Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:47]([O:51][CH2:52][CH2:53][OH:54])([CH3:50])([CH3:49])[CH3:48].[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:47]([O:51][CH2:52][CH2:53][O:54][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OCCO
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OCCOC(C)(C)C)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.218 mmol), Cu(I)I (0.0416 g, 0.218 mmol), 1,10-phenanthroline (0.0394 g, 0.218 mmol), 2-tert-butoxyethanol (0.774 g, 6.55 mmol) and KF on Al2O3 (40%; 0.222 g, 1.53 mmol) in toluene (4 mL) were stirred at 120° C. for 40 hours. The reaction was then cooled to room temperature. Ethyl acetate (10 mL) was then added. The reaction was filtered through a pad of celite and concentrated to dryness. The resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-(2-tert-butoxyethoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.080 g, 68%) as a solid. MS APCI (+) m/z 540.5 detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1>>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]2[C:35]([C:26]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH2:12]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)=[CH:27][CH:28]=[N:29]2)=[CH:34][CH:33]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
In the manner given in Example 4C, 1-(p-aminophenylsulfonyl)-4-(2,2,2-trichloroethoxycarbonyl)piperazine is heated with 4-chloro-7-trifluoromethylquinoline to give 1-[[4-[(7-trifluoromethyl-4-quinolinyl)amino]phenyl]-sulfonyl]-4(2,2,2-trichloroethoxycarbonyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OCC)(=[O:10])[C:8]#[CH:9].C1(C)C=CC=CC=1>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1
Reactant: C#CC(=O)OCC
Reactant: Nc1cc[nH]n1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Oc1ccn2nccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-aminopyrazole (11.5 g, 0.138 mol) in 65 mL of 1,4-dioxane was added ethyl propiolate (14.7 g, 15.2 mL, 0.150 mol) dropwise, and the resultant light yellow solution was warmed to reflux. After 4 h, the blood-red solution was cooled to room temperature and 100 mL of toluene was added with stirring. The resultant precipitate was collected with toluene and air-dried to afford the title compound as a tan solid. MS 136.0 (M+1)
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][CH:23]2[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:42])=[O:41])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:51](Br)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(#N)C.ClCCl>[CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][C:23]2([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:41])=[O:42])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Cc3ccccc3)(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Reaction time: 4 h

Procedure:
A solution of 2-(6-benzhydryloxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide (300 mg) in acetonitrile (5 ml) was treated at room temperature with triethylamine (0.067 ml) and benzyl bromide (0.172 ml). After 4 hr, the reaction mixture was diluted with dichloromethane, washed with brine and dried over Na2SO4. The solvent was then removed and the residue purified by flash chromatography, thereby obtaining the title compound as a white solid (180 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:35]1[CH:36]=[CH:37][C:32]([O:31][C:28]2[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=2)=[CH:33][CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Oc2ccccc2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-phenoxy-benzene in analogy to Example 1a): MS (ISP): 472.0 (M+H)+.
Reaction SMILES: C#C.[Na].[CH2:4]([C:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH3:6].[CH3:12][CH2:13]OCC>N>[CH2:4]([C:7]([CH2:9][CH2:10][CH3:11])([OH:8])[C:12]#[CH:13])[CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCC(=O)CCC
Agent: C#C
Agent: N
Agent: [Na]
Product: C#CC(O)(CCC)CCC
Reaction time: 12 h

Procedure:
To the acetylene solution in ammonia were added 23 g of finely divided sodium. The bubbling of acetylene was maintained for 1 hour after the introduction of the sodium. After that, 114 g (1 mol) of di-n-propyl ketone were added and the acetylene flow was maintained for 1 hour after which 500 ml of ether were added and the mixture was allowed to stand for 12 hours at room-temperature. It was then hydrolysed by adding damp ether followed by crushed ice. After acidification with 10% sulphuric acid, the ethereal phase was separated out, dried over magnesium sulphate and concentrated under reduced pressure.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10]1
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1 eq 1-(pyridin-2-ylmethyl)piperazine hydrochloride in dry dichloromethane are added 1.5 eq butanoyl chloride and 2.5 eq triethylamine. After stirring for 6 hours at room temperature the solvent is removed in vacuo and the residue re-dissolved in ethyl acetate. The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, ethyl acetate is removed in vacuo and the crude product is purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=[C:6]([N+:18]([O-:20])=[O:19])[C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1Cl
Yield: 89 %

Procedure:
A mixture of 3,4-dichloro-α,α,α-trifluorotoluene (430 g., 2.0 moles), concentrated sulfuric acid (1200 ml.) and concentrated nitric acid (1200 ml., excess) was stirred at 90°-100° C. for one half hours. The mixture was then cooled and the acid phase discarded. The organic phase was washed with water, dilute sodium bicarbonate solution, potassium carbonate solution, dried, and distilled to give an approximately equal mixture (456 g., 89%) of 3,4-dichloro-α,α,α-trifluoro-5-nitrotoluene and 3,4-dichloro-α,α,α-trifluoro-6-nitrotoluene, b.p. 86° C./3 mm.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1COC1C=C(C=CC=1)OCC1C=C(C2NN=NN=2)C=CC=1.N1C2C(=CC=CC=2)C=CC=1COC1C=C(CC2C=CC=CC=2CC2NN=NN=2)C=CC=1.[N:63]1[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=[CH:65][C:64]=1[CH2:73][O:74][C:75]1[CH:76]=[C:77]([CH:92]=[CH:93][CH:94]=1)[O:78][CH2:79][C:80]1C=[C:82]([CH:89]=[CH:90][CH:91]=1)[CH2:83][C:84]1[NH:88][N:87]=[N:86][N:85]=1.N1C2C(=CC=CC=2)C=CC=1COC1C=C(C=CC=1)OCC1C=CC(CC2NN=NN=2)=CC=1>>[N:63]1[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=[CH:65][C:64]=1[CH2:73][O:74][C:75]1[CH:76]=[C:77]([CH:92]=[CH:93][CH:94]=1)[O:78][CH2:79][C:80]1[CH:91]=[CH:90][CH:89]=[CH:82][C:83]=1[C:84]1[NH:88][N:87]=[N:86][N:85]=1
Reactant: c1cc(COc2cccc(OCc3ccc4ccccc4n3)c2)cc(Cc2nnn[nH]2)c1
Agent: c1cc(Cc2ccccc2Cc2nnn[nH]2)cc(OCc2ccc3ccccc3n2)c1
Agent: c1cc(OCc2ccc(Cc3nnn[nH]3)cc2)cc(OCc2ccc3ccccc3n2)c1
Agent: c1cc(OCc2cccc(-c3nnn[nH]3)c2)cc(OCc2ccc3ccccc3n2)c1
Product: c1cc(OCc2ccc3ccccc3n2)cc(OCc2ccccc2-c2nnn[nH]2)c1

Procedure:
(M.P. 166°-170° C.), 5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole (M.P. 155° C. dec.), 5-(2-(3-(2-quinolinylmethyloxy)phenylmethyl)benzyl tetrazole (M.P. 145.5°-147° C.), 5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzyl tetrazole (M.P. 161°-164° C.), or 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzyl tetrazole (M.P. 149°-152° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4][NH:3]1.[OH:12]O>CO>[CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4](=[O:12])[NH:3]1
Reactant: OO
Reactant: CC1(C)N[Se]c2ccccc21
Solvent: CO
Product: CC1(C)N[Se](=O)c2ccccc21
Reaction time: 0.25 h
Yield: 55 %

Procedure:
The derivative 3,3-dimethyl-benzisoselenazoline BXT-51056 (212 mg; 1 mmole) was dissolved at room temperature in methanol (5 ml) with stirring. After addition of 5% hydrogen peroxide (600 μl; 1.05 mmole), stirring was continued for 15 min. The solvent was evaporated off under reduced pressure. The residue was taken up in 25 ml of dichloromethane and washed with 3×3 ml of a saturated NaCl solution, dried over Na2SO4 then filtered. After evaporation of the solvent under reduced pressure, the desired product was obtained in the form of yellowish crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[C:25]([CH3:33])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[C:25]([CH3:33])=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(Cl)cccc1B(O)O
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: Cc1c(Cl)cccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chloro-2-methylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2-fluoro-2′-methylbiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 413 [MH+].
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:23])(=O)=O.O.CCOC(C)=O>C(Cl)Cl>[Cl:23][CH:11]([C:6]1[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)n1nc(C(Cl)C(=O)c2ccccc2)ccc1=O
Reaction time: 5 h

Procedure:
A mixture of 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (100 g) and sulfurylchloride (32.9 ml) in CH2Cl2 (200 ml) was refluxed with stirring for 5 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(1-chloro-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone (100 g) as white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18](=O)[CH3:19])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:18]([CH3:19])=[CH:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(CC(C)=O)Cc2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: COc1ccc2c(c1)c(C)cn2Cc1ccccc1
Yield: 62.5 %

Procedure:
A solution of 1-[N-benzyl-N-(4-methoxyphenyl)amino]propan-2-on (863 mg, 3.20 mmol) in 9.6 mL of ethanol was added zinc chloride (1.3 g, 9.6 mmol) at room temperature. After the reaction mixture was stirred over night, zinc chloride (1.3 g, 9.6 mmol) was added with additional stirring for 10 h. After the reaction mixture was concentrated in vacuo, the residue was diluted with ethyl acetate, and washed with water, 1 M HCl, saturated NaHCO3 aqueous solution and brine, successively, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound (503 mg, 62%).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].N1C=CC=CC=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:7][CH:6]1[CH2:2][O:3][CH2:4][O:5][CH2:1]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1COCO1
Solvent: c1ccncc1
Product: CC(=O)OC1COCOC1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 10.0 g (96 mmole) of glycerol formal, 8.35 g (105 mmole) of pyridine, and 20 ml of acetic anhydride was stirred at ambient temperature under protection from moisture. After a period ranging from a few hours to 5 days, the solution was fractionally distilled under vacuum. The early fractions consisted primarily of pyridine, acetic acid, and acetic anhydride. The bulk of the product distilled at 56°-57° (1.1 mm). The product fractions (10.8 g) were separated into the 5- and 6-membered ring isomers by preparative HPLC on silica gel in 3:1 hexane-ethyl acetate with recycling. Fractions were identified and checked for purity by analytical HPLC. In total 3.19 g (23%) of 1,3-dioxolane-4-methyl acetate (shorter retention time) and 5.23 g (37%) of 1,3-dioxan-5-yl acetate (longer retention time) were obtained. The structures were confirmed by NMR.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:24][CH:25]1[C:45](=[O:46])[N:27]2[C:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])=[CH:29][CH2:30][S:31][C@H:26]12.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O.O1CCCC1.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([NH:24][CH:25]2[C:45](=[O:46])[N:27]3[C:28]([C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=4)=[O:33])=[CH:29][CH2:30][S:31][C@H:26]23)=[O:17])[N:13]=1)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Phosphoryl chloride (13.2 g.) was added dropwise to a stirred solution of N,N-dimethylformamide (6.3 g.) and tetrahydrofuran (24.7 ml.) at -5° C., and stirred at the same temperature for 30 minutes. Tetrahydrofuran (120 ml.) and 2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 19.5 g.) were added to the solution at -5° C., and stirred at the same temperature for 30 minutes. The solution was added dropwise a stirred suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (24.7 g.), tetrahydrofuran (120 ml.), acetone (60 ml.) and water (60 ml.) at -5° to 5° C. over 15 minutes while adjusting to pH 7 to 7.5 with 20% aqueous solution of sodium carbonate, and then the solution was stirred for 30 minutes. The insoluble substance was filtered off, and a saturated aqueous solution of sodium chloride was added to the filtrate. The solution was extracted with tetrahydrofuran twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 34.6 g.).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.477 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.268 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.11 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: CN1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[N:5][CH2:4][C:3]1=[O:23].[CH2:24]([O:26]C(=O)OCC)[CH3:25].[H-].[Na+]>>[CH2:24]([O:26][C:3]([C:4]1[NH:5][C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:23])[CH3:25]
Reactant: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1[nH]c(-c2cccc(C(F)(F)F)c2)c2ccccc12

Procedure:
According to the procedure described in Example 1, 1,3-dihydro-1-methyl-5-(α,α,α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one is reacted with diethylcarbonate in the presence of sodium hydride, and there is obtained 3-(α,α,α-trifluoro-m-tolyl)-isoindole-1-carboxylic acid ethyl ester, having a melting point of 155°-157° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:14]([C:10]3[CH:9]=[C:8]([NH:7][C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:17])[N:12]([CH3:13])[N:11]=3)=[O:16])[CH2:20][CH2:21]2)=[CH:32][CH:31]=1)#[N:30]
Reactant: CC(C)CNC(=O)Nc1cc(C(=O)O)nn1C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)Nc1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)nn1C
Yield: 13.3 %

Procedure:
A solution of 5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylic acid (compound 351.6, 0.11 g, 0.46 mmol), 4-(piperidin-4-yl)benzonitrile HCl salt (compound 1.5, 0.097 g, 0.4 6 mmol), EDCI (0.090 g, 0.51 mmol), HOBT (0.065 g, 0.51 mmol, with 20% H2O) and DIEA (0.22 ml, 1.38 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was then diluted with 50 ml of ethyl acetate and washed with 2×20 ml of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using prep.-TLC and developed using neat ethyl acetate to yield 25 mg of the title compound as an off-white solid. m/z (ES+) 409 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ8.46 (s, 1H), 7.76 (d, 2H), 7.49 (d, 2H), 6.48 (t, 1H), 6.37 (s, 1H), 4.84 (d, 1H), 4.63 (d, 1H), 3.65 (s, 3H), 3.14 (m, 1H), 2.92 (t, 3H), 2.79 (m, 2H), 1.85 (m, 1H), 1.67 (m, 1H), 1.57 (m, 2H), 0.87 (d, 6H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([OH:15])(=[O:14])[CH:12]=O>O1CCOCC1>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]/[C:2]/1=[CH:12]\[C:11]([OH:15])=[O:14]
Reactant: O=C1CCc2ccccc21
Reactant: O=CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)/C=C1\Cc2ccccc2C1=O
Yield: 91.7 %

Procedure:
A mixture of 1-indanone (145) (25 g, 190 mmol), glyoxylic acid (50% aqueous solution, 70 g, 470 mmol), and CH2SO4 (6.25 mL) in dioxane (25 mL) were stirred at reflux temperature for 4 h. The mixture was cooled, the product filtered off, washed with water and dried to give acid 146 (32.8 g, 92%) as a white solid: mp 201-203° C. [lit. (Nagasawa et al., Japanese Patent 04338358, 1992) 205-206° C.]; 1H NMR [(CD3)2SO] δ 12.00 (br s, 1H, OH), 7.73-7.80 (m, 2H, H-5, H-7), 7.68 (br d, J=7.7 Hz, 1H, H-4), 7.49 (t, J=7.9 Hz, 1H, H-6), 6.55 (t, J=2.4 Hz, 1H, CHCO2), 4.08 (d, J=1.8 Hz, 2H, H-3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][N:13]=1
Reactant: OCc1ccnc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (42.2 ml) in methylene chloride (1100 ml) is added dropwise a solution of dimethyl sulfoxide (68.7 ml) in methylene chloride (220 ml) at −60° C. to −50° C., and thereto is further added dropwise a solution of 2-chloro-4-hydroxymethylpyridine (63.2 g) in methylene chloride (440 ml) at the same temperature. The mixture is stirred for 15 minutes, and thereto is added dropwise triethylamine (306.6 ml) at the same temperature. The mixture is stirred for five minutes, and warmed to room temperature. After the reaction is complete, to the reaction mixture is added water (2.2 liters). The methylene chloride layer is separated, and the aqueous layer is extracted again with methylene chloride (2.2 liters). The methylene chloride layers are combined, and washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated under reduced pressure to remove the solvent to give 2-chloropyridine-4-carbaldehyde.