Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH:18]([NH:22][CH:23]([CH2:25][CH3:26])[CH3:24])([CH2:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCOCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:2][N:22]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:18]([CH2:20][CH3:21])[CH3:19]
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Reactant: CCC(C)NC(C)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CCC(C)N(CC(=O)c1cccn1Cc1ccccc1F)C(C)CC
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 16.0 g of 2-chloroacetyl-1-(o-fluorobenzyl)pyrrole, Example 1a, 8.3 g of di-sec-butylamine and 20.0 g of potassium carbonate in 250 ml xylene is stirred at 120° C for 72 hours. The mixture is cooled, washed with water, dried and filtered and the xylene is evaporated leaving a brown oil. The oil is dissolved in ether and extracted into a 2N hydrogen chloride solution. The aqueous acidic solution is basified with a sodium carbonate solution and extracted with ether. The ether solution is washed, dried and filtered and the ether removed leaving a brown oil of 1-(o-fluorobenzyl)-2[(di-sec-butylamino)acetyl]pyrrole. Infrared and nuclear magnetic resonance spectra confirm this structure.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-tert-butylphenyl isocyanate (0.214 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 235 mg (68.7%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:14])=[C:4]([O:9][C:10]([F:11])([F:13])[F:12])[CH:3]=1
Reactant: CI
Reactant: FC(F)(F)Oc1cc(Br)ccc1S
Product: CSc1ccc(Br)cc1OC(F)(F)F
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Bromo-1-methylthio-2-trifluoromethoxybenzene was prepared from 4-bromo-2-trifluoromethoxybenzenethiol and methyl iodide by following Method C. The reaction was conducted at room temperature overnight. The crude residue was chromatographed in 20% EtOAc/Hexanes to afford 4-bromo-1-methylthio-2-trifluoromethoxybenzene (85% yield).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 128° C. and MS: m/e=281 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 3-methyl-butylamine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])O.[K+].O>ClCCl>[CH2:29]([O:28][C:26]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:27])[CH3:30]
Reactant: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Benzyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (45.2 mg) was dissolved in dichloromethane (0.9 ml), added with ethyl chloroformate (27 μl) and potassium hydrogencarbonate (28 mg) and stirred at room temperature for 30 minutes. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 38.3 mg of the title compound. Yield: 90%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([CH3:21])([CH3:20])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (5.0 g, 42.0 mmol) and imidazole (7.15 g, 105 mmol) in N,N-dimethylformamide (100 mL) was treated with tert-butyl-chloro-dimethyl-silane (7.6 g, 50.4 mmol) in N,N-dimethylformamide (50 mL) over 10 min. The reaction was stirred at rt overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (10:1) to give the title compound (9.27 g, 95%). MS (DCI/NH3) m/z 234 (M+1)+. 1HNMR (500 MHz, DMSO-d6) δ ppm 0.26 (s, 6H) 1.00 (s, 9H) 7.26 (dq, J=7.93, 1.22 Hz, 1H) 7.35 (t, J=2.44 Hz, 1H) 7.50 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29]C)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]3=[O:28])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl.O>C1COCC1>[OH:29][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]3=[O:28])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(Cn1ncc2cc(-n3ccc(CCc4ccccc4)cc3=O)ccc21)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(O)Cn1ncc2cc(-n3ccc(CCc4ccccc4)cc3=O)ccc21
Yield: 100.6 %

Procedure:
A solution of 1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-4-phenethylpyridin-2(1H)-one (1.77 g, 4.39 mmol) in THF (20 mL) was treated with aqueous HCl (20 mL, 2.0 M). The solution was heated at 60° for 18 h, allowed to cool and then treated with H2O (50 mL). The mixture was extracted with EtOAc (3×100 mL), dried with Na2SO4, filtered and concentrated to give the title compound (1.72 g, 98%) as an orange solid: ESI MS m/z 390 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([NH2:13])=O)[N:10]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]#[N:13])[N:10]=1
Reactant: NC(=O)c1csc(-c2ncc[nH]2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1csc(-c2ncc[nH]2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic acid amide (120 mg) in 2 mL of anhydrous pyridine is added 0.25 mL of POCl3 dropwise at 0° C. The reaction mixture is stirred at the same temperature for 2 hours, poured into ice water, neutralized with solid NaHCO3, and extracted with 5% MeOH in CH2Cl2. The extract is washed with brine, dried and concentrated to a solid. 1H NMR (DMSO): δ 13.45 (br, 1H), 8.82 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H). LRMS calcd 176, found 177 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[CH:20]=[CH:19][N:18]=[C:17]5[CH:21]=[CH:22][S:23][C:16]=45)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Reactant: NCCCN1CCOCC1
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCCN1CCOCC1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 3-(morpholin-4-yl)propylamine in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ 8.50 (1H, d, J=5.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.07 (1H, bm), 7.80 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=2.0 Hz), 7.59 (1H, d, J=5.6 Hz), 7.24 (1H, dd, J=8.3, 2.0 Hz), 6.61 (1H, d, J=5.6 Hz), 3.56 (4H, bm), 3.35–3.27 (4H, m), 2.63 (3H, s), 2.36 (4H, bm), 1.73 (2H, bm).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.N[N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@H:11]1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.S(=O)(=O)(O)O>C(O)C>[CH:20]1([C@H:11]2[N:10]3[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:4][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([C:15]=43)[O:13][CH2:12]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: NN1c2ccccc2OC[C@H]1C1CCCCC1
Reactant: CCOC(=O)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cccc3c2n1[C@H](C1CCCCC1)CO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
Ethyl pyruvate (882 mg, 7.59 mmol) was added to a solution of (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6.33 mmol) in ethanol (40 ml). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture, sulfuric acid (10% v/v in ethanol; 8.0 ml) was added. The reaction mixture was refluxed for 2 h. The mixture was cooled to room temperature and partitioned between ethyl acetate and sodium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography eluting with 0-10% (v/v) ethyl acetate in heptane to afford ethyl (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5-carboxylate (1.49 g, 4.76 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: Clc1cnc2ccccc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cnc2ccccc2n1
Temperature: 0 °C

Procedure:
15.0 g (91.1 mmol) of 2-chloroquinoxaline are initially charged in 150 ml of ethanol. 45.6 g (911.3 mmol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off, washed with ethanol and dried under high vacuum.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:28]=[C:29]=[O:30])=[C:18]([Cl:31])[CH:17]=1>O1CCCC1.O>[Cl:15][C:16]1[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([Cl:31])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC1(C)Oc2c(N=C=O)c(Cl)cc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Oc2c(c(Cl)cc(Cl)c2-n2c(=O)cc(C(F)(F)F)[nH]c2=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.78 g, 0.019 mole) was placed in a flask, and the mineral oil was removed from it with two heptane washes. The sodium hydride was suspended in 40 mL of dry tetrahydrofuran, and this suspension was cooled to 0°-10° C. A solution of 2.96 g (0.0162 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 5 mL of dry tetrahydrofuran was added dropwise to the suspension of sodium hydride. This mixture was then stirred at ambient temperature for 30 minutes. A solution of 4.40 g (0.0162 mole) of 4,6-dichloro-2,3-dihydro-2,2-dimethyl-benzofuran-3-on-7-yl isocyanate in 10 mL of dry tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes and then was heated at reflux for three hours. At the conclusion of this period the mixture was diluted with water, and the resulting mixture was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure, yielding 9.58 g of a gummy, pale yellow residue. This residue was triturated with methylene chloride, yielding 4.79 g of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-6-trifluoromethyluracil as an off-white solid, m.p. 308°-320° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)(=[O:21])=[O:20])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)(=[O:20])=[O:21])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(F)(F)F)c4)CCN3C2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(F)(F)F)c4)CCN3C2)cn1
Yield: 86.4 %

Procedure:
(7R,8aS)-7-{[5-(Prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine (196 mg, 0.418 mmol, Example 115) in ethanol (10 mL) was added to 20% palladium hydroxide on carbon (12 mg, 0.084 mmol). The mixture was stirred at room temperature for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=1:1) to give the title compound (170 mg, 86%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (s, 6H), 1.77 (m, 1H), 1.91 (m, 1H), 2.09 (m, 1H), 2.20-2.30 (m, 2H), 2.39 (m, 2H), 3.01 (m, 2H), 3.56 (m, 1H), 3.66 (m, 1H), 3.84 (m, 1H), 5.21 (m, 1H), 7.95 (m, 2H), 8.10 (m, 2H), 8.26 (m, 1H), 8.38 (m, 1H); MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.C([Li])CCC.CCCCCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[CH2:7]([C:5]1[S:6][C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:3][N:4]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ncc(Br)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
To a solution of 5-bromo-2-isobutylthiazole (2.10 g, 9.54 mmol) in THF (20 mL) was added 1.6 M n-butyllithium in hexane solution (7.15 mL, 11.44 mmol) dropwise over 45 minutes at −78° C. The resulting solution was stirred at −78° C. for 10 minutes. Then the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.13 g, 11.44 mmol) was added to the above solution and stirred at −78° C. for 1.5 hours. The reaction was quenched with 1:1 saturated ammonium chloride and water and warmed up to close to room temperature. The resulting mixture was extracted with ethyl acetate, washed with water, brine and concentrated. The residue was subjected to flash column chromatography using 30% ethyl acetate/hexane to give a yellow oil (454 mg, 18% yield). 1H NMR, 400 MHz, CDCl3: δ 8.13 (s, 1 H), 2.95 (d, J=7.1 Hz, 2 H), 2.10-2.19 (m, 1 H), 1.36 (s, 12 H), 1.00 (d, J=6.6 Hz, 6 H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12]
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(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
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@@H](CO)NC(=O)c1csc(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
Yield: 56.2 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (920 mg, 1.23 mmol) (obtained as described in Example 39(1)) in tetrahydrofuran (46 ml) were added acetic acid (208 μl, 3.63 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (3.63 ml, 3.63 mmol) in an ice bath and the mixture was stirred for 2 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate:methanol (95:5) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-hydroxymethyl-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (437 mg, yield 56%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[CH:20]=[C:21]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25].O>CC(C)=O>[C:28]([NH:27][C:21]1[CH:22]=[C:23]([Cl:26])[C:24]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([Cl:18])[CH:20]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1c(Cl)cc(NC(C)=O)cc1Cl

Procedure:
13.3 ml (74.9mmol) of ethyl 6-bromohexanoate and 52.1 g (160 mmol) of cesium carbonate were added to a solution of 15.0 g (68.1 mmol) of N-(3,5-dichloro-4-hydroxyphenyl)acetamide in 300 ml of acetone. The suspension was boiled under reflux for 8 hours, and then 600 ml of water were added. The mixture was extracted twice with 400 ml of dichloromethane and with 400 ml of MTB ether each time. The combined organic phases were washed with water and concentrated in a rotary evaporator. The product was employed in the next step without purification. Crude yield was 30 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]1[O:6][CH2:5]1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([OH:6])[CH2:5][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: NCCCCCCO
Reactant: Clc1ccccc1C1CO1
Solvent: CO
Solvent: CCOC(C)=O
Product: OCCCCCCNCC(O)c1ccccc1Cl
Yield: 41 %

Procedure:
From 2-chlorostyrene oxide and 6-amino-1-hexanol. Working up by means of chromatography (ethyl acetate/methanol 1:1). Yield: 41%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26](Br)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[N:3]3[CH:4]=[CH:5][C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:7][C:2]3=[N:1][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Br)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3cc(C(C)(C)C)ccn23)CC1

Procedure:
The title compound was prepared from 470 mg of 1-t-butyloxycarbonyl-4-(1-bromo-formylmethyl)piperidine (from Piperidine 1, Step C) and 277 mg of 2-amino-4-tert-butyl pyridine (from Step A) in 12 mL ethanol using a procedure analogous to that described in Piperidine 1, Step D to provide the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]1([C@@H:30]2[CH2:34][O:33][C:32](=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[N:6]=[CH:7][C:2]([N:31]3[C@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:34][O:33][C:32]3=[O:35])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)cn3)CC2)c(C)c1
Yield: 20.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 21 and (R)-(−)-4-phenyloxazolidin-2-one (326 mg), the title compound (183 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:16]([C:20]([O:22]CC)=[O:21])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].[ClH:27]>C1COCC1.CO>[ClH:27].[F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:16]([C:20]([OH:22])=[O:21])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3ncccc3F)cccn2c1C(=O)O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4.66 g of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 116A, 14.2 mmol) were dissolved in 304 ml of THF/MeOH (5/1), 70.8 ml of 1 N aqueous lithium hydroxide solution (70.8 mmol) were added and the mixture was stirred at 40° C. overnight. The reaction mixture was acidified (pH about 3-4) using 1 N aqueous hydrochloric acid, and the solution was concentrated. The precipitate formed was cooled with ice-water and then filtered off with suction and dried under reduced pressure. This gave 3.97 g of the product (83% of theory).