Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([O:25]C)=[O:24].[I-].[Li+].Cl>N1C=CC=CC=1.O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cnc2c3ccc(NC(=O)C(C)(C)C)cc3ncn2c1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)ncn1c(=O)c(C(=O)O)cnc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A mixture of methyl 4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (6.5 g) and anhydrous lithium iodide (16.25 g) in dry pyridine (65 ml) was stirred at 100° C. for 1 hour and 30 minutes and at 120° C. for additional 30 minutes. The reaction mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in water. The resulting solution was adjusted to pH 1 with conc. hydrochloric acid to give yellow crystals, which were separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. The solution was filtered to remove insoluble materials. The solution was concentrated under reduced pressure until crystallization began and cooled. The resulting crystals were collected by filtration and dried. There was obtained 4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (2.9 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O=[CH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59](=[O:73])[NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59](=[O:73])[NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH2:56][CH2:57]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To a 300 mL round-bottomed flask was added 5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (5 g, 9.73 mmol), dichloromethane (100 mL) and glacial acetic acid (0.6 mL, 10 mmol). This mixture was cooled to 0° C. using an ice bath and biphenyl-2-ylcarbamic acid 1-(9-oxononyl)piperidin-4-yl ester (4.6 g, 9.73 mmol) was added with stirring. This mixture was stirred at 0° C. for 30 minutes and then sodium triacetoxyborohydride (6.15 g, 29 mmol) was added in portions over 15 minutes. The reaction mixture was stirred at 0° to 10° C. for 2 hours and then aqueous saturated sodium bicarbonate solution (50 mL) was added and this mixture was stirred for 15 minutes. The layers were then separated and the organic layer was washed with 5% aqueous sodium chloride solution (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.5 g, 80% purity by HPLC), which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=2)[CH3:11])=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(#N)C>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:10]([CH3:11])[C:8](=[O:9])[C:7]2[CH:22]=[CH:23][C:4]([C:3]([OH:24])=[O:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([OH:20])=[O:19]
Reactant: COC(=O)c1ccc(C(=O)N(C)c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CN(C(=O)c1ccc(C(=O)O)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.99 g of N-(4-methoxycarbonylphenyl)-N-methyl-terephthalamic acid methyl ester was dissolved in 10 ml of acetonitrile and treated with 10 ml of 1N sodium hydroxide solution and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then acidified with 1N hydrochloric acid and the resulting precipitate was filtered off yielding N-(4-carboxy-phenyl)-N-methyl-terephthalamic acid, which was used directly in the next step.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][OH:33])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][O:33][S:44]([CH3:43])(=[O:46])=[O:45])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCO)cc34)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCOS(C)(=O)=O)cc34)CC2)cc1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A solution of 4-[6-(3-hydroxy-prop-1-ynyl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (816 mg, 1.84 mmol), as prepared in Example 12, and DIEA (350 μL, 2.12 mmol) in DCM (13 mL) was treated with methanesulfonyl chloride (157 μL, 2.02 mmol) dropwise over 1 min with stirring at 0° C. under positive argon pressure. The ice bath was immediately removed, and the reaction was stirred at rt for 1 h 15 min. Flash chromatographic purification of the crude reaction mixture (1:9 hex/EtOAc→EtOAc) afforded the title compound (896 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.31 (d, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.26 (m, 2H), 6.85 (m, 2H), 6.34 (br s, 1H), 5.15 (s, 2H), 4.49 (heptet, 1H), 4.33-4.23 (m, 2H), 3.73 (m, 1H), 3.25-3.11 (m, 2H), 3.18 (s, 3H), 2.22-1.94 (m, 4H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 522.2, found 523.3 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ncco2)cc2nc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1ccc2[nH]c(-c3ncco3)cc2n1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-2-(1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (2.09 g, 5.81 mmol, from Step 2) in THF (30 mL) and EtOH (10 mL) was treated with 1.0 M NaOH in water (30 mL, 30 mmol). After stirring for 1 hour, the reaction mixture was diluted with water, and the volatile components were removed in vacuo. The aqueous mixture was extracted with three portions of EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was triturated in EtOAc/DCM/MeOH, and the yellow solid was isolated by filtration and air dried. Yield: (0.78 g, 61%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:16][CH:15]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=Cc2ccc(C)cc2[N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
To a solution of 1-Bromo-4-methyl-2-nitro-benzene (0.76 g, 3.5 mmol), 1-methoxy-4-vinyl-benzene (0.59 g, 4.4 mmol), triethylamine (0.88 g, 8.8 mmol), tri-o-tolylphosphine (0.022 g) and palladium acetate (0.008 g) in N,N-dimethylformamide (7 mL) was placed in a high-pressure tube and purged with nitrogen for 10 mins. The tube was sealed and heated at 120° C. for 16 hours. The mixture was partitioned with water and ethyl acetate adjusting the pH to 3. The organic layer was washed with brine, dried (sodium sulfate) and filtered through a plug of silica. The filtrate was evaporated under vacuum and the residue was triturated with hexane/ethyl acetate (9:1) to provide the title compound (0.55 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([OH:12])[CH:3]=1.FC1[CH:21]=[C:20]([O:22]C)[CH:19]=C(O)C=1C=O.C(#N)C.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].ClCC(=O)C>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]2[CH:6]=[C:19]([C:20](=[O:22])[CH3:21])[O:12][C:4]=2[CH:3]=1
Reactant: COc1cc(O)c(C=O)c(F)c1
Reactant: COc1cc(F)cc(O)c1C=O
Agent: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(F)cc2oc(C(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-fluoro-2-hydroxy-6-methoxybenzaldehyde and 2-fluoro-6-hydroxy-4-methoxybenzaldehyde (Example 36A, 4.63 g, 27.2 mmol) in acetonitrile (49.7 mL, 952 mmol) was added potassium iodide (0.903 g, 5.44 mmol), cesium carbonate (9.75 g, 29.9 mmol) and 1-chloropropan-2-one (2.395 mL, 28.6 mmol). The mixture was stirred at r.t. for 2 h, was treated with 0.1 eq of cesium carbonate and heated to 60° C. for 1 h and 80° C. for another hour. The reaction was left overnight at r.t., then filtered over a small pad of silica and rinsed with ethyl acetate (approx 500 mL). The residue obtained after concentration was purified by silica gel chromatography (ISCO, 120 g of silica with 100% toluene using UV at 315 nm, then polarity was increased over time up to 10% ethyl acetate). The fractions were evaporated to give a 7:1 mixture of the desired/undesired isomers which was recrystallized overnight with ethyl acetate. The title material was obtained (216 mgs, 3.8%) as colorless crystals. LC (Method B): 1.928 min. LCMS (APCI) calcd for C11H10FO3 [M+H]+ m/z 209.06, found 209.1. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.55-7.61 (m, 1H), 6.78-6.99 (m, 1H), 6.46-6.53 (m, 1H), 3.96 (s, 3H), 2.55-2.60 (m, 3H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3c(F)cccc3F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: O=C(NCc1c(F)cccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 20.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,6-difluorobenzyl)-1-piperidinecarboxamide formate (0.50 g, 1.15 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.465 g, 1.15 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.192 g, 0.24 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[O:18][N:17]=2)[S:6][C:7]=1[CH2:8][O:9]C1CCCCO1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=3)[O:18][N:17]=2)[S:6][C:7]=1[CH2:8][OH:9])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CO
Yield: 93 %

Procedure:
To a solution of 3-{4-ethyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-thienyl}-5-(4-phenoxyphenyl)-1,2,4-oxadiazole (0.25 g, 0.54 mmol) that was obtained in Example 22 (22e) in ethanol (5 ml) was added pyridinium p-toluenesulfonate (0.014 g, 0.54 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 4 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo to afford the title compound (0.19 g) in a yield of 92% as a crystalline white solid.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([C:11]([OH:13])=[O:12])[CH:8]([CH3:10])[CH3:9]>[OH-].[Na+].O1CCOCC1>[CH3:1][O:2][C:3]([NH:6][C@H:7]([C:11]([OH:13])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.67 g (60 mmol) of chloroformic acid methyl ester are added to 7.0 g (60 mmol) of L-valine in 100 ml of 2N NaOH and 30 ml of dioxane (→exothermic reaction) and the mixture is then stirred for 18 h at RT. The reaction mixture is extracted with methylene chloride and the aqueous phase is acidified with 27 ml of 4N HCl and extracted again with methylene chloride. Drying and concentration by evaporation of the latter methylene chloride phase yields the title compound: tRet (I)=7.2 min; 1H-NMR (200 MHz, CD3OD): 0.96 (t, J=7 Hz, 6H), 2.16 (m, 1H), 3.67 (s, 3H), 4.06 (m, 1H), 7.07 (d, J=8 Hz, HNpartially exchanged).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]([CH3:25])[CH:10]([C:12]1[CH:24]=[CH:23][C:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1)O)(=O)C.S(Cl)(Cl)=O.C1CCN2C(=NCCC2)CC1.[Cl-].[Na+]>C(Cl)Cl.CN(C)C=O.O>[OH:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH3:25])=[CH:10][C:12]1[CH:24]=[CH:23][C:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)OCCOCC(C)C(O)c1ccc(Cc2cccnc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(=Cc1ccc(Cc2cccnc2)cc1)COCCO
Reaction time: 2 h
Yield: 50 %

Procedure:
In 10 ml of methylene chloride was dissolved 2.07 g of 3-[p-[3-(2-acetoxyethyl)oxy-1-hydroxy-2-methylpropyl]benzyl]pyridine, and to the resulting solution was added 0.88 ml of thionyl chloride with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for one hour. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure. The residue thus obtained was dissolved in 10 ml of N,N-dimethylformamide, and to the resulting solution was dropwise added 4.5 ml of DBU, after which the resulting mixture was subjected to stirring at 100° to 110° C. for 2 hours. Subsequently, 5 ml of water was dropped into the mixture, and the mixture was subjected to reaction at 100° C. for 2 hours. The reaction mixture was poured into 80 ml of a saturated aqueous sodium chloride solution, and the resulting mixture was subjected to extraction with two 40-ml portions of ethyl acetate. The extracts were combined, washed with 20 ml of water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform] to obtain 850 mg (yield 50.0%) of colorless, oily 3-[p-[3-(2-hydroxyethyl)oxy-2 -methyl-1-propenyl]benzyl]pyridine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3cccc(Cl)c3)cc2)no1
Temperature: 90 °C
Yield: 70.7 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 40 mg, 0.142 mmol) in CH3CN (2 mL) were added 3-chlorophenol (28 mg, 0.22 mmol) and K2CO3 (40 mg, 0.29 mmol). The mixture was heated at 90° C. for 4 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-chloro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (33 mg, 71%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.92 (d, J=8.1 Hz, 2H), 7.55-7.66 (m, 3H), 7.23-7.36 (m, 1H), 7.09-7.15 (m, 1H), 6.95-7.05 (m, 2H), 5.21 (s, 2H).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([C:26]1([CH:30](O)[CH2:31][C:32]#[CH:33])[CH2:29][CH2:28][CH2:27]1)[CH2:24][CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH:30]([C:26]1([CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH2:29]1)[CH2:31][C:32]#[CH:33])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CCC(O)C1(CCC)CCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(O[Si](C)(C)C(C)(C)C)C1(CCC)CCC1
Reaction time: 1 h
Yield: 153.8 %

Procedure:
t-Butyldimethylsilyltrifluoromethanesulfonate (1.8 mL, 7.88 mmol) was added to a solution of triethylamine (2.2 mL, 15.8 mmol) and alcohol 4 (650 mg, 3.94 mmol) in CH2Cl2 (5.0 mL) at 0° C. The reaction was stirred for 1 h and then saturated aqueous NaHCO3 was added. The mixture was extracted with CH2Cl2. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. FCC (silica gel, 100% hexane) gave 1.7 g (100%) of the silyl ether 5 as a clear, colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)ON=C(C1N=C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)SC=1)C(N[C@@H:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([O-:33])=[O:32])=[C:20]([CH2:23][N+:24]3[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:21][S:22][C@H:17]12)=O>>[CH3:30][N:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[N+:24]1[CH2:23][C:20]1[CH2:21][S:22][C@@H:17]2[CH2:16][C:34](=[O:35])[N:18]2[C:19]=1[C:31]([O-:33])=[O:32]
Reactant: Cc1ccn(C)[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn(C)[n+]1CC1=C(C(=O)[O-])N2C(=O)C[C@H]2SC1

Procedure:
7β-[2-(2-Aminothiazol-4-yl)-2-difluoromethoxyimino)acetamido]- 3-(2,5-dimethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared from trifluoroacetic acid salt of 7β-[2-difluoromethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(2,5-dimethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) according to a similar manner to that of Example 29.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)(=O)C.O1CCCC1.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)=[O:12]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of 3-({[4-(trifluoromethyl)phenyl]amino}carbonyl)phenyl acetate (27.7 g, 85.5 mmol) in methanol (100 mL)/tetrahydrofuran (100 mL) was added 8N aqueous sodium hydroxide solution (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hr and dried under reduced pressure to solidness. The residue was poured into dilute hydrochloric acid (pH=2) and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (21.7 g, 90%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O.O>[CH3:20][O:19][C:17](=[O:18])[NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5]
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
To a solution of 5.0 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide in 20 ml of dimethylformamide was added 2.3 g of methyl chloroformate. The resulting solution was warmed for 2 hours and then diluted with a small volume of water. The solid which formed on cooling was separated by filtration to give [2-((1H-tetrazol-5-yl)-aminocarbonyl)phenyl]carbamic acid methyl ester melting at about 236°-237° C. after recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O:18][P:19]1(=[O:26])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CN(C=O)C>[CH3:10][C:9]([CH3:11])([CH3:12])[C:8]#[C:7][C:5]1[S:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][CH:22]2[CH2:23][CH2:24][P:19]([O:18][CH3:17])(=[O:26])[CH2:20][CH2:21]2)[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: COP1(=O)CCC(=O)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCP(=O)(OC)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
A solution of methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (474 mg, 2 mmol) and 1-Methoxy-1-oxo-1λ5 phosphinan-4-one (390 mg, 2.4 mmol) in THF (1 mL) and DMF (1 mL) was treated with dibutyltin dichloride (60 mg, 0.2 mmol). After 5 min, phenylsilane (272 μL, 2.2 mmol) was added, and the mixture was stirred for one hour at room temperature and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with 5% LiCl and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using EtOAc:Hexanes as eluent to provide 650 mg (85%) of title compound: MS (m/z) 384.0 [M+H]−; HPLC retention time: 4.463 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).