Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][OH:12].I([O-])(=O)(=O)=[O:14].[Na+].CC#N.O>[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([OH:14])=[O:12]
Reactant: OCc1c(F)cc(F)c(F)c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1c(F)cc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
(2,3,4,6-Tetrafluorophenyl)methanol (1.50 g, 8.33 mmol), sodium periodate (8.91 g, 41.6 mmol) and ruthenium (III) chloride (345 mg, 1.67 mmol) was added to a mixture of MeCN (20 mL), water (10 mL) and carbon tetrachloride (20 mL). The reaction was stirred at room temperature for 6 hours, then filtered through arbocel (eluting with EtOAc) and the filtrate evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with EtOAc to afford the title compound as a colourless oil (1.60 g, 99% yield):
Reaction SMILES: FC1C=CC=CC=1C([O:6][C:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])=[CH:8][C:9]1[N:10](C(=O)C2C=CC=CC=2F)[C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=1)=O.O.[ClH:37]>>[ClH:37].[CH3:14][C:12]1[N:13]=[C:9]([CH2:8][C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:6])[NH:10][C:11]=1[CH3:15]
Reactant: Cc1nc(C=C(OC(=O)c2ccccc2F)c2ccccc2F)n(C(=O)c2ccccc2F)c1C
Agent: Cl
Solvent: O
Product: Cc1nc(CC(=O)c2ccccc2F)[nH]c1C
Yield: 14 %

Procedure:
12.97 g crude crude compound of Example V are refluxed 1.5 h in 200 ml concentrated hydrochloric acid. The mixture is cooled to rT and 200 mL water are added. The solution is extracted twice with toluene and the aqueous phase is concentrated under vacuum. The residue is stirred with ethanol, filtered, washed once with ethyl acetate and once with petrol ether and dried to yield 1.04 g (14% of th.) 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(2-fluorophenyl)ethanone hydrochloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:23])[S:8](=[O:22])(=[O:21])[C:9]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(Cl)CCl>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:4]([C:6]2[N:7]([CH3:23])[S:8](=[O:21])(=[O:22])[C:9]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:10]=3[C:11]=2[OH:12])=[O:3])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 71 %

Procedure:
N-(3-Chloro-phenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid ethyl ester-1,1-dioxide and 3-chloroaniline. Yield: 71% of theory; m.p. 248°-249° C (decomp.; from ethylene chloride).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH:6]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[CH2:7].ClCI.[Cl-].[NH4+]>ClCCCl>[CH:6]1([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:1][CH2:7]1
Reactant: C=COCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(COC2CC2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 63 mL of diethylzinc (1.0 M hexane solution) was added to 92 mL of 1,2-dichloroethane at −40° C., and subsequently a solution of 2.5 g of tert-butyl 4-[(vinyloxy)methyl]piperidine-1-carboxylate in 134 mL of 1,2-dichloroethane was added thereto, followed by stirring at −40° C. for 30 minutes. 7.5 mL of chloroiodomethane was added thereto, followed by stirring for 4 hours while elevating the temperature from −40° C. to −15° C. To the reaction mixture was added portionwise a saturated aqueous ammonium chloride solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 2.0 g of tert-butyl 4-[(cyclopropyloxy)methyl]piperidine-1-carboxylate.
Reaction SMILES: [Na].[CH2:2]([C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14](=[S:16])[NH:15][C:11]=2[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22](=O)[CH2:23]Br)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[SH:16][C:14]1[NH:15][C:11]2[CH:10]=[C:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:18]=[CH:17][C:12]=2[N:13]=1)[CH3:23])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na]
Solvent: CCO
Product: CCOC(C)=[SH]c1nc2ccc(Cc3ccccc3)cc2[nH]1
Reaction time: 4 h
Yield: 97.1 %

Procedure:
0.46 g (20 mmoles) of metal sodium are dissolved in 40 ml of ethanol. To the ethylate 4.8 g (20 mmoles) of 5-benzyl-benzimidazoline-2-thione are added and 2.4 ml of bromoacetic acid ethyl ester are added dropwise at room temperature. After 4 hours boiling the salt is filtered off, the mother liquor is evaporated and 60 ml of petrol-ether are added to the distillation residue. Thus 7.23 g of crude title product are isolated. This is purified by suspending in water. Thus 6.33 g (97.1%) of title compound melting at a temperature of 103° C. are obtained, which can be crystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: NCCN1CCOCC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN1CCOCC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with (2-morpholin-4-ylethyl)amine using an analogous method to that described for the equivalent step in Example 1 to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(2-morpholin-4-ylethyl)amino]methyl}quinazolin-4-amine; 1H NMR Spectrum: (DMSO-d6) 2.14 (brs, 1H); 2.31 (m, 4H); 2.42 (t, 2H); 2.66 (t, 2H); 3.55 (m, 4H); 3.85 (s, 2H); 3.97 (s, 3H); 7.21 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.54 (t, 1H); 8.32 (s, 1H); 8.44 (s, 1H); 9.77 (s, 1H); Mass Spectrum: (M+H)+ 446.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34](OCC)[O:35]CC)=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=[O:35])=[CH:4][N:3]=1
Reactant: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of Example 176B (90 mg, 0.16 mmol) in acetone (9 mL) and water (1 mL) was treated with p-toluenesulfonic acid (5 mg, 0.016 mmol) then stirred for 30 minutes. The solvent was evaporated under reduced pressure then the residue was partitioned between dichloromethane and water. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel to provide the desired product (77 mg). 1H NMR (DMSO-d6, 400 MHz) δ 9.67 (d, 1H), 9.52 (s, 1H), 8.34 (s, 1H), 8.03 (d, 1H), 7.91 (d, 1H), 7.75 (s, 1H), 7.70 (d, 1H), 7.32 (m, 2H), 7.25 (s, 1H), 7.10 (m, 3H), 6.69 (m, 1H), 4.04 (s, 3H), 3.92 (s, 3H); MS m/e 483.3.
Reaction SMILES: O.O.[Na+].[Na+].[CH2:5]([N:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])[CH2:6][N:7]([CH2:12][C:13]([O-:15])=[O:14])[CH2:8][C:9]([O-:11])=[O:10]>O>[CH2:6]([N:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][N:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
3.7224 g of ethylenediamine-tetraacetic acid disodium salt dihydrate are dissolved in 50 ml of RO water (using a magnetic stirrer about 30 minutes).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15].[C:17]([O:24][CH2:25][CH3:26])(=[O:23])[C:18]([O:20]CC)=O>CCOCC>[CH2:25]([O:24][C:17](=[O:23])[C:18](=[O:20])[CH:12]([CH3:11])[C:13](=[O:16])[CH2:14][CH3:15])[CH3:26]
Reactant: CCC(=O)CC
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C(=O)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
LHMDS solution (35.7 mL, 35.7 mmol, 1M in hexanes) was added to 200 mL of diethyl ether and the mixture was cooled to −78° C. 3-Pentanone (3.8 mL, 35.7 mmol) dissolved in 50 mL of ether was added dropwise, and the resulting mixture was stirred at −78° C. for 1 h. Diethyl oxalate (5.3 mL, 39.3 mmol) was added dropwise, and the cooling bath was removed and the mixture was allowed to come to room temperature. After the mixture was stirred for 16 h, the resulting precipitate was isolated by filtration. The solid was partitioned between CH2Cl2 (150 mL) and 1M hydrochloric acid (100 mL), and the aqueous layer was extracted with additional CH2Cl2. The combined organic layer was dried over MgSO4 and concentrated to give 6.37 g of the title compound. MS: (−) m/z 185.28 (M−1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[CH3:19])[CH:13]([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then 2-methyl-benzoyl chloride (4.64 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 9.47 g of brown liquid. MS: m/e 333(M++1), 332(M+), 287(M+—OCH2CH3), 197(M+—CH3C6H4CO2), 119(base), 91, 77.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:26])(=[O:25])[NH:13][CH:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH3:16])[C:6]=1[C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1.[H-].[Na+].Cl[C:37]1[N:42]=[CH:41][C:40]([Br:43])=[CH:39][N:38]=1>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:43][C:40]1[CH:39]=[N:38][C:37]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:26])(=[O:25])[NH:13][CH:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH3:16])[C:6]=2[C:27]2[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=2)=[N:42][CH:41]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCC(NS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(NS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 1-benzyloxypropanesulfamic acid[6-(2-hydroxyethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (237 mg, 0.441 mmol) in THF (10 mL) is added NaH (58 mg, 60% dispersion in mineral oil, 1.32 mmol). The mixture is stirred for 5 min before 2-chloro-5-bromopyrimidine (128 mg, 0.662 mmol) is added. The reaction mixture is stirred at 60° C. for 2 h, diluted with 10% aq. citric acid solution (75 mL) and extracted with EA (75 mL). The organic extract is washed twice with water (2×50 mL) and concentrated. The remaining residue is purified on prep. tlc plates (silica gel, heptane/EA 1:1) to afford 1-benzyloxypropanesulfamic acid[6-(2-(5-bromopyrimid-2-yloxy)-ethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (283 mg) as a colourless foam. LC-MS: tR=1.09 min, [M+H]+=693.12; 1H NMR (CDCl3): δ 8.48 (s, 2H), 8.34 (s, 1H), 7.58-7.53 (m, 2H), 7.38-7.28 (m, 5H), 7.16-7.11 (m, 2H), 6.84 (s, 1H), 5.97 (t, J=5.9 Hz, 1H), 4.73-4.68 (m, 2H), 4.64-4.60 (m, 2H), 4.50 (s, 2H), 3.56 (t, J=5.9 Hz, 2H), 3.17 (q, J=6.4 Hz, 2H), 1.88 (p, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:27]1([C:33]#[CH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:34]#[C:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C#Cc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C#Cc3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
To a stirred solution of 1-[4-(methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole (445 mg; 1 mmol) and phenylacetylene (102 mg; 1 mmol) in pyrrolidine (2 mL) was added tetrakis(triphenylphosphine)palladium (35 mg) under a nitrogen atmosphere, and the mixture was heated at 80° C. for 1 hour. After cooling, the volatiles were removed by evaporation. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1:3) to give the title compound (0.4 g, 86% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.[CH3:26][N:27]([CH:29]=O)[CH3:28].P(Cl)(Cl)Cl>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[ClH:10].[CH3:26][N:27]([CH:29]=[N:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12)[CH3:28]
Reactant: CN(C)C=O
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)C=N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
To a solution of 12.8 g. (31.5 mmole) of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride in 115 ml. of dry DMF were added with stirring 10.4 g (6.5 ml., 72 mmole) of phosphorus trichloride. The reaction mixture was stirred at room temperature for about 2 days and was then dispersed in a mixture of 5% aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated and treated with 1 N hydrochloric acid. The title compound precipitated from solution and was filtered and dried under vacuum. There were obtained 11.3 g. (67% yield) of the salt.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:17](I)[CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:2]=1[O:1][CH2:17][CH2:18][CH3:19]
Reactant: CCCI
Reactant: COC(=O)c1cc2ccccc2c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1c(C(=O)OC)cc2ccccc2c1C
Temperature: 60 °C
Reaction time: 120 h

Procedure:
3-Hydroxy-4-methyl-2-naphthoic acid was prepared according to a literature procedure (Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol. 2 (1979), 786; Farmaco, Ed. Sci. 33 (1978), 822) and esterified with methanol using standard conditions to give methyl 3-hydroxy-4-methyl-2-naphthoate. A suspension of 300 mg (1.39 mmol) of this ester, 263 mg (1.55 mmol) propyl iodide, and 215 mg (1.55 mmol) of dry potassium carbonate in 60 ml of absolute butanone was stirred at 60° C. for 5 days. After addition of the same amounts of propyl iodide and potassium carbonate stirring was continued at 60° C. for another 2 days. The inorganic salts were filtered off, washed with acetone, and together with a small amount of silica gel the filtrate was evaporated to dryness. The remaining powder was applied to column chromatography on silica gel using hexane followed by a hexane/tert.-butylmethylether gradient up to 9:1.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](O)=[O:20].C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][NH:12][C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)=[O:20]
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NNC(=S)NC1CC2C=CC1C2)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
A mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.545 mmol), picolinic acid (67 mg, 0.545 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (104 mg) in dichloromethane (5 mL) was stirred at room temperature for 24 h and isolated as a white solid (47 mg, 30%). 1H NMR (CDCl3): 10.57 (s, 1H), 9.20 (s, 1H), 8.63 (d, J=4.2 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.89-7.83 (m, 1H), 7.51-7.47 (m, 1H), 7.02 (brs, 1H), 6.16-6.06 (m, 2H), 4.11 (s, 1H), 2.96 (s, 1H), 2.83 (s, 1H), 1.84-1.76 (m, 1H), 1.38-1.28 (m, 3H).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@H:17]([O:19][C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:16]([CH2:28][O:29][C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:15][C@H:11]1[S:12][CH2:13][CH3:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[CH2:1]([O:9][C@@H:10]1[CH2:18][C@H:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:16]([CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:15][C@H:11]1[S:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C[C@H]1OC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCS[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C[C@H]1OCc1ccccc1

Procedure:
Compound 25 (608 mg, 1.17 mmol) gave 364 mg substantially pure product (65%). [α]D=−11.8° (c=1, CHCl3); 1H NMR (CDCl3) 7.44–7.14 (m, 15H), 4.74 (d, 1H, J=11.6 Hz), 4.66–4.56 (m, 4H), 4.50 (d, 1H, J=9.4 Hz), 4.45 (d, 1H, J=11.4 Hz), 3.83 (d, 1H, J=10.7 Hz), 3.69 (dd, 1H, J=4.4, 10.7 Hz), 3.49 (m, 2H), 3.35 (m, 1H), 2.79 (m, 2H), 2.69 (m, H), 1.54 (m, 1H), 1.35 (t, 3H, J=7.3 Hz); 13C NMR (CDCl3): 138.8, 138.4, 135.8, 128.9, 128.7, 128.4, 128.2, 128.1, 127.4, 86.9, 81.3, 75.6, 73.8, 73.3, 72.5, 71.6, 69.8, 45.3, 36.7, 25.1, 20.3, 15.5; MS: calcd for C29H34O4SNa 501.2, found m/z 501.0 (M+Na).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:32][C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[NH:38])=[CH:35][CH:34]=3)[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH2:28][CH2:29][OH:30])[C:20]=3F)=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1.COC(=O)N=C(SC)C(C1C=C(OC)C=C(O)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([NH2:39])=[NH:38])=[CH:40][CH:41]=3)[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH2:28][CH2:29][OH:30])[CH:20]=3)=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)cc(OC)c1
Solvent: CC(=O)O
Product: COc1cc(OCCO)cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (200a) to (200c), except that {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (4c)) was used instead of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (200a), to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[N:13]=2)=[N:6][CH:7]=1.[CH3:30][N:31]([CH2:36][C:37](O)=[O:38])[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[NH2:21][C:14]1[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:2]([N:1]3[C:37](=[O:38])[CH2:36][N:31]([CH3:30])[CH2:32][C:33]3=[O:34])=[CH:7][N:6]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine, and 2 mmol of methyliminodiacetic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-4-methylpiperazine-2,6-dione.