Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.C1C=CC(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[CH2:8][C:9]([N:39]=[N+:40]=[N-:41])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC(c1ccccc1)c1ccnnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)CC(c1ccccc1)c1ccnnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-phenyl-3-(pyridazin-4-yl)propanoic acid (570 mg, 2.5 mmol) in DMF (30 mL) was added Et3N (505 mg, 5.0 mmol), followed by the DPPA (722 mg, 2.6 mmol) in portions at 0° C., the resulting mixture was stirred at room temperature for 1.5 hour. The reaction was diluted with water, extracted with AcOEt (3×40 ml), the combined organic layer was washed by brine, dried over Na2SO4 and concentrated to get the 3-phenyl-3-(pyridazin-4-yl)propanoyl azide (crude 650 mg), which was used for next step directly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[N:6][CH:7]=1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[N:19]=[C:18]([NH:20][C:21]4[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=4)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[O:29][CH2:28][CH2:27][O:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nc(C3(c4ccc(F)cn4)OCCO3)nc3ccccc23)n[nH]1
Temperature: 25 °C

Procedure:
To a mixture of (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 and toluene are added ethylene glycol 5 equiv) and p-toluenesulfonic acid monohydrate (0.2 equiv), and the mixture is heated at reflux while collecting water in a Dean-Stark trap. As needed, additional ethylene glycol and p-toluenesulfonic acid monohydrate are added and heating and water collection are continued to achieve substantially complete reaction After cooling to rt, the mixture is concentrated, and the residue is dissolved in DMSO and purified by reverse phase HPLC.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=1>CC#N>[CH2:5]([O:4][C:2]([C:11]1[N:12]([CH3:13])[C:8]([Br:7])=[CH:9][N:10]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cn1cncc1Br
Solvent: CC#N
Product: CCOC(=O)c1ncc(Br)n1C
Temperature: 25 °C
Yield: 55.3 %

Procedure:
Ethyl chloroformate (1.19 mL, 12.4 mmol) in MeCN (5 mL) was added dropwise to a 1.00 g (6.21 mmol) of 5-bromo-1-methyl-1H-imidazole (Aldrich) in 30 mL of MeCN under N2. The mixture was stirred and allowed to warm to rt overnight. The mixture was concentrated and the residue was treated with 2M NaOH (100 mL) and extratcted with CH2Cl2 (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (0–50% EtOAc in hexanes) to give the 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester as a yellow oil (800 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[C:27]([C:33]#[N:34])=[N:28][CH:29]=[C:30](Cl)[N:31]=1>C1COCC1>[Cl:25][C:26]1[N:31]=[C:30]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:2]2[CH3:1])[CH:29]=[N:28][C:27]=1[C:33]#[N:34]
Reactant: C[C@H]1NCCC[C@H]1NC(=O)OC(C)(C)C
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
tert-Butyl (2R,3R)-2-methylpiperidin-3-ylcarbamate (310) (1.1 g, 5.1 mmol) was dissolved in THF (20 mL). To the stirred solution was added DIEA (1.34 mL, 7.7 mmol), followed by 3,5-dichloropyrazine-2-carbonitrile (1.07 g, 6.2 mmol). The reaction was stirred at room temperature for 1 hour. An additional amount of 3,5-dichloropyrazine-2-carbonitrile (200 mg, 1.2 mmol) was added, and the reaction was stirred for another hour. The solvent was removed under reduced pressure, and the residue was suspended in EtOAc. The organic mixture was washed with 1N HCl (aq), saturated NaHCO3(aq) and brine, dried, and concentrated in vacuo. The residue was then purified by silica flash column chromatography (EtOAc/hexanes) to give tert-butyl (2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (311), (1.54 g, 4.38 mmol, 86% yield).
Reaction SMILES: [CH2:1]([C:4]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:27])[C:22]2[S:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(C(OCC)=O)[C:5]([O:7]CC)=[O:6])[CH:2]=[CH2:3].[OH-].[Na+]>>[C:22]1([C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:4]([CH2:1][CH:2]=[CH2:3])[C:5]([OH:7])=[O:6])=[CH:16][CH:17]=2)=[O:27])[S:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 20.3 parts of diethyl 2-allyl-2-[p-(2-thenoyl)phenyl]malonate and 150 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and washed twice with 80 parts of ether. The aqueous phase is separated and acidified with concentrated hydrochloric acid solution till strongly acid: an oil is separated which solidifies. The product is extracted with ether. The extract is washed with water, dried and evaporated. The oily residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from 32 parts of acetonitrile at -20° C, yielding 2-[p-(2-thenoyl)phenyl]-4-pentenoic acid; mp. 117.1° C; also named p-(2-thenoyl)-α-allyl-phenylacetic acid.
Reaction SMILES: [C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([O:18]C(=O)C)=[C:13]4[C:22]5[C:35]([CH:36]=[CH:37][C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:34]([O:38][CH3:39])[C:33]2[C:32](=[O:40])[C:31]3[C:26](=[CH:27][C:28]([O:46]C(=O)C)=[C:29]([CH3:45])[C:30]=3[O:41]C(=O)C)[C:25](=[O:50])[C:24]=2[C:23]=5[O:51]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CN(C)C=O>[C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[C:22]5[C:35]([CH:36]=[CH:37][C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:34]([O:38][CH3:39])[C:33]2[C:32](=[O:40])[C:31]3[C:26](=[CH:27][C:28]([OH:46])=[C:29]([CH3:45])[C:30]=3[OH:41])[C:25](=[O:50])[C:24]=2[C:23]=5[OH:51])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c2c(c(OC(C)=O)c3c1ccc1cc4cnn(-c5ccccc5)c(=O)c4c(OC(C)=O)c13)C(=O)c1cc(OC(C)=O)c(C)c(OC(C)=O)c1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1c2c(c(O)c3c1ccc1cc4cnn(-c5ccccc5)c(=O)c4c(O)c13)C(=O)c1cc(O)c(C)c(O)c1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 112 mg (0.15 mmol) of the resulting intermediate 2-phenyl-10,12,15,16-tetraacetoxy-8-methoxy-11-methyl-9,14-dioxo-9,14-dihydronaphthaceno[1,2-g]phthalazin-1-one in 2.3 m of N,N-dimethylformamide is mixed, while cooling in ice, with 2.3 m of 1 M potassium hydroxide solution and stirred at room temperature for 2 hours. The product is precipitated as a red solid (78 mg) by acidification with aqueous citric acid. The yield is 93% of theory.
Reaction SMILES: C(N[NH:9][CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+].O.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:12]([N:9]([CH2:10][CH:11]([OH:28])[CH:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:34](=[O:35])[CH2:33][Cl:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CNNCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1OC(c1ccccc1)C(O)CN(Cc1ccccc1)C(=O)CCl
Temperature: -50 °C
Yield: 93 %

Procedure:
To a solution of N-benzylamino-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (3.5 g) in CH2Cl2 (60 ml), NaOH (0.6 g) and water (16 ml) were added at 0° C. The whole was cooled to -50° C. and chloroacetyl chloride (1.1 ml) diluted in CH2Cl2 (10 ml) was added dropwise. The organic extracts were combined and washed with a saturated solution of NaCl, drying was carried out over Na2SO4 and the solution was then evaporated to dryness, so obtaining N-benzyl-N-chloroacetyl-2-hydroxy-3-(2-methoxy-phenoxy)-3-phenylpropylamine (4.0 g; yield 93%) as an oil, chromatographically pure, which is used as such.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH:20]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=3[S:9](=[O:10])(=[O:11])[NH:12]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Product: N#Cc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
5-Cyano-2-aminobenzenesulfonamide (see compound 37) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 234–237.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][N:18]([C:27]([CH:29]3[CH2:33][O:32]C(C)(C)[N:30]3C(OC(C)(C)C)=O)=[O:28])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][CH:29]([C:27]([N:18]1[CH2:19][C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:16]([O:15][C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:44])([F:1])[F:43])[CH:4]=2)[CH3:14])[CH2:17]1)=[O:28])[CH2:33][OH:32]
Reactant: C[C@@H](O[C@H]1CN(C(=O)C2COC(C)(C)N2C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CN(C(=O)C(N)CO)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 48 mg tert-butyl 4-{[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]carbonyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Example 4) in 3 mL methylene chloride was added 0.5 mL anisole and 3 mL TFA. The reaction mixture was stirred at RT for 2 hr and then the volatiles were removed under vacuum. The residue was partitioned between methylene chloride (5 mL) and sat. aq. sodium carbonate (5 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by prep TLC eluting with methylene chloride/methanol (9/1) to afford the title compound. 1H-NMR (CDCl3): δ: 1.43 (d, 3H, 6.5 Hz), 2.0 (br. s, 3H), 3.30-4.18 (m, 9H), 4.54 (m, 1H), 7.00-7.08 (m, 2H), 7.22-7.31 (m, 3H), 7.56 (s, 2H), 7.75 (s, 1H)ppm. MS: 491.2 (MH+) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14](O)=[O:15])=[CH:4][CH:3]=1.CN(C)C=O.O=S(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([Cl:26])=[O:15])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccccc1Oc1ccc(Cl)cc1

Procedure:
[2-(4-chloro-phenoxy)-phenyl]-acetic acid (IX) (47.3 grams; 180 mmol) was suspended in toluene (140 ml) at 48° C. To this suspension dimethyl-formamide (4.0 ml) and SOCl2 (19.8 ml; 271 mmol; 1.5 eq) in toluene (18 ml) were added. After 10 min the reaction mixture was concentrated under vacuo and stripped twice with toluene, to yield a brownish oil of [2-(4-chloro-phenoxy)-phenyl]-acetyl chloride. The oil was suspended in toluene (75 ml). To the suspension was added at 5° C. a solution of sarcosine methylester (30.3 grams 217 mmol) and triethylamine (57 ml) in a mixture of dimethyl-formamide (236 ml) and toluene (47 ml). The brownish suspension was stirred for 2 hours at room temperature. To the reaction mixture water (750 ml) was added and the mixture was extracted twice with ethyl acetate (500 ml). The organic phase was washed with saturated brine (700 ml) and dried on magnesium sulphate. The solvent was removed in vacuum to yield methyl-N-[2-(4-chloro-2-phenoxyphenyl)-1-oxethyl]-N-methylglycinate (X) (61.3 grams, 202 mmol) as a brownish oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=[C:26]([O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.O.C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)Cl.CO>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH:27]=[C:26]([O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH:25]=1)[O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCOCCOCCOCCOCCOc2cc(OCCOCCOCCOCCOCCOCc3ccccc3)cc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: OCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To an ice-cooled solution of Compound 46 (1.22 g, 1.01 mmol) in methylene chloride (15 ml), a methylene chloride solution containing 10% trifluoroacetic acid (7 ml) was added, and water (650 μl) was further added thereto, after which the ice bath was removed, and this was followed by stirring at room temperature for 30 minutes. Triethylamine was poured to the reaction solution, and this was followed by concentration under reduced pressure. The residue obtained was subjected to silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate:methanol 9:1)) to yield Compound 47 (light-yellow oil 977 mg, Y. quant.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH2:7]1.Cl.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15]1.[Na+].[I-]>C(#N)C>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH2:7]3)[CH2:27][CH2:28]2)=[N:15]1
Reactant: CC1SCN(CCCCBr)C1=O
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1SCN(CCCCN2CCN(c3nsc4ccccc34)CC2)C1=O
Yield: 58.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (4.00 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.46 g), K2 CO3 (8.00 g) and NaI (300 mg) in acetonitrile (210 ml) was heated at 40°-45° C. for 64 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.64 g of crystals, m.p. 113°-115° C.
Reaction SMILES: Cl[C:2]1[CH2:3][S:4][C@@H:5]2[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:24](=[O:36])[N:6]2[C:7]=1[C:8]([O:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].O>C(O)(=O)C.C(Cl)Cl.[Zn]>[C:29]1([CH2:28][C:27]([NH:26][CH:25]2[C:24](=[O:36])[N:6]3[C:7]([C:8]([O:10][CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:9])=[CH:2][CH2:3][S:4][C@H:5]23)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To benzhydryl 3-chloro-7-phenylacetamido-3-cephem-4-carboxylate (1.038 g) in a mixture of acetic acid (30 ml) and methylene chloride (10 ml) one adds activated zinc powder (3.9 g), stirs at room temperature for 1 hour, filters, dilutes with water, extracts with methylene chloride, washes with water, dries, concentrates, and crystallizes from ether to give benzhydryl 7-phenylacetamido-3-cephem-4-carboxylate (865 mg), m.p. 168°-170° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][CH2:31]3)=[O:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1ccc2c(Nc3c(C(=O)N4CCC(c5ccccc5)CC4)cnc4c(C(=O)O)cnn34)cccc21
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4c3ccn4C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 44.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(1-methyl-4-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.065 g, 0.6 mmol), the title compound (0.026 g, 44%) was obtained.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([OH:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:15])[CH:5]=1.C(N(CC)C(C)C)(C)C.C1(=O)N([O:30][C:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)C(=O)CC1>CN(C)C=O>[ClH:1].[NH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([OH:14])[CH:13]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)c1c(O)cc(CN)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cc(CNC(=O)CCCCCN)cc1O
Reaction time: 4 h

Procedure:
Methyl 4-(aminomethyl)-2,6-dihydroxybenzoate hydrochloride (1.50 grams, 6.4 mmoles) was suspended in anhydrous N,N-dimethylformamide (25 mL), and N,N-diisopropylethylamine (2.2 mL, 12.8 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (2.10 grams, 6.4 mmoles). The mixture was stirred under dry nitrogen for 4 hours, during which time all solids dissolved. The solvent was then evaporated to leave a light brown syrup, which was partitioned between ethyl acetate (70 mL) and 1 M aqueous hydrochloric acid (50 mL). The layers were separated, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to an amorphous off-white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[C:24]([N:27]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([CH2:39][C:40]([NH:42][C@@H:43]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:44](=[O:54])[CH2:45][O:46][Si](C(C)(C)C)(C)C)=[O:41])[C:29](=[O:62])[C@H:28]1[CH:63]([CH3:65])[CH3:64])(=[O:26])[CH3:25]>O1CCCC1>[C:24]([N:27]1[CH:32]=[C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:30]([CH2:39][C:40]([NH:42][C@@H:43]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:44](=[O:54])[CH2:45][OH:46])=[O:41])[C:29](=[O:62])[C@H:28]1[CH:63]([CH3:65])[CH3:64])(=[O:26])[CH3:25]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)CO[Si](C)(C)C(C)(C)C)C(=O)[C@H]1C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)CO)C(=O)[C@H]1C(C)C
Reaction time: 2.5 h
Yield: 24 %

Procedure:
A 1.0 M tetrabutylammonium fluoride/tetrahydrofuran solution (0.5 ml) is added to a solution of (3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-tert-butyldimethylsilyloxy-2-oxo-4-phenylbutane (130 mg, Compound No. 7-10) in tetrahydrofuran (0.5 ml), and the mixture is stirred for 2.5 hours. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (25.2 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=3)[NH:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
Following the method of Example 1, N-methyl-4-piperidone (-0.68 g) and methyl 1H-indole-5-carboxylate (0.5 g) gave the title compound as microcrystals (0.18 g), m.p. 202°-204° following recrystallisation from ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([Si:14]([CH3:28])([CH3:27])[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH:23]=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:23]/[CH2:22][C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:27])[CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)CCOCCO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CCOCCO[Si](C)(C)C(C)(C)C
Yield: 99.6 %

Procedure:
Step C In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.13 g, 1 mmol) was reacted with 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal (0.27 g, 1 mmol) in CH2Cl2 at room temperature for 18 h to give [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.4 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22]
Reactant: Cc1n[nH]c(=O)c(-c2ccccc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ccccc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
1.95 g of 5-(4-chlorophenyl)-4-(2-fluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.96 g of 3-chloro-5-(4-chlorophenyl)-4-(2-fluorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xvii) of the present invention).