Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[N:30]=[CH:31][C:32]([C:35]2([CH3:42])[NH:39][C:38](=[O:40])[NH:37][C:36]2=[O:41])=[N:33][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][C:32]([C:35]3([CH3:42])[C:36](=[O:41])[NH:37][C:38](=[O:40])[NH:39]3)=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CC1(c2cnc(N)cn2)NC(=O)NC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(c2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 200 mg, 0.606 mmol) in methylene chloride (5 mL) was treated with oxalyl chloride (116 μL, 1.212 mmol) and N,N-dimethylformamide (1 drop). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo, and the residue was dried in vacuo. The residue was then dissolved in benzene, and the solvents were concentrated in vacuo. The residue was dried in vacuo. This material was dissolved in methylene chloride (5 mL), cooled to 0° C., and then treated with a mixture of 5-(5-amino-pyrazin-2-yl)-5-methyl-imidazolidine-2,4-dione (150 mg, 0.727 mmol) and pyridine (98 μL) in methylene chloride (1 mL) and dimethyl sulfoxide (1 mL). The ice bath was removed, and the solution was stirred at 25° C. overnight. The reaction mixture was concentrated in vacuo and then extracted with ethyl acetate and a 0.1N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/4 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-pyrazin-2-yl]-propionamide (82 mg, 26%) as a light yellow solid: (ES)+-HRMS m/e calcd for C23H26ClN5O5S (M+H)+ 520.1416, found 520.1403.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:15][CH2:14]1.O>C(Cl)Cl.CN(C=O)C>[C:1]([CH2:3][C:4]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:17][CH2:18]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: NC(=O)c1ccc(Nc2nc(NC3CCNCC3)c3cc[nH]c3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC(Nc2nc(Nc3ccc(C(N)=O)cc3)nc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.9 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF), oxalyl chloride (0.082 mL, 0.94 mmol) was added. The mixture was stirred at room temperature for 50 min. To the above solution cooled in an ice bath, a solution of 4-(4-(piperidin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (20 mg, 0.057 mmol) and TEA (0.450 mL, 3.22 mmol) in DMF (2 mL) was added. The mixture was stirred at room temperature for 20 h. Water was added. CH2Cl2 was removed in vacuo. The residue was purified by HPLC to give the titled compound (10 mg). MS 419.3 (M+H); UV 200.0, 311.9 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of the ester from step 1 (1.0 g, 2.6 mmol) was dissolved in THF (5 mL) and methanol (5 mL) was treated with a 2.5 N NaOH solution (4.0 mL, 10.4 mmol). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue taken up in ethyl acetate and acidified with 3 N HCl. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo yielding a yellow solid. Recrystallization from ethyl acetate-hexanes afforded the title compound as a pale yellow solid (0.42 g, 46%): mp 196.3–197.7° C. 1H NMR (CDCl3/300 MHz) d 7.65 (s, 1H), 7.40–7.23 (m, 6H), 7.15 (s, 1H), 5.63 (q, 1H, J=6.5 Hz), 3.35 (broad s, 1H). 19F NMR (CDCl3/282 MHz) d −78.71 (d, J=5.8 Hz). FABLRMS m/z 355 (M+H). ESHRMS m/z 353.0198 (M−H, Calc'd 353.0192).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[OH:25][C@@H:26]([CH2:39][NH2:40])[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[OH:25][C@H:26]([CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH2:39][NH:40][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:23][CH:24]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-sulfonyl)-benzyl]-thiazolidine-2,4-dione and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one according to the reductive amination procedure of Intermediate 21 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6): δ 1.20-1.40 (m, 2 H), 1.80-2.00 (m, 2 H), 2.30-4.00 (m, 12 H), 4.65 (dd, J=8.0, 3.5 Hz, 1 H), 6.56 (d, J=3.2 Hz, 1 H), 6.59 (d, J=3.8 Hz, 1 H), 6.85 (t, J=3.5 Hz, 1 H), 7.50 (d, J=8.1 Hz, 2 H), 7.66 (d, J=8.1 Hz, 2 H), 10.70 (s, 1 H), 10.79 (brs, 1 H); MS (ES) m/z : 576.0 (M++H); HRMS Calcd. for C25H30N507S2 (M++H): 576.1587. Found: 576.1596.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16](OC)=[O:17])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH2:16][OH:17])[CH:20]=[CH:21][C:22]=3[CH3:23])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Methyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-methylbenzoate (15-4) (570 mg, 1.6 mmol, 1.0 eq.) was dissolved in dry THF (6.2 mL) and cooled to −78° C. Diisobutylaluminum hydride (6.2 mL, 6.2 mmol, 4.0 eq, 1M in heptane) was carefully added under nitrogen. The resulting mixture stirred at −78° C. for 10 minutes. The reaction was warmed to 0° C. and quenched with a saturated solution of Rochelle's Salt (5 mL). The resulting mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was then extracted with ethyl acetate and the combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to afford 1-(2,2-dimethylpropyl)-5-[5-(hydroxymethyl)-2-methylphenyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (51-1) as a white solid. MS (M+H)+: observed=340.2021, calculated=340.2020.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[CH2:4].[CH3:7][C:8]([CH3:10])=O.COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:10])[O:5][CH:2]([CH:3]=[CH2:4])[CH2:1][O:6]1
Reactant: CC(C)=O
Reactant: C=CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: c1ccccc1
Product: C=CC1COC(C)(C)O1
Reaction time: 3 h
Yield: 56.7 %

Procedure:
3-Butene-1,2-diol (5.00 g, 56.7 mmol), acetone (9.88 g, 170 mmol), 2,2-dimethoxy propane (17.7 g, 170 mmol), and p-toluene sulfonic acid (1.62 g, 8.5 mmol) were added to benzene (100 mL). After 16 hours of reflux, starting material was observed by TLC. 2,2-Dimethoxy propane (9.99 g, 95.1 mmol) and acetone (1.58 g, 27.3 mmol) were then added, followed by an additional 3 hour reflux. The mixture was washed with saturated aqueous NaHCO3 and extracted with EtOAc (3×40 mL). The organic extracts were dried over MgSO4, filtered, concentrated and purified by column chromatography (5% ethyl acetate in hexanes) to provide the titled compound (4.12 g, 57%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[NH:12])[NH:10][OH:11])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=O>C1(C)C=CC=CC=1>[C:14]([C:19]1[O:11][N:10]=[C:9]([C:4]2[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)([CH3:18])([CH3:15])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N=C(NO)c1cnc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(-c2cnc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
5,6-Dichloro-N-hydroxy-3-pyridinecarboximidamide (3.0 g, 0.015 mol) was slurried in toluene (30 mL) and trimethylacetyl chloride (1.93 g, 0.016 mol) added. The mixture was stirred at room temperature for one hour and then heated under reflux conditions for four hours. This was then cooled and filtered through Celite, washing with additional toluene (20 mL). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (0-10% ethyl acetate:hexane) gave the desired product as a white solid (2.77 g, 68%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[CH3:34][O:35][C:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+].P(OC)(OC)OC>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:34][O:35][C:36](=[O:37])[C:38]1[CH:43]=[CH:42][C:41]([C:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:9]([C:8](=[O:23])[N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=3)[CH3:24])=[CH:10][N:11]=2)=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: COP(OC)OC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 24.6 %

Procedure:
A mixture of 200 mg (0.346 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4), 95 mg (0.52 mmol) 4-methoxycarbonylphenylboronic acid and 155 mg (0.692 mmol) potassium phosphate in 4 ml dioxane was deoxygenated by three freeze-thaw cycles. After addition of 9.5 mg (0.010 mmol) tris(dibenzylideneacetone)dipalladium(0) and 0.0025 ml (0.02 mmol) trimethyl phosphite the reaction mixture was stirred at 95° C. for 5 h. Cooling to room temperature was followed by dilution with tert-butyl methyl ether, filtration over Decalite and evaporation of the solvent in vacuo. Column chromatography afforded 50 mg (25%) of the title compound as a light brown solid.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH2:29]([C:31]1[N:32]=[C:33]([O:38][CH3:39])[C:34]([NH2:37])=[N:35][CH:36]=1)[CH3:30].C(N(C(C)C)CC)(C)C>C(#N)CCC>[CH2:29]([C:31]1[N:32]=[C:33]([O:38][CH3:39])[C:34]2[N:35]([C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12][CH2:13][CH2:14]4)=[CH:7][CH:6]=3)[N:37]=2)[CH:36]=1)[CH3:30]
Reactant: CCc1cnc(N)c(OC)n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: CCc1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(OC)n1
Temperature: 120 °C

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (288 mg, 0.55 mmol, 1.0 eq), 5-ethyl-3-methoxypyrazin-2-amine (84.4 mg, 0.55 mmol, 1 eq.; see step 2) and diisopropylethylamine (0.110 mL, 0.61 mmol, 1.1 eq) in 3.9 mL butyronitrile was heated at 120° C. for 20 hours. The reaction mixture was concentrated in vacuo. The crude mixture was purified via MPLC (Isolera, 50 g Snap-cartridge, eluent:hexane→hexane/ethyl acetate 1/1) to deliver 128 mg (25%) of the title compound in approximately 50-60 purity (UPLC). The title compound observed this way was forwarded to the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:20])=[O:2])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (527 mg, 1.66 mmol) in ethanol (15 mL) was treated with a solution of potassium hydroxide (233 mg, 4.15 mmol) in water (2 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water (5 mL), and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to give rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (487 mg, 97% yield) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2O3 (M+) 302.0477, found 302.0486.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[CH3:16][Bi:17](Br)[CH3:18]>C1COCC1>[CH3:16][Bi:17]([CH3:18])[C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)C
Reactant: C[Bi](C)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)[Bi](C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
A 2.86 g quantity (28 mmole) of methyl isobutyrate was dissolved in 25 ml of THF, and the mixture was chilled to −78° C. under argon atmosphere. To the mixture was slowly added dropwise 14.0 ml (28 mmole) of lithium diisopropylamide (Aldrich Corp., 2.0M heptane.THF.ethylbenzene solution) over a period of 10 minutes. The reaction mixture was gradually heated (one hour) and thereto was added dropwise a solution of 8.9 g of dimethylbismuthanyl bromide prepared in Preparation Example 2 in 25 ml of THF between −40° C. and −30° C. The reaction mixture was further stirred until reached to 0° C. (one hour). After the solids were filtrated with quartz wool and THF was removed in a vacuum, the reaction mixture was distilled in a vacuum, giving 4.45 g (yield 46.7%) of a yellow oily product. b.p. 59° C./2.0 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26]1[N:30]=[CH:29][S:28][C:27]=1[CH:31]=O.[BH4-].C([Na])#N.S([O-])(O)(=O)=O.[K+]>CO.C(O)(=O)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:7]1[CH:6]=[C:5]([CH:4]([OH:20])[C:3]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:2]=2[NH:1][CH2:31][C:27]2[S:28][CH:29]=[N:30][CH:26]=2)[CH:10]=[CH:9][CH:8]=1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=Cc1cncs1
Agent: N#C[Na]
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2cncs2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
In methanol (10 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-chlorobenzyl alcohol (1 g) produced in Example (1) and thiazole-5-carboxyaldehyde (0.34 g). To the solution were added acetic acid (0.33 g) and cyano sodium borohydride (0.21 g). The mixture was stirred for one hour at 60° C. The reaction mixture was added to a 5% aqueous solution of potassium hydrogensulfate, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give α-(3-tert-butoxycarbonylaminomethylphenyl)-5-chloro-2-(thiazol-5-yl)methylamino-benzyl alcohol (1.22 g) as a colorless amorphous solid product.
Reaction SMILES: [Cl:1][C:2](=[CH:10][C:11]1[CH:16]=[C:15]([C:17]2[C:21]([Cl:22])=[C:20]([O:23][CH:24]([F:26])[F:25])[N:19]([CH3:27])[N:18]=2)[C:14]([F:28])=[CH:13][C:12]=1[Cl:29])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2](=[CH:10][C:11]1[CH:16]=[C:15]([C:17]2[C:21]([Cl:22])=[C:20]([O:23][CH:24]([F:25])[F:26])[N:19]([CH3:27])[N:18]=2)[C:14]([F:28])=[CH:13][C:12]=1[Cl:29])[C:3]([OH:5])=[O:4]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)OC(C)(C)C)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 16 h

Procedure:
A solution of 44 g of tert-butyl 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acrylate (93 mmol) in 200 ml of dichloromethane was treated with 200 ml of trifluoroacetic acid. After the mixture had been stirred for 16 hours, it was concentrated. The residue was recrystallized from hexane/ethyl acetate (2:1). Yield: 23 g; a further 4 g by concentrating the mother liquor.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[CH:32][CH:31]=1>>[CH3:26][CH:24]([CH3:25])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:34]4[C:33](=[CH:32][CH:31]=[C:30]([CH3:29])[CH:35]=4)[NH:36][CH:2]=3)[CH2:11][CH2:12]2)[CH:17]=1)=[O:27]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]cc(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][NH:15][C:16]([O:18][CH3:19])=[O:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:41]2[C@H:42]([CH3:65])[C@H:43]3[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:44]3[C:45]=2[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=2)=[O:47])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH3:19][O:18][C:16]([NH:15][CH2:14][C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:41]3[C@H:42]([CH3:65])[C@@H:43]4[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:44]4[C:45]=3[C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=3)=[O:47])[CH2:8]2)[S:10][CH:11]=1)=[O:17]
Reactant: COC(=O)NCc1csc(N2CC(SC(C)=O)C2)n1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)NCc1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
To a solution of 3-acetylthio-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (441 mg, 1.39 mmol) (obtained as described in Reference Example 63) in dimethylformamide (13 ml) was added hydrazine acetate (154 mg, 1.67 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (993 mg, 1.67 mmol) in acetonitrile (26 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.97 ml, 5.56 mmol). The mixture was stirred for 30 minutes while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (307 mg, yield 53%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:21](=[N:27]/O)\[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:15])[CH:7]([O:8]/[N:27]=[CH:21]/[C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CC(=O)OC1NC(=O)NC(=O)C1(F)C(=O)OCC(C)C
Reactant: O/N=C/c1ccco1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 21 h
Yield: 70 %

Procedure:
In 10 ml of pyridine were dissolved 2.9 g (10 mmol) of isobutyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 2.22 g (20 mmol) of (E)-furfuraldoxime, and 1.01 g (10 mmol) of dried triethylamine was added to the solution, followed by stirring at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and 50 ml of ethyl acetate was added to the residue. The organic layer was washed three times with 10-ml portions of water, and the solvent was dried and evaporated under reduced pressure. The residue was recrystallized twice from ethyl acetate-hexane to give 2.39 g of isobutyl 5-fluoro-6-(E)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 167°-168° C.