Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].CO.[BH3-]C#N.[Na+]>C(O)=O.O>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1

Procedure:
To a solution of 2.45 g (5.10 mmol) of N-[(6-{2-[(tert-butylamino) methyl]-1-naphthyl}pyridin-2-yl)methylene]-2,6-diisopropylaniline in 50 ml of hot methanol 0.53 g (8.40 mmol) of NaBH3CN was added in one portion followed by the addition of four drops of 88% formic acid. The resulting mixture was refluxed under inert atmosphere for 1 hour and then poured into 50 ml of water. The crude product was extracted with 3×20 ml of ether. The combined extract was washed by 2×50 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:5:1, vol.). Yield 1.60 g (65%) of orange oil. Anal. calc. for C33H41N3: C, 82.63; H, 8.61; N, 8.76. Found: C, 82.74; H, 8.79; N, 8.60. 1H NMR (CDCl3): 7.89 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.86 (m, 1H, 8-H in naphthyl), 7.82 (m, 1H, 4-H in Py), 7.65 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 7.47 (m, 11-1, 3-H in Py), 7.44 (m, 1H, 7-H in naphthyl), 7.33-7.40 (m, 3H, 5-H in Py and 5,6-H in naphthyl), 7.04-7.11 (m, 3H, 3,4,5-H in Ph), 4.37 (d, J=14.7 Hz, 1H, CHH′N′Bu), 4.25 (d, J=14.7 Hz, 1H, CHH′NtBu), 3.56 (m, 2H, CH2NAr), 3.33 (sept, J=7.1 Hz, 2H, CH2Me2), 2.04 (s, 1H, NHAr), 1.18 (d, J=7.1 Hz, 6H, CHMeMe'), 1.16 (d, J=7.1 Hz, 6H, CHMeMe′), 0.96 (s, 9H, tBu).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](SC)=[N:10][C:9]=2[CH:15]=1.[C:16]1(C)C=CC(S(OC)(=O)=O)=CC=1.[C:28]([C:31]1[CH:32]=[CH:33][C:34]([NH:50][CH2:51][CH3:52])=[C:35]([N:37]=[C:38]2[N:42]([CH2:43][C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)[C:41](=[O:49])[CH2:40][S:39]2)[CH:36]=1)(=[O:30])[CH3:29]>>[C:28]([C:31]1[CH:32]=[CH:33][C:34]([NH:50][CH2:51][CH3:52])=[C:35]([N:37]=[C:38]2[N:42]([CH2:43][C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)[C:41](=[O:49])[C:40](=[C:11]3[N:10]([CH3:16])[C:9]4[CH:15]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:6]=[CH:7][C:8]=4[S:12]3)[S:39]2)[CH:36]=1)(=[O:30])[CH3:29]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2cc(OCCCl)ccc2s1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccco1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccco1

Procedure:
In a manner similar to Example 45, intermediate 5-(2-chloroethoxy)-2-(methylthio)benzothiazole was alkylated with methyl p-toluenesulfonate and then condensed with the above 2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-thiazolidin-4-one. MS(ESI): 583 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][CH:3]=1.[N:12]#[C:13]Br.C(Cl)Cl.N>C(O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH3:10])[C:13]([NH2:12])=[N:11][C:5]2=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CCNc1nc(Cl)ccc1N
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCn1c(N)nc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
To a solution of 6-chloro-N˜2˜-ethylpyridine-2,3-diamine (401 mg, 2.34 mmol) in ethanol (10 mL) is added a 3M solution of cyanogen bromide in CH2Cl2 (0.93 mL, 2.8 mmol) and the resulting solution is stirred for 6 h at room temperature. The solution is basified with ammonia in methanol and evaporated. The residue is purified via flash column chromatography using a gradient elution of 0-15% CH2Cl2/methanol containing 1% NH4OH to afford the title compound (212 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=O)=[CH:14][CH:15]=3)[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][NH:31][C:30]4=[O:34])[CH2:23][CH2:22]3)=[CH:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][NH:19][CH3:20])=[CH:14][CH:15]=3)[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][NH:31][C:30]4=[O:34])[CH2:25][CH2:26]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc2c(c1)c(C1CCN(CCN3CCNC3=O)CC1)cn2-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNCc1ccc2c(c1)c(C1CCN(CCN3CCNC3=O)CC1)cn2-c1ccc(F)cc1
Temperature: 0 °C

Procedure:
1-(4-Fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]4-piperidinyl]-N-methyl-1H-indole-5-carboxamide (7a) (2g) and LiAIH4 was refluxed in dry THF (150 mL) for 3 h. After cooling to 0° C., water (100 mL) and aqueous NaOH (1 M, 5 mL) was carefully added. The phases were separated and the aqueous phase was extracted with ethyl acetate. After removal of the solvent, the compound was purified by flash chromatography (EtOAc/MeOH/TEA 80/15/5). Yield 0.3 g (oil). 1H-NMR (DMSO) 1.72 (q, 2H), 1.97 (d, 2H), 2.12 (t, 2H), 2.28 (s, 3H), 2.45 (t, 2H), 2.77 (tt, 1H), 3.00 (d. 2H), 3.10-3.60 (m, 6H) 3.72 (s, 2H), 6.25 (s, 2H), 7.14 (d. 1H), 7.35-7.45 (m, 4H), 7.55-7.65 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:13])[C:5]2[NH:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C1(N(C)C2CCCCC2)CCCCC1.Cl[CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56].[O:59]1[CH2:63][CH2:62]C[CH2:60]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:13])[C:5]2[N:9]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:8](=[O:10])[N:7]([CH2:60][O:59][CH2:63][CH2:62][Si:55]([CH3:57])([CH3:56])[CH3:54])[C:6]=2[CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3[nH]c(=O)[nH]c23)(c2ccc(F)cc2)CC1
Reactant: C1CCOC1
Agent: CN(C1CCCCC1)C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3c2n(COCC[Si](C)(C)C)c(=O)n3COCC[Si](C)(C)C)(c2ccc(F)cc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.5 g, 0.99 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.70 mL, 3.3 mmol) in tetrahydrofuran (6.5 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (0.56 mL, 3.2 mmol). After 5 min, the ice bath was removed and stirring continued at room temperature for 24 h. The reaction was allowed to stir overnight. The reaction was diluted with diethyl ether, washed with water, then 1M potassium bisulfate, then water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% ethyl acetate/n-hexane) gave 580 mg (76%) as an amorphous white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.37 (dd, J=8.9, 5.2 Hz, 2H), 7.27 (d, J=2.1 Hz, 1H), 7.08 (m, 3H), 5.43 (s, 2H), 5.27 (s, 2H), 4.26 (s, 2H), 3.78 (m, 2H), 3.55 (t, J=8.1 Hz, 2H), 3.27 (t, J=8.1 Hz, 2H), 3.08 (m, 2H), 2.23 (m, 2H), 1.88 (m, 2H), 1.42 (s, 9H), 0.89 (t, J=8.2 Hz, 2H), 0.71 (t, J=8.1 Hz, 2H), −0.05 (s, 9H), −0.12 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.6, 161.7 (d, J=247 Hz), 154.9, 154.7, 137.1 (d, J=3.8 Hz), 131.3, 128.9 (d, J=7.7 Hz), 127.1, 125.4, 122.8, 116.9, 115.7 (d, J=20 Hz), 112.3, 79.7, 73.3, 71.9, 70.9, 66.5, 65.6, 40.6, 39.9, 32.2, 28.5, 17.8, 17.7, −1.3, ″1.4. Mass spec.: 786.00 (MNa)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH:23](N)[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.C([N:34](CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH:23]([C:4]2([CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH2:3]2)[C:7]([NH2:34])=[O:8])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: CC(C)C(N)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Product: CC1=CCC(C(N)=O)(C(CC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)C=C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
p-Toluoyl chloride (0.077 ml, 0.58 mmol) was added to a solution of 1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropylamine(0.16 g, 0.49 mmol) in dichloromethane (2 ml) and triethylamine (0.12 ml, 1.63 mmol). The reaction mixture was stirred at room temperature for 1.5 h and was quenched with water. The product was then extracted with dichloromethane and the organic layer was washed with brine and dried over sodium sulfate. The crude product was purified on preparative TLC with 25% acetone, 25% dichloromethane in hexanes to give 0.21 g of N-{1-[1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropyl}-4-methylbenzamide as an oil, which was then converted to its dihydrochloride salt (0.15 g); m.p. 233.9-235.5° C.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH+:7]=1.[C:16](=[C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)([CH3:18])[CH3:17]>CN(C)C=O.C(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N+:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[CH:17]=1
Reactant: CC(C)=C1CCCCC1=O
Reactant: C1=[NH+]CCc2ccccc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc2[n+](c3c1CCCC3)CCc1ccccc1-2

Procedure:
3,4-Dihydroisoquinolinium perchlorate (4.6 g) and 2-isopropylidenecyclohexanone (3 g) were dissolved in dimethylforamide (12 ml) and refluxed for 12 hours. The reaction mixture was cooled, diluted with ethanol, and filtered. The product was purified by recrystallization from methanol. Yield 3 g; m.p. 205°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:16].C([O-])([O-])=O.[K+].[K+]>>[ClH:7].[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:15][CH3:16])[CH2:29][CH2:28]1
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccccc1N1CCN(Cc2cc(OC)c(OC)c(OC)c2)CC1
Product: Cl
Yield: 81.8 %

Procedure:
8.3 g of 3,4,5-trimethoxybenzyl chloride and 4.1 g of N-(2-ethyoxyphenyl)-piperazine and 3.5 g of K2CO3 are reacted and processed according to example 2. 7.2 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2-ethoxyphenyl)-piperazine dihydrochloride is obtained.
Reaction SMILES: [CH3:1][C:2]([CH:13]([C:16]([C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH:19]=1)=[O:17])[CH2:14][CH3:15])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].O1CCOCC1.[OH-].[Li+].Cl>O>[CH3:1][CH:2]([CH:13]([C:16]([C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=1)=[O:17])[CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C(=O)OCC)C(CC)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(=O)c1ccc2nc(-c3ccccc3)oc2c1)C(C)C(=O)O
Reaction time: 8 h

Procedure:
850 mg (1.94 mmol) diethyl 2-methyl-2-[1-(2-phenyl-benzoxazole-6-carbonyl)-propyl]-malonate are mixed with 10 ml dioxane, then a solution of 300 mg (12.53 mmol) lithium hydroxide in 10 ml of water is added and the mixture is left overnight at RT with stirring. The next day the reaction mixture is acidified with 4N hydrochloric acid and extracted with DCM. The org. phase is dried on magnesium sulphate and concentrated by rotary evaporation i. V., the residue is stirred with 5 ml DMSO and 500 mg lithium chloride for 1.5 h at 150° C., the reaction mixture is purified by RP-HPLC.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+]([O-])=O)=O.C([O-])([O-])=O.[K+].[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>CN(C=O)C>[CH3:27][O:26][C:22]([C:23]1[S:24][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:3]=2[CH:1]=1)=[O:25]
Reactant: COC(=O)CS
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C(=O)OC)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 4-formyl-3-nitrobenzoate (6.68 g, 31.9 mmol) and K2CO3 (5.55 g, 38.3 mmol) in DMF (70 mL) was slowly added methyl thioglycolate (2.91 mL, 31.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 24 h. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The green solid was filtered. 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 8.25 (s, 1H), 8.12 (d, J=8.0 Hz), 7.95 (d, J=8.0 Hz), 3.87 (s, 6H). MS (EI): cal'd (MH+) 251.03, exp (MH+) 251.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:12]C=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:25]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:27]C)=[O:26].[CH:49]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:12]/[CH:49]=[CH:29]/[C:25]([OH:27])=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=CC=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Product: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3-bis(3,4-dimethoxyphenyl)-2-propenal (19.6 g) and (carbomethoxymethylene)triphenylphosphorane (22 g) in benzene (150 mL) was stirred overnight at 55° C. The solvent was removed under reduced pressure and the residue (45 g), consisting of mainly triphenylphosphine oxide and (E)-5,5-bis(3,4-dimethoxyphenyl)-2,4-pentadienoic acid methyl ester, was taken up a mixture of methanol (100 mL) and 2N sodium hydroxide solution (50 mL) and heated at reflux for 30 minutes. After the methanol was removed in vacuo, the concentrate was diluted water (100 mL) and the precipitated triphenylphosphine oxide was filtered off. The basic filtrate was first extracted with ether to remove neutral impurities, then was poured into 1N hydrochloric acid (300 mL) and extracted with dichloromethane (3×150 mL). The dried (MgSO4) extracts were evaporated and the residue triturated with ether to give 18.7 g of (E)-5,5-bis(3,4-dimethoxyphenyl)-2,4-pentadienoic acid mp 174°-175,5° C. Crystallization from dichloromethane-2-propanol furnished the analytical sample, mp 174°-175,5° C. Anal. Calculated for C21H22O6 : C, 68.10; H, 5.99 Found: C, 68.32; H, 6.16.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(OCC)([O:18][CH2:19][CH3:20])[CH3:17]>CCCCCC>[CH2:16]([O:18][C:19](=[N:15][S:12]([C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)(=[O:14])=[O:13])[CH3:20])[CH3:17]
Reactant: CCOC(C)(OCC)OCC
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Solvent: CCCCCC
Product: CCOC(C)=NS(=O)(=O)c1nc(-c2ccccc2)ns1
Temperature: 25 °C

Procedure:
A mixture of 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide and 10 ml of triethyl orthoacetate was warmed at reflux for 4 hours. The mixture was cooled to room temperature and diluted with hexane (30 ml) and the precipitated solid was collected, washed with hexane and dried to give 3.25 g of solid, m.p. 120°-122°.
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])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[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])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cccc(C=O)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and 3-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzene as a colorless solid. APCI-Mass m/Z 660/662 (M+NH4).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:42])[CH2:4][C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([C:15]3[S:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:43]([O-])=[O:44].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:42])[C:4](=[N:43][OH:44])[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[C:12]([C:15]3[S:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CC(=O)CBr)[C@H]3SC2)s1
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]3SC2)s1
Yield: 89.4 %

Procedure:
In 4 ml of acetic acid there was dissolved 0.37 g of benzhydryl 7-(4-bromo-3-oxobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate and, under ice-cooling and stirring, a solution of 0.048 g of sodium nitrite in 0.4 ml of water was added dropwise. After this dropwise addition, the mixture was stirred at room temperature for one hour. Then, 20 ml of a saturated aqueous solution of sodium chloride were added and extraction was carried out with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was loosened up with a solvent mixture of petroleum ether and ether (2:1 volume/volume). The resultant powder was recovered by filtration and dried. By the above procedure there was obtained 0.345 g of benzhydryl 7-(4-bromo-3-oxo-2-hydroxyiminobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate-(syn-isomer).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[CH:20](Cl)(Cl)C(Cl)Cl>Cl>[Cl:5][C:6]1[C:7]([OH:12])=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:16]([CH2:15][CH2:14][C:13]([O:18][CH3:20])=[O:19])=[O:17].[Cl:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[OH:12])[C:16]([CH2:15][CH2:14][C:13]([O:18][CH3:20])=[O:19])=[O:17]
Reactant: ClC(Cl)C(Cl)Cl
Reactant: O=C1CCC(=O)O1
Reactant: Oc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCC(=O)c1ccc(O)c(Cl)c1
Product: COC(=O)CCC(=O)c1cccc(Cl)c1O

Procedure:
Aluminium chloride powder (66.75 g, 0.5 mole) was added during one hour to a stirred mixture of dry 2-chlorophenol (27.3 g, 0.22 mole), powdered succinic anhydride (20 g, 0.2 mole) and dry sym-tetrachlorethane (150 ml) while the temperature was allowed to rise from 20°C to 40°C. The resultant mixture was heated in an oil bath at 135°C for 2 hours, then cooled in ice and hydrolysed with cold 10% hydrochloric acid solution (100 ml). Tetrachloroethane was removed by steam distillation and the aqueous residue precipitated a gum which was purified by standard procedures to give 31.97 g, 70%, of a mixture of 3-(3-chloro-2-hydroxybenzoyl) propionic and 3-(3-chloro-4-hydroxybenzoyl)propionic acids. Esterification of the mixed acids with methanol - hydrogen chloride and separation of the products by column chromatography (silica, 5/1 chloroform/petroleum ether B.p. 60°-80°C) gave methyl 3-(3-chloro-2-hydroxybenzoyl)propionate (m.p. 60°-62°C) and methyl 3-(3-chloro-4-hydroxybenzoyl)propionate (m.p. 85°-89°C). Hydrolysis of the latter ester with dilute sodium hydroxide solution gave 3-(3-chloro-4-hydroxybenzoyl)propionic acid (m.p. 155°-160°C). The pure acid, on recrystallisation from water, had m.p. 160°-162°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[Br:21]Br>O.[OH-].[Na+]>[Br:21][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: CC(CO)Nc1ccnc2cc(Cl)ccc12
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(CO)Nc1c(Br)cnc2cc(Cl)ccc12
Yield: 57 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine and 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. The product precipitated from the solution as the hydrobromide salt and it was isolated by filtration, dissolved in water and basified with sodium hydroxide. The free base was extracted into dichloromethane and evaporation of solvents resulted in a solid which was purified by HPLC using 95:5 dichloromethane/methanol as the eluent. Recrystallization from isopropanol yielded 9 g of crystalline solid with a melting point of 145°-147° C.
Reaction SMILES: [C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Yield: 87 %

Procedure:
A solution of 3.00 g. (0.0105 mole) of methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of 1N sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30 minutes. The solution is diluted with water and the ethanol is evaporated in vacuo. The solution is filtered and the filtrate acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, dried and recrystallized from methanol-water to give about 2.4 g. (87% yield) of white 5-(p-anisoyl)-1-methylpyrrole-2-acetic acid, m.p. 170°-171°C.