][CH2:11][CH3:12]
Reactant: CCCc1nc(CC)c(C=O)[nH]1
Reactant: Fc1cc(I)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(C=O)n1Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
4-Ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (6.32 g, 38.0 mmol), potassium carbonate (10.57 g, 76.5 mmol), and 2-fluoro-4-iodobenzyl bromide (13.90 g of 86%, 38.0 mmol) were added together with 50 mL of DMF. The reaction mixture was stirred at room temperature overnight under N2. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic mixture was washed with H2O and brine, dried over MgSO4 and concentrated. The crude product mixture was purified by flash chromatography (silica gel, 30-50% EtOAc/hexane) to yield 10.63 g orange oil (70%). MS m/e 401.0, [M+H]+ ; 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, CH3), 1.32 (t, 3H, CH3), 1.70 (m, 2H, CH2), 2.60 (m, 2H, CH2), 2.82 (q, 2H, CH2), 5.52 (s, 2H, CH2Ar), 6.42 (t, 1H, ArH), 7.38 (d, 1H, ArH), 7.42 (d, 1H, ArH), 9.73 (s, 1H, CHO). ##STR62##
Reaction SMILES: Cl[C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[C:16]=2[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:12]1[C:21]2[C:16](=[C:17]([C:2]3[O:11][C:5]4=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]4[CH:3]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1nccc2cc(Cl)oc12
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccc2cc(-c3cccc4cnccc34)oc12
Yield: 90.1 %

Procedure:
A mixture of 2-chlorofuro[2,3-c]pyridin-7-amine (4.0 g, 23.8 mmol) and 5-isoquinoline boronic acid (4.33 g, 25.0 mmol) in 1,4-dioxane (150 mL) and water (50 mL) was sparged with nitrogen for 15 min and then treated with Pd(PPh3)2Cl2 (250 mg). After sparging with nitrogen for another 5 min, K2CO3 (2.2 g, 59.5 mmol) was added and the mixture heated at reflux overnight. The 1,4-dioxane was removed in vacuo and DCM was added. The phases were separated and the organic phase was washed with water, then brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (2% MeOH:DCM) to provide the 5.6 g (90%) of the title compound. 1H NMR (300 MHz, CD3OD): δ 6.99 (d, J=5.4 Hz, 1H), 7.27 (s, 1H), 7.73 (d, J=5.4 Hz, 1H); 7.81 (t, J=8.1 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.29 (dd, J=7.4 Hz, J=1.0 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.55 (d, J=6.0 Hz, 1H); 9.32 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])=[C:6]([C:8]2[C:16]3[C:11](=[C:12]([O:30][CH3:31])[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:15]=3)[N:10]([CH3:32])[CH:9]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.[CH2:51]([S:53](Cl)(=[O:55])=[O:54])[CH3:52].[OH-].[Na+]>ClCCl>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[O:33][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:53]([CH2:51][CH3:52])(=[O:55])=[O:54])=[CH:7][C:6]=1[C:8]1[C:16]2[C:11](=[C:12]([O:30][CH3:31])[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]3)[CH:15]=2)[N:10]([CH3:32])[CH:9]=1
Reactant: COc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(C4CCN(C(=O)OC(C)(C)C)CC4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of Example 183B (205 mg, 0.363 mmol) in 10 mL dichloromethane was added N-ethyl-N-isopropylpropan-2-amine (254 μL, 1.452 mmol) and ethanesulfonyl chloride (120 μL, 1.271 mmol). The mixture was stirred at ambient temperature overnight. The mixture was concentrated. The viscous oil residue was taken into dioxane (10 mL) and treated with sodium hydroxide (5446 μL, 5.45 mmol, 1N aqueous solution). The mixture was stirred at ambient temperature for 80 minutes and then quenched with saturated ammonium hydroxide solution, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-60% ethyl acetate in heptanes to give the title compound (110 mg, 0.167 mmol, 46.1% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])#[CH:21].C(N(CC)CC)C>CCOC(C)=O.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>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]#[C:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2F)c1)c1ccccc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31 mmol) and 1-ethynyl-2-fluorobenzene (75 mg, 0.62 mmol) in 2.0 mL EtOAc was degassed with argon at 70° C. Upon cooling to room temperature the reaction mixture was treated with triethylamine (0.16 mL, 1.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I) iodide (2 mg, 0.012 mmol). The reaction was heated at 70° C. for 20 hours then partitioned between EtOAc and H2O. The EtOAc layer was washed with acetic acid solution, saturated NaHCO3, brine, dried with anhydrous Na2SO4 and concentrated. The dark film obtained was purified by chromatography (silica gel, hexane/EtOAc) to give the title compound as a tan foam (110 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:27].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[C:50]2([OH:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][C:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)([OH:56])[CH2:51][CH2:52]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27]
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccc(Cl)c(Cl)c3)C2=O)cc(OC)c1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(Cl)c(Cl)c3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(3,4-dichloro-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.60 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([C:37]([OH:40])([CH3:39])[CH3:38])[N:29]=[C:28]2[CH2:41][CH2:42][CH3:43])=[CH:22][CH:21]=1)=O)(C)(C)C>C(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([C:37]([OH:40])([CH3:38])[CH3:39])[N:29]=[C:28]2[CH2:41][CH2:42][CH3:43])=[CH:22][CH:21]=1)#[N:11]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
0.345 ml of oxalyl chloride was added dropwise, whilst ice-cooling, to a solution of 1.00 g of ethyl 1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl }methyl -4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of methylene chloride, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 0.69 g of the title compound as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N+:3]=1[O-].P(Cl)(Cl)Cl>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(C)(C)c1c[n+]([O-])c(N)c(C#N)n1
Solvent: ClP(Cl)Cl
Product: CC(C)(C)c1cnc(N)c(C#N)n1

Procedure:
The pyrazine 1-oxide obtained above was then allowed to react with phosphorus trichloride to yield 2-amino-3-cyano-5-t-butylpyrazine, which was in turn hydrolyzed and decarboxylated to yield 2-amino-5-(t-butyl)pyrazine, identified by IR spectrum.
Reaction SMILES: F[C:2]1[C:3]([C:11](=O)[CH3:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:14][NH:15][NH2:16]>>[CH:8]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:11]([CH3:12])=[N:16][N:15]([CH3:14])[C:2]=12)([CH3:10])[CH3:9]
Reactant: CNN
Reactant: CC(=O)c1nccc(C(C)C)c1F
Product: Cc1nn(C)c2c(C(C)C)ccnc12
Temperature: 140 °C
Reaction time: 2 h

Procedure:
1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanone (prepared in the previous step, 2.50 g, 15.15 mmol) and methyl hydrazine (1.04 g, 23.00 mmol) were combined in 8 mL of glycol. The reaction solution was stirred at 140° C. for 2 hours. After cooling, it was quenched with water, extracted with DCM, then washed with water, brine and concentrated. Column chromatography using 15 to 35% ethyl acetate in hexane as eluant afforded the title compound as a pale yellow solid. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.39 (d, J=6.73 Hz, 6 H), 2.64 (s, 3 H), 3.65 (hept, J=6.73 Hz, 1 H), 4.23 (s, 3 H), 7.14 (d, J=4.69 Hz, 1 H), 8.44 (d, J=4.69 Hz 1 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][CH:17]([O:26][CH3:27])[C:18](N1CCOCC1)=[O:19]>C1COCC1>[CH3:15][O:16][CH:17]([O:26][CH3:27])[C:18]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:19]
Reactant: c1ccc2sccc2c1
Reactant: COC(OC)C(=O)N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of benzothiophene (7.11 g., 0.053 mol) in 120 ml. dry THF was cooled to 0°. Butyl lithium (35.3 ml. of 1.5 M in hexane, 0.053 mol) was added dropwise, maintaining 0°-5°, and the mixture then warmed to ambient temperature for 1.25 hours, cooled to -75° C. and N-(dimethoxyacetyl)morpholine (10.0 g., 0.053 mol) in 50 ml. dry THF added dropwise maintaining -75° to -70°. The reaction was quenched by adding to 300 ml. saturated NH4Cl and 300 ml. ether. The organic layer was separated, washed with brine, dried over MgSO4 and stripped to an oil, 14 g., which was distilled to yield purified title product, 8.00 g.; bp 137°-139°/0.25 mm.; tlc Rf 0.23 (6:1 hexane:ethyl acetate), 0.47 (2:1 hexane:ethyl acetate); 1H-nmr 3.6 (s, 6H), 5.2 (s, 1H), 7.3-7.6 (m, 2H), 7.8-8.05 (m, 2H), 8.4 (s, 1H), tlc Rf 0.31 (4:1 hexane:ethyl acetate), 0.47 (2:1 hexane:ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C@@H:10]([CH3:16])[NH:11][O:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Br:25][CH2:26][C:27](Br)=[O:28]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:17])[C@@H:10]([CH3:16])[N:11]([C:27](=[O:28])[CH2:26][Br:25])[O:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)CBr
Reactant: C=CCON[C@H](C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCON(C(=O)CBr)[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of (R)-N-allyloxyalanine benzyl ester (2a) (2.59 g, 11 mmol) and Et3N (1.11 g, 11 mmol) in dry CH2Cl2 (30 mL), a solution of bromoacetyl bromide (2.22 g, 11 mmol) in dry CH2Cl2 (20 mL) was added dropwise with cooling (−25˜−30° C.) and stirring. The reaction mixture was stirred for 1 h at 0˜+5° C. and allowed to warm up to RT. After dilution with CH2Cl2 (ca. 30 mL), the mixture was washed with water (2×30 mL), 1N HCl (30 mL), sat. aq. NaHCO3 (30 mL), and dried over MgSO4. Removal of the solvent afforded 3.90 g (99%) of the product 3 as a yellowish oil. 1H NMR (100 MHz) in CDCl3 (J, Hz): δ 1.60 (3H, d, 3J=7.3, MeCH), 4.08 (2H, CH2Br), 4.49 (2H, dt, 3J=6.1, 4J=0.9, OCH2CH═CH2), 4.98 (1H, q, MeCH, 3J=7.3), 5.16-5.48 (2H, m, CH═CH2), 5.20 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=6.1, 3Jcis=10.0, 3Jtrans=17.3, CH═CH2), 7.29-7.41 (5H, m, Ph). IR (film), cm−1: 1746, 1678, 1455, 1214. MS (CI, isobutane), m/Z: 357 (M++1), 356 (M+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[CH:4]=1)=[O:8])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (194 mg, 0.357 mmol) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (2-5% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:18]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19]1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:18]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:14]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C=O)CCC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a stirred mixture of tert-butyl(piperidin-4-ylmethyl)carbamate (12.8 g, 60 mmol) and methyl 1-formylcyclobutanecarboxylate (2.13 g, 15 mmol, Davis, Charles R.; Swenson, Dale C.; Burton, Donald J., J. Org. Chem., 1993, 58, 6843) in tetrahydrofuran (50 mL) was added acetic acid (8.6 mL, 150 mmol) at ambient temperature. After 30 min, sodium triacetoxyborohydride (12.7 g, 60 mmol) was added to the mixture. Then, the mixture was heated to 60° C. for 2 h. After cooling, the reaction mixture was poured into sat. NaHCO3 aq. The aqueous layer was extracted with CH2Cl2 for 3 times. The combined organic phase were washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (1:1) to give 4.25 g (83%) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:28])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: COC(=O)CCS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 12 h

Procedure:
A mixture of methyl 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate (0.5 g, 1.5 mmole) and meta-chloroperoxybenzoic acid (0.32 g, 1.5 mmole) in dichloromethane (25 ml) was stirred under argon for 12 hours. Excess peroxide was destroyed with saturated aqueous potassium bisulfite and the phases were separated. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness Recrystallization from diethyl ether and dichloromethane gave the title compound m.p. 106°-108°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([C:24]([C:26]2[S:30][C:29]([C:31]([NH:33][NH2:34])=[O:32])=[CH:28][CH:27]=2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:34][NH:33][C:31]([C:29]3[S:30][C:26]([C:24]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:25])=[CH:27][CH:28]=3)=[O:32])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)N2CCOCC2)s1
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCOCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 86 %

Procedure:
28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene and 26 mg of 5-(morpholine-4-carbonyl)thiophene-2-carbohydrazide prepared in Reference Synthetic Example 2 were heated in isopropyl alcohol with 3 mg of p-tosylic acid monohydrate at 105° C. for 18 hours and cooled to room temperature. The precipitated solid was recovered by filtration and washed with 1 mL of isopropyl alcohol, and the resulting crystals were dried to give the desired product (yield 86%).