Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[CH:22]1(O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:22]1([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 34 %

Procedure:
To a tetrahydrofuran (250 mL) solution of diethylazodicarboxylate (16.1 mL, 40.9 mmol) were added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), cyclohexanol (4.31 mL, 40.9 mmol) and triphenylphosphine (10.7 g, 40.9 mmol). This mixture was stirred for 30 hours at room temperature. The mixture was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (2.84 g, 34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:12]
Reactant: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c(F)c1
Yield: 76 %

Procedure:
A solution of 2-fluoro-4-methyl-6-nitrophenol D41 (400 mg, 2.337 mmol) (D41) in ethanol (50 mL) was hydrogenated using a Pd/C cartridge in the H-cube™ hydrogenator at 1 mL/min and full hydrogen. Evaporation gave 2-fluoro-4-methyl-6-aminophenol (250 mg, 1.771 mmol, 76% yield) as a fawn solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15]CC)=[O:14])=[CH:6]2.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ncc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-methoxy-3-ethoxycarbonylquinoline (Step D, 6 g, 0.026 mol) in EtOH (65 mL) was added at RT a 2N aqueous solution of NaOH (26 mL, 0.052 mol). The reaction mixture was stirred at RT overnight. After concentration under vacuum, the mixture was acidified with 1N HCl and the resulting solid was filtered off, washed with water and dried over P2O5 to give 6-methoxy-3-carboxyquinoline.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].[ClH:28]>C(O)C>[ClH:28].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:7]2[C:8]3[NH:14][N:13]=[C:12]([NH:15][CH3:16])[C:9]=3[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2=[O:27])=[CH:23][CH:22]=1
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Agent: Cl
Solvent: CCO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(N)cc2)c1=O
Yield: 46 %

Procedure:
To a suspension of 5-butyl-3-methylamino-7-(4-nitrobenzyl)pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1 g, 2.6 mM) in concentrated hydrochloric acid (5 ml) and ethanol (2.5 ml) was added dropwise a solution of stannous chloride (3.75 g) in ethanol (5 ml) at room temperature with stirring. The mixture was stirred at room temperature for 24 hours and concentrated to dryness. The residue was crystallized from hot water to give yellow crystals (0.42 g, 46%), m.p. >310° C.
Reaction SMILES: [O:1]=[O+][O-].CC(C)=[CH:6][CH2:7][C:8]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1.CSC.C(N(CC)CC)C>C(Cl)Cl>[O:1]=[CH:6][CH2:7][C:8]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1
Reactant: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(CC=O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ozone was passed through a solution of 1-benzyl 3-ethyl 3-(3-methylbut-2-en-1-yl)piperidine-1,3-dicarboxylate (35.2 g, 0.0979 mol) in methylene chloride (800 mL) at −78° C. until the color of the solution turned blue. The reaction mixture was then flushed with nitrogen until the blue color dissipated. Dimethylsulfide (Aldrich, cat #: 274380) (14 mL, 0.19 mol) and triethylamine (26.5 mL, 0.19 mol) were added and the mixture was stirred at ambient temperature overnight. The volatile solvent were removed under reduced pressure and purified directly by flash chromatography on a silica gel column with 20% ethyl acetate in hexanes to afford the desired product in quantitative yield. LC/MS 334.2 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([N:24]1[CH2:25][CH2:16][C:10]([C:8]#[N:9])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C#N)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C#N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
TFA (4.31 mmol, 0.49 g) was added to a solution of ethyl 2-cyanoacrylate (17.58 mmol, 2.20 g) in DCM (100 mL) under nitrogen atmosphere. Subsequently, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (21.49 mmol, 5.10 g) in DCM (50 mL) was added dropwise while cooling with an ice-bath in order to keep the reaction temperature at room temperature (exothermic reaction). The reaction mixture was stirred overnight at room temperature. Then the mixture was washed with saturated aqueous NaHCO3 (100 mL). The aqueous phase was extracted with DCM (100 mL). The combined organic phase was dried over MgSO4 and evaporated in vacuo. The crude product was purified by flash silicagel chromatography (100% heptane to 50% EtOAc) yielding 4.27 g of a colorless oil (94%). 1H-NMR (400 MHz, CDCl3, 300K): δ=1.32 (3H, t, J=7.1 Hz), 2.44 (1H, m), 2.59 (1H, m), 2.69 (1H, m), 2.89 (1H, m), 2.99 (1H, d, J=9.8 Hz), 3.17 (1H, d, J=9.8 Hz), 3.69 (2H, s), 4.27 (2H, q, J=7.1 Hz), 7.29 (5H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8].Cl.[NH2:13][C:14]([NH2:16])=[NH:15].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH:7]([C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:15]=[C:14]([NH2:16])[N:13]=1)([CH3:9])[CH3:8]
Reactant: N=C(N)N
Reactant: COCC(=O)CC(=O)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCc1cc(C(C)C)nc(N)n1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a stirred solution of 1-methoxy-5-methylhexane-2,4-dione (1.08 g, 6.8 mmol) in EtOH (15 mL) was added guanidine hydrochloride (1.3 g, 13.7 mmol). 5 min later, a solution of Na2CO3 (1.45 g, 13.7 mmol) in H2O was added and the resulting mixture was heated to reflux for 20 h. The reaction was cooled to room temperature and the solvent was removed. The residue was dissolved in EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes) to provide 4-isopropyl-6-(methoxymethyl)pyrimidin-2-amine (482 mg, 39%). 1H NMR (CDCl3): d 6.43 (s, 1H), 6.11 (s, 2H), 4.16 (s, 2H), 3.26 (s, 3H), 2.56-2.66 (m, 1H), 1.03 (d, J=6.9 Hz, 6H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:8])[NH:7][CH2:6][CH2:5][S:4]1.C(N(CC)CC)C.[C:16](=[S:18])=[S:17].C([O-])(=O)C.[Zn+2:23].C([O-])(=O)C>C(O)(C)C>[CH3:2][C:3]1([CH3:8])[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][S:4]1.[CH3:2][C:3]1([CH3:8])[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][S:4]1.[Zn+2:23]
Reactant: CC1(C)NCCS1
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(C)SCCN1C(=S)[S-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
While cooling and stirring at 10°C, 76.8 g. (0.50 mole) 2,2-dimethylthiazolidine hydrochloride [preparation described by B. Sweetman et al, J. Med. Chem. 12, 888 (1969)] was added to a mixture of 30 ml isopropanol and 101 g. (1.00 mole) triethylamine. Likewise, 38.0 g. (0.50 mole) of carbon disulfide was gradually added, followed by 45.8 g. (0.25 mole) of anhydrous zinc acetate. After standing overnight at room temperature, the precipitate was filtered, twice water-washed with 1 liter portions of water and air-dried to give 80.5 g. of the yellow product melting at 148° - 153°C (decomp.) and having the following analysis: Found: C, 31.51; H, 4.70%. Calcd for C12H20N2S6Zn: C, 32.04; H, 4.45%.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:18]1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH:27]([CH3:28])[CH2:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (760 μl, 6.03 mmol.) and pyridine (510 μl, 6.31 mmol.) were added to a solution of rac. 2-(1H-indol-3-yl)-1-methylethylamine (1.0 g, 5.74 mmol.) in abs. DCM (20 ml), and stirring was carried out for 24 h at RT. For working up, the mixture was washed with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml), then dried, filtered and concentrated. [2-(1H-Indol-3-yl)-1-methylethyl]carbamic acid phenyl ester was obtained in the form of a white solid in a yield of 1.35 g.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5]
Reactant: CCCCCC(O)CC#N
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CC#N)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A mixture of 3-hydroxycaprylonitrile (5.2 g., 36.8 millimole), dihydropyran (3.8 g., 45 millimole) and p-toluenesulfonic acid. hydrate (catalytic amount) is stirred at 25° C. for 16 hours, then diluted with ether (100 ml.). The resulting solution is washed with 5% aqueous sodium hydroxide (25 ml.) and water (2 × 25 ml.), dried over magnesium sulfate and filtered. Evaporation of the filtrate in vacuo affords the title compound as a pale yellow oil (7.9 g., 95%), pmr (CDCl 3) δ 0.93 (3H, t), 2.54 (2H, q) and 4.68 (H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:28]([CH3:31])([O-:30])=[O:29].[H-].[Na+].[N-]1C=CN=C1.Cl>C1COCC1.O>[N+:28]([CH2:31][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:8][CH:7]=1)([O-:30])=[O:29]
Reactant: C[N+](=O)[O-]
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCc1ccc(C(F)(F)F)cc1)C[N+](=O)[O-]
Yield: 70.8 %

Procedure:
To a solution of 3-[4-(trifluoromethyl)phenyl]propanoic acid (4.36 g, 20.0 mmol) in THF (100 ml) was added carbonyldiimidazole (3.89 g, 24.0 mmol) and the mixture was refluxed for 1 h. Into a separate flask was placed nitromethane (4.5 ml, 80.0 mmol), THF (40 ml) and sodium hydride (0.96 g, 24.0 mmol) and the mixture was stirred for 10 min. To this was added slowly the imidazolide from the first reaction and the mixture was refluxed for 16 h. To the reaction mixture was added water (100 ml) and the pH was adjusted to 3 with HCl. The THF was removed by rotary evaporation. The product was extracted with ethyl acetate. The product was purified by silica gel column chromatography (silica gel/30% ethyl acetate in petroleum ether) giving A as an oil (3.70 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, 2H), 7.28 (dd, 2H), 5.20 (s, 2H), 3.03 (m, 2H), 2.87 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]([OH:16])[C@@H:10]([C:13]([OH:15])=[O:14])[NH:11][CH3:12])=[CH:7][CH:6]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]Cl)([O-:33])=[O:32].[OH-].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]([OH:16])[C@@H:10]([C:13]([OH:15])=[O:14])[N:11]([CH3:12])[S:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N+:31]([O-:33])=[O:32])=[CH:17][CH:18]=1
Reactant: CN[C@H](C(=O)O)C(O)c1ccc(OCOC)cc1
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCOc1ccc(C(O)[C@@H](C(=O)O)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-β-hydroxytyrosine (15.1 g) and bis(trimethylsilyl)acetamide (25 ml) in dichloromethane (150 ml) was added a solution of 2-nitrophenylsulfenyl chloride (11.2 g) in dichloromethane (50 ml). After stirring for 2 hours at 0° C., bis(trimethylsilyl)acetamide (10 ml) and 2-nitrophenylsulfenyl chloride (5.6 g) was added to the solution. The mixture was stirred for 3 hours at room temperature and added to 1N-sodium hydroxide (200 ml). The organic layer was washed with water (300 ml) and the aqueous solutions were combined. After the aqueous solution was acidified with diluted hydrochloric acid, the product was extracted with ethyl acetate (300 ml) and the extract was washed with water (100 ml×3). After the solution was dried over magnesium sulfate, the solvent was removed in vacuo to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine (20.5 g).
Reaction SMILES: [F:1][CH:2](F)[CH2:3]I.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][NH:9][CH2:8]1.BrCCF.C([O-])([O-])=O.[K+].[K+]>>[F:1][CH2:2][CH2:3][N:9]1[CH2:8][C:7]([CH3:6])([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CC1(C)CNCc2cc(N)ccc21
Reactant: FC(F)CI
Agent: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)CN(CCF)Cc2cc(N)ccc21

Procedure:
The title compound was prepared as described in Example 224B, substituting Example 224A and 1,1-difluoro-2-iodoethane with 4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine and 1-bromo-2-fluoroethane, respectively, and using 2.5 equivalent of K2CO3.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCc1ccccc1

Procedure:
The title compound, white solid, m.p. 100-101° C. and MS: m/e=345 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and benzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH:30]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g) and triethylamine (3.16 mL) in tetrahydrofuran (45 mL) was added 2-methylpropyl chlorocarbonate (2.84 mL) at 10° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (2.19 g) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 7 days. Ethyl acetate (50 mL) and aqueous sodium hydrogen carbonate (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (50 mL) was added 2M aqueous sodium hydroxide solution (24.8 mL), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was neutralized with 6M hydrochloric acid (8.5 mL) under ice-cooling, and water (10 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (3.03 g) as a pale-yellow solid. The optical purity was 73.8% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: O[CH:2]([CH2:20]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19].[H-].[Na+].CN1C=C(C)C(=O)NC1=O.BrCCCCCCCC=C>CS(C)=O.O>[CH2:9]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:20]
Reactant: Cc1cn(C)c(=O)n(CCCCCCCC(O)CO)c1=O
Agent: C=CCCCCCCCBr
Agent: Cc1cn(C)c(=O)[nH]c1=O
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 73 %

Procedure:
3-(8,9-Dihydroxynonyl)-1-methylthymine (CT1918) was used as an intermediate for the synthesis of CT1908 (example 12). A mixture of sodium hydride (343 mg, 14 mmol) and 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (40 ml) was stirred for 15 min and then 9-bromo-1-nonene (2.93 g, 14 mmol) was added. After stirring for 20 hr, the mixture was poured into water (40 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (40 ml), with saturated aqueous sodium chloride solution (20 ml), and dried over sodium sulfate. The solvent was evaporated to give 3-(8-nonenyl)-1-methylthymine (CT1917) (2.76 g, 73% yield) as a colorless oil which solidified upon standing.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.C([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:31]#[C:32][CH3:33])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([CH2:31][CH2:32][CH3:33])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=1
Reactant: CC#CC(CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCCC(CC(=O)OC)c1ccc(O)cc1
Reaction time: 2 h
Yield: 0.8 %

Procedure:
To a 500 mL parr hydrogenater flask with ethyl acetate (5 mL) and quinoline (0.117 g, 1.4 mmol), was added methyl 3-[4-(benzyloxy)phenyl]hex-4-ynoate (0.2 g, 65.0 mmol) and 10% Pd/C (0.015 g) under N2 atmosphere. The RM was hydrogenated for 2 h. The RM was diluted with ethyl acetate (10 mL), filtered the catalyst through celite and evaporated to dryness under reduced pressure. The crude was purified by flash column chromatography on silica gel (100/200 mesh), to give the product (0.11 g, yield: 76.38%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:72][C:73]1[S:74][C:75]2[CH:80]=[CH:79][N:78]=[CH:77][C:76]=2[N:81]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:72][C:73]4[S:74][C:75]5[CH:80]=[CH:79][N:78]=[CH:77][C:76]=5[N:81]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2cnccc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cnccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 78.3 %

Procedure:
Using 402 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 74 mg of 2-mercaptothiazolo[4,5-c]pyridine, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 356 mg of the title compound in a yield of 78%.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:31][CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH:33]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]1>>[CH2:1]([C@@:4]1([CH2:31][CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][NH:39][S:36]([CH:33]2[CH2:35][CH2:34]2)(=[O:38])=[O:37])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Product: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O

Procedure:
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253, Step C,) was coupled with cyclopropanesulfonamide by the procedure described in example 202, step C to afford the title compound as a white foam.