Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[NH4+:12].[C:13]1([CH2:23][C:24]([OH:26])=O)([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N>C(O)(CC)C.O>[CH2:16]1[CH2:17][CH2:18][C:13]2([CH2:23][C:24](=[O:26])[NH:12][C:20](=[O:21])[CH2:19]2)[CH2:14][CH2:15]1
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCC(C)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCCCC2)CC(=O)N1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
A flask is charged with 66.5 g of acetic anhydride, 66.5 g of ammonium acetate, and 100 g of 1,1-cyclohexane diacetic acid. The reaction mass is heated to 160° C.-170° C. for eight hours, eliminating by distillation the acetic acid that has formed. It is cooled to 90° C.-110° C., and 200 g of water and 100 g of secondary butyl alcohol are added. It then undergoes further cooling to room temperature, and the pH is brought to approximately 9 using 30% of aqueous ammonia. This is followed by filtration, washing the solid with water. 87.7 g of dry 3,3-pentamethylene glutarimide are obtained (yield 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:16](Cl)[CH2:17][OH:18].[C:20]([OH:25])(=[O:24])[C:21]([CH3:23])=[CH2:22].C1C=CC=CC=1>[OH-].[K+].C(Cl)(Cl)Cl>[C:20]([O:25][CH2:16][CH2:17][O:18][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: OCCCl
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=C(C)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCOc1ccc(-c2ccc(OC)cc2)cc1

Procedure:
4-(methacryloyloxy) ethoxy-4'-methoxybiphenyl is prepared from 4-methoxy-4'hydroxybiphenyl by reaction with ethylenechlorohydrine in aqueous-alcoholic potassium hydroxide solution and subsequent azeotropic esterification with methacrylic acid in chloroform, catalyzed by p-toluol-sulfonic acid. This substance is heated for 8 hours to 65° C. in a benzene solution under nitrogen in the presence of 1 mol percent 2.2-azoisobutylonitrile. The reaction product is dissolved in chloroform and precipitated in a mixture of acetone and methanol. A solution of the liquid-crystal polymer in N-methyl-pyrrolidone is applied via a rubber roller to a glass substrate provided with a conductor structure and dried at 100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O)([O-:3])=[O:2].Cl.[CH3:17][NH:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:17][N:18]([CH3:19])[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:15]
Reactant: CNC
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of 5-nitro-1H-indazole-3-carboxylic acid (1.01 g, 4.88 mmol), dimethylamine hydrochloride (1.99 g, 24.4 mmol) and HATU (2.78 g, 7.31 mmol) in DMF at RT was added DIPEA (4.3 mL, 24 mmol) and the reaction mixture kept at RT for 18 hr and then diluted with water (150 mL). The resulting precipitate was collected by filtration and was dried in vacuo to afford N,N-dimethyl-5-nitro-1H-indazole-3-carboxamide as a pale yellow solid (1.10 g, 92%); Rt 0.26 min (Method 2, acidic); m/z 235 (M+H)+ (ES+).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:18][CH:19]=1>C(O)C>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCBr
Reactant: OCCCc1cccc(O)c1
Solvent: CCO
Product: CCCCCCCCCCCOc1cccc(CCCO)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A 15N aqueous sodium hydroxide solution (2 ml) and a solution (10 ml) of 8.0 g of undecyl bromide in ethanol was added to a solution (30 ml) of 4.56 g of 3-(3-hydroxyphenyl)propanol in ethanol and the mixture was stirred at 70° C. for 12 hours. The solvent was distilled away and the residue was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20-1:3) to give 7.37 g of 3-(3-undecyloxyphenyl)propanol as a colorless, oily substance.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1[C:30]([OH:31])=[CH:29][C:28]([OH:32])=[N:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:32][C:28]3[N:27]=[CH:26][N:25]=[C:30]([OH:31])[CH:29]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cc(O)ncn1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3cc(O)ncn3)CC2)n1
Yield: 14.8 %

Procedure:
1.5 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (4.27 mmol), 0.72 g of pyrimidine-4,6-diol (6.4 mmol) and 1.31 g of triethylamine in 30 ml of dimethylformamide were stirred for 16 h at 80° C. The mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (1-10%). Fractions containing the product were combined. The solvents were evaporated and the oily residue was treated with acetonitrile. The precipitate was collected by filtration and dried to yield 0.27 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:5]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Si](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:26][N:25]=[N:24]2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(Cl)cn2)c1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester (1.90 g, 5.71 mmol) was dissolved in acetonitrile, and NaN3 (3.71 g, 5.71 mmol) and SiCl4 (1.64 mL, 14.28 mmol) were added. The reaction mixture was stirred at 60° C. for 18 hours, then cooled and poured in to cold saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.84 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester, MS (M+H)=358.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:24]=3)[CH:18]=2)[C:13]([F:34])=[CH:12][N:11]=1>>[F:34][C:13]1[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[O:27][C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][N:24]=3)[CH:18]=2)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1cccc(-c2nnc(-c3ccccc3)o2)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(-c4nnc(-c5ccccc5)o4)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.72 (bs, 1H), 7.96 (bd, 3H), 7.85 (m, 2H), 7.56 (m, 4H), 7.14 (d, 1H, J=2.1 Hz), 6.91 (m, 2H), 6.28 (dd, 1H, J=1.8 and 6.9 Hz); LCMS: purity: 80%; MS (m/e): 441 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]([CH2:13][CH2:14][CH3:15])([CH2:11][OH:12])[CH2:9][OH:10].[OH2:16]>N1C=CC=CC=1.C(OCC)C>[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[CH3:1][S:2]([OH:4])(=[O:16])=[O:3].[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[OH:6][CH2:7][C:8]([CH2:13][CH2:14][CH3:15])([CH2:11][OH:12])[CH2:9][OH:10]
Reactant: O
Reactant: CS(=O)(=O)Cl
Agent: CCCC(CO)(CO)CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (74.0 g) was added dropwise over 30 minutes to a solution of 2-hydroxymethyl-2-n-propylpropan-1,3-diol (28.0 g) in dry pyridine (200 ml) under nitrogen at 0° C. The mixture was allowed to warm to room temperature. After stirring for 18 hours the mixture was poured into water (200 ml) and extracted with chloroform (2×200 ml). The chloroform extracts were washed with water (2×100 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give a brown solid. This was stirred in dry diethyl ether (200 ml) to give 2-hydroxymethyl-2-n-propylpropan-1,3-diol trimethanesulphonate as a white solid. (70.0 g)(m.pt.103.6°).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][CH:34]=1>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][CH:34]=2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCCOc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
To a stirred solution of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)-carbamate (1.76 g, 5.9 mmol) in DMF (10 mL) was added cesium carbonate (4.0 g, 12.0 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. 4-(2-Bromoethoxy)benzenecarboxaldehyde (1.35 g, 5.9 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine (×3), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 50% ethyl acetate/iso-hexane to afford the title compound (1.6 g, 61%).
Reaction SMILES: [Ti:1].[S:2](=[O:6])(=[O:5])([OH:4])[OH:3]>O>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Ti+4:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: [Ti]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: [Ti+4]

Procedure:
Referring to FIG. 1, titanium ore 2 (typically, ilmenite) is digested with sulfuric acid 4 at temperatures greater than 100° C., then leached with water or dilute acid to produce a solution 6 of titanium sulfate and iron sulfates, also referred to as a “black liquor”. The solution 6 is cooled to a temperature of about 65° C. and clarified, and iron sulfates are separated from the solution 6 by crystallization 8. Scrap iron may be added at this stage of the process to reduce ferric sulfate to the less soluble ferrous sulfate 10, thus promoting separation of the iron sulfates by crystallization 8. The hydrolysis of the titanium sulfate is performed next, typically in the same stage as the precipitation 12 of the titanium oxide. Precipitation 12 is achieved by boiling the solution 6 for a number of hours. The conditions of precipitation 12 are controlled so that the precipitate can be easily filtered and washed 14, and to produce crystals that will have the correct crystal structure and crystallite size after calcination 16. The washing step 14 removes any soluble metal salts that may remain and reduces the sulfuric acid content of the resulting slurry. During calcination 16, the titanium oxide slurry is heated to temperatures in the region of 700-1000° C. in air to drive off water and sulfur oxides, and to control the crystal size of the titanium oxide 18 produced. The final stages of calcination 16 may be performed so as to convert the crystalline product to rutile structure. The resulting titanium oxide 18 is then finished 20 in a series of processes that provide the desired properties to the titanium oxide product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([O:17][CH3:18])[C:14](O)=[O:15].[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([O:17][CH3:18])[C:14]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=1)=[O:15]
Reactant: COC(C(=O)O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
(RS)-(2,4-Bis-trifluoromethyl-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(2,4-bis-trifluoromethyl-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Colorless gum.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][CH:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([Cl:22])=[O:21])=[N:12]1)[CH3:10].[OH2:23].Cl>CN(C=O)C.C(O)C>[ClH:22].[OH:23][C:14]1[CH:19]=[CH:18][C:17]([CH2:2][CH2:1][N:3]2[CH2:6][CH2:7][CH:8]([CH2:9][NH:11][C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:11]([CH:9]([CH3:10])[CH3:8])[N:12]=3)=[O:21])[CH2:5][CH2:4]2)=[CH:16][CH:15]=1
Reactant: CC(C)n1nc(C(=O)Cl)c2ccccc21
Reactant: O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NCC2CCN(CCc3ccc(O)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the product obtained in step 1b) (10.0 g, 0.043 moles) and triethyl-amine (30 ml, 0.21 moles) in DMF (100 ml) was added dropwise to a solution of 1-(1-methylethyl)-1H-indazole-3-carboxylic acid chloride (9.5 g, 0.043 moles), prepared as described in EP-A-0 975 623, in DMF (50 ml). After having been stirred continuously at room temperature for 18 hrs, the reaction mixture was transferred into a separatory funnel, added with H2O, and extracted with ethyl acetate (3×150 ml). The organic phase was separated and dried over Na2SO4. The solvent was removed by evaporation under reduced pressure. The residue thus obtained was taken up with absolute ethanol and transformed into the corresponding hydrochloride salt by addition of ethanolic hydrogen chloride. The solution was evaporated under reduced pressure and the residue was crystallised from ethanol to give the desired product (20 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:66]/[O:67]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:12]([NH:14][C@@H:15]2[C:64](=[O:65])[N:17]3[C:18]([C:48]([O:50]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:49])=[C:19]([S:22][CH2:23][C:24]4[CH:25]=[N:26][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:66]/[OH:67])/[C:12]([NH:14][C@@H:15]2[C:64](=[O:65])[N:17]3[C:18]([C:48]([OH:50])=[O:49])=[C:19]([S:22][CH2:23][C:24]4[CH:25]=[N:26][NH:27][CH:28]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)CS[C@H]23)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
Under nitrogen atomosphere, a solution of aluminium chloride (2.65 g) in anisole (5.7 ml) was added dropwise to a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (3.32 g) in a mixture of anisole (5.7 ml) and nitromethane (22.5 ml) at −24° C. After stirring for 1 hour at the same temperature, the reaction was quenched with 1N hydrochloric acid (22.5 ml). The mixture was poured into a mixture of water and ethyl acetone. The aqueous layer was separated and the organic layer was reextracted with water. The combined aqueous layer was concentrated in vacuo, chromatographed on a HP-20 column (eluent: water-methanol). After the concentration, the resulting precipitate was collected by filtration to afford 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[C:17]1([C:16]2[N:3]3[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]4[C:11]([C:2]3=[N:25][N:24]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COC(=O)c1cnc(Cl)c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-Chloroisoquinoline-4-carboxylate, prepared essentially according to procedures described in Example 1, part 4, (293 mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100° C. overnight. The mixture is cooled and poured into water. The solid is then collected by filtration and dried to give the title compound as a solid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS (ES+) m/e 304 [M+H]+. (The HPLC retention time is obtained by the method of Example 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][N:29]([CH2:30][CH3:31])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1Cl)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
[4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.250 g, 0.722 mmol) was dissolved in DCM (10 ml) and N-(2-chlorobenzyl)-N-ethylamine (0.116 g, 0.686 mmol) was added. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.255 g, 0.0.794 mmol) and N-ethyl-N,N-diisopropylamine (0.187 g, 1.443 mmol) were added. The solution was stirred for 2 hours at room temperature. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The substance needed to be purified once more and it was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. The ammonium acetate was removed by freeze drying the product overnight to give 0.111 g of methyl 2-{[2-(4-{2-[(2-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 30.9%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccccc1
Yield: 881 %

Procedure:
Benzene (0.5 mg), 4-chlorobutyryl chloride (141 mg), and aluminium chloride (170 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (10.3 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[CH3:17][O:18][C:19](=[O:42])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=2)=[C:22](N)[CH:21]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:17][O:18][C:19](=[O:42])[C:20]1[CH:21]=[CH:22][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:29][CH:28]=2)=[C:24]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH:9]([CH3:10])[CH3:11])=[N:5][C:4]=3[N:12]=[CH:13][N:14]=2)[CH:25]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 120 °C

Procedure:
A suspension of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (2.00 g, 9.3 mmol) and 3-amino-4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-benzoic acid methyl ester (3.46 g, 9.3 mmol) in AcOH (40 mL) was heated at 120° C. for 20 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between AcOEt (150 mL) and H2O (200 mL), and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give pale brown oil. The oily residue was separated by silica gel column chromatography (AcOEt/n-hexane=5/1) to give yellow crystal. Further purification by washing with cold AcOEt (15 mL) gave the title compound as slightly yellow crystal (3.27 g, 65%).