Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH2:18][C:19]1[C:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:23][CH:22]=[C:21]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:18][C:19]1[N:20]=[C:21]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:33]2)[CH:22]=[CH:23][C:24]=1[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccc(F)cc2)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 120 °C

Procedure:
55 mg (0.24 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 83 mg (0.28 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.206 ml (1.18 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 72 mg (54% of theory) of the product were obtained in solid form.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([CH:15]=[O:16])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[C:8]([CH3:21])([CH3:20])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Mg]Cl)[CH3:23]>C1COCC1.CN1CCCN(C)C1=O>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([CH:15]([OH:16])[CH2:22][CH3:23])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[C:8]([CH3:20])([CH3:21])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2c(cc1C=O)C(C(C)(C)C)=CCC2(C)C
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOc1cc2c(cc1C(O)CC)C(C(C)(C)C)=CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalene-2-carbaldehyde (Compound A-27, 450 mg, 1.57 mmol) in THF (7 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.3 mL) was added ethylmagnesium chloride (2 M in THF, 1.6 mL, 3.1 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with 1N HCl. The resulting mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C)c1C
Reaction time: 36 h

Procedure:
To a solution of 2,3-dimethylphenol (25.0 g, 205 mmol) in dimethylsulfoxide (200 mL) were added ethyl 2-bromo-isobutyrate (60 mL, 409 mmol) and potassium carbonate (56.5 g, 409 mmol) at room temperature, and the mixture was stirred for 36 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude oily ethyl 2-(2,3-dimethylphenoxy)-2-methylpropionate. 12 N Aqueous sodium hydroxide solution (20 mL, 240 mmol) was added to the mixed solution of this compound in THF (160 mL) and methanol (40 mL) at room temperature, stirred for 12 hours, and then concentrated under reduced pressure. Water and hydrochloric acid were added to the reaction solution to acidity the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was crystallized from ethyl acetate-hexane to obtain 21.3 g (yield 50%) of the title compound. Melting point: 71-73° C.
Reaction SMILES: [O:1]([CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:36][N:37]1[C:41]([NH2:42])=[CH:40][CH:39]=[N:38]1>CN(C=O)C>[Si:2]([O:1][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:42][C:41]3[N:37]([CH3:36])[N:38]=[CH:39][CH:40]=3)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: Cn1nccc1N
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Solvent: CN(C)C=O
Product: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(2-(tert-Butyldimethylsiloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridine-2(1H)-one (47 mg, 0.087 mmol), 2-methyl pyrazole-3-amine (0.175 mmol, 2.0 equivalents) and anhydrous DMF (3.0 mL) were added to a 25 mL round bottomed flask equipped with a stirring bar. The flask was capped with a rubber septum and flushed with nitrogen. Under a blanket of nitrogen, sodium hydride (8.5 mg, 60% dispersion in mineral oil) was added in one portion. The flask was flushed with nitrogen, capped and stirred at room temperature. The reaction progress was monitored by LCMS, and after 30 minutes, the starting material was consumed. The reaction mixture was quenched by the addition of water (0.5 mL) and ethyl acetate (15 mL) The contents of the round bottomed flask were transferred to a 125 mL separatory funnel, and the reaction flask was rinsed several times with additional ethyl acetate. Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one was partitioned between ethyl acetate and water (80 mL/30 mL). The ethyl acetate layer was washed once with brine, dried (MgSO4), filtered and concentrated to give crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one. The crude was taken directly into the deprotection step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH2:20][CH2:21][CH2:22][OH:23])[CH:14]=[CH:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH2:20][CH2:21][CH:22]=[O:23])[CH:14]=[CH:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CCCO)ccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CCC=O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
The compound (1.18 g) obtained in Example 121-6 was dissolved in anhydrous dichloromethane (25 ml) and added with Dess-Martin periodinane (1.82 g), followed by stirring at room temperature for 2 hours. After completion of the reaction, a sodium thiosulfate aqueous solution and a saturated aqueous sodium bicarbonate solution were added to the solution, and the whole was stirred. Then, the solution was extracted with chloroform and the extract was then washed with an aqueous mixture solution of a sodium thiosulfate aqueous solution and a saturated sodium bicarbonate aqueous solution. Then, the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (981 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[CH2:31][CH2:30]1)#[N:27]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(C(F)(F)F)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1cccc(C(F)(F)F)c1
Yield: 25.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.4 g), the title compound (1.0 g) was obtained, melting point: 215–216° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][N+:14]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccccc1C=C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccccc1CCN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
1-tert-Butoxy-2-(2-nitrovinyl)benzene (685 mg, 3.10 mmol) in tetrahydrofuran (10 ml) was cooled to 0° C. under an argon atmosphere (balloon). Lithium aluminum hydride (1 M in THF) (12384 μL, 12.4 mmol, equivalent to 470 mg) was added dropwise over 5 minutes. The reaction was stirred at 0° C. for 30 minutes and then at ambient temperature 4 hours. The reaction was quenched with 0.470 ml water at 0° C., followed by 0.470 ml 1 N aqueous NaOH at 0° C. After 15 minutes, an additional 1.45 ml water was added and the reaction mixture was warmed to ambient temperature and stirred rapidly for 1 hour, after which ethyl acetate (20 ml) and potassium were added. The reaction mixture was filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo to afford the title compound (575 mg, 2.97 mmol, 96.1% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=1)[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:18]2([CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:22]=[CH:23]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(N(Cc2ccccc2)C(=O)c2ccccc2I)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
To N-benzyl-N-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-iodobenzamide (2.4 g) dissolved in acetonitrile, palladium acetate (80 mg), triphenylphosphine (187 mg), anhydrous K2CO3 (987 mg) and tetraethylammonium chloride (591 mg) were added and stirred at 80° C. for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (1.64 g).
Reaction SMILES: N[C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH3:18])=[O:16].C(N([CH2:24][CH3:25])CC)C>ClCCl>[CH2:11]([O:10][C:8]([C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH3:18])=[O:16])=[O:9])[C:25]1[CH:24]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 184.6 %

Procedure:
A solution of 260B (0.75 g, 2.90 mmol) in dichloromethane (30 mL) at 0° C. was treated with triethylamine (0.35 g, 3.48 mmol) and N-(benzyloxycarbonyoxy)succinimide (0.72 g, 2.90 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with dichloromethane, washed with 10% citric acid (2×50 mL), then saturated NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 1.01 g (yield: 89%) of Compound 260C as an oil. It was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C@@H:7]([NH2:9])[CH3:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:19][C:20]1[C:21](Cl)=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1>C(O)C.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([NH:9][C@H:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH3:8])=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[C@H](N)C1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)ncc1Br)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine (1.0 g, 7.75 mmol) in ethanol (15 mL) was added N,N-diisopropylethylamine (3.0 g, 23.3 mmol) and 5-bromo-2,4-dichloropyrimidine (2.0 g, 8.53 mmol) at 25° C. under N2. The reaction was stirred at 25° C. for 18 hrs. The mixture was diluted with ethyl acetate and washed with water. The crude product was purified by column chromatography on silica gel eluted with petroleum ether: ethyl acetate=20:1 to give (S)-5-bromo-2-chloro-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)Pyrimidin-4-amine (1.5 g, 60.7%) as a yellow oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])=[CH:5][N:6]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][CH2:7][C:4]1[S:3][C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=2)=[N:6][CH:5]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(NCc1cnc(Br)s1)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1

Procedure:
In analogy to example 1, step 3, N-(2-bromo-thiazol-5-ylmethyl)-2-chloro-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a light yellow oil. MS: 443.3 ([M+H]+)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Cl[C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:6][C:8]1[CH:13]=[C:12]([O:6][CH2:3][C:4]#[CH:5])[N:11]=[CH:10][N:9]=1)[C:4]#[CH:5]
Reactant: Clc1cc(Cl)ncn1
Reactant: C#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1cc(OCC#C)ncn1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.27 g of sodium hydride (60% in oil), to which 0.7 ml of a tetrahydrofuran solution containing 0.33 g of 2-propyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.7 ml of a tetrahydrofuran solution containing 0.4 g of 4,6-dichloropyrimidine was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 40 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.35 g of 4,6-bis(2-propynyloxy)pyrimidine (the present compound (52)), m.p.: 74.0° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[CH:7]=1)(=[O:3])[CH3:2].[NH2:14][N:15]1[C:19]([C:20](=[O:22])[NH2:21])=[CH:18][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:16]1>>[O:4]([CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3=[CH:18][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:16][N:15]3[N:14]=2)[CH:9]=[CH:10][CH:11]=1)[C:1]([CH3:2])=[O:3]
Reactant: COC(=O)c1cc(C(N)=O)n(N)c1
Reactant: CC(=O)OCc1cccc(C=O)c1
Product: COC(=O)c1cc2c(=O)[nH]c(-c3cccc(COC(C)=O)c3)nn2c1
Yield: 39 %

Procedure:
According to the general preparation methods described in example 5 above, 3-formylbenzyl acetate reacts with compound 3 to give compound IIIb as offwhite solid in 39.0% yield. m.p. 202-203° C. 1H NMR (300 MHz, DMSO-d6): δ 12.29 (s, 1H), 8.19 (d, J=1.7 Hz, 1H), 7.96 (s, 1H), 7.92 (dt, J=1.7, 7.2 Hz, 1H), 7.58-7.53 (m, 2H), 7.24 (d, J=1.7 Hz, 1H), 5.16 (s, 2H), 3.81 (s, 3H), 2.10 (s, 3H). LC-MS: 342 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[CH:15]([C:21]([OH:23])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C[Si](Cl)(C)C.C(OCC)(=O)C>C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH3:20])[CH2:18][S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylic acid (429 mg.) was suspended in dry benzene (10 cc), and pyridine (400 mg.) and trimethylsilylchloride (5 cc) were added thereto. The mixture was stirred for 1.5 hours at room temperature and pyridine (400 mg.) was added thereto. The mixture was heated under reflux for 3 hours, mixed with ethyl acetate (30 cc), washed with dilute phosphoric acid and further with an aqueous solution saturated with sodium chloride, dried and then concentrated. A small amount of ethyl acetate was added to the residue and the precipitate was collected by filtration to yield crystals (250 mg.) of 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid, m.p. 170.5°-172° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[C:21]([CH3:22])([O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:15]=1)[CH3:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 54 %

Procedure:
3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 125 mL of 20% trifluoroacetic acid/methylene chloride and stirred for 20 minutes. The reaction mixture was evaporated under reduced pressure. The resultant oil was taken up in 400 mL water, made basic with 5N aqueous sodium hydroxide and extracted with ethyl acetate (3×300 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 11.72 g (54% 3 steps) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[K+].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Temperature: 50 °C
Yield: 91.5 %

Procedure:
180 g of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine was dissolved into 725 g of toluene, followed by adding 31 g of tetra-n-butyl ammonium bromide and 16 g of potassium iodide as a catalyst. Further, after 1924 g of 10% aqueous solution of sodium hydroxide was added and the mixture was heated to 50° C., 158 g of benzyl chloride was dropped. After the reaction finished, the mixture was cooled to 25° C. and an organic layer was washed with water. The resultant organic layer was concentrated, thereby obtaining 244 g of N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine (yield of 92%). A residual quantity of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine with respect to N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine was 1.1 wt %.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@@H:6]1Br)(=[O:3])[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl.CCOCC.[Cl-].[Zn+2].[Cl-].[N-]1C=CN=C1.[Ag+]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:29][C:26]1[CH:27]=[CH:28][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 25.2 %

Procedure:
A suspension of 5.6 g (15.8.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 2 g (14.3.10-3 mol) of 4-nitrophenol, 4 g (29.3.10-3 mol) of zinc chloride and 3.8 g (21.7.10-3 mol) of silver imidazolate in 80 ml of anhydrous methylene chloride is stirred at 50° C., under an inert atmosphere, in the absence of light and in the presence of a molecular sieve (400 pm). After 48 h at this temperature, the reaction mixture is filtered on Celite®, washed with a 1N aqueous solution of hydrochloric acid, then a 1N solution of sodium hydroxide and finally water and dried over magnesium sulfate (MgSO4). After evaporation to dryness, the residue is purified by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent. 1.5 g (yield: 25%) of the expected product are obtained by precipitation in ether.