Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=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.[I-].[Na+].[SH:64][C:65]1[N:70]([CH3:71])[C:69](=[O:72])[C:68]([OH:73])=[N:67][N:66]=1.O>CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:64][C:65]4[N:70]([CH3:71])[C:69](=[O:72])[C:68]([OH:73])=[N:67][N:66]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=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
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1c(S)nnc(O)c1=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)nnc(O)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
To a mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (1.5 g) and sodium iodide (769 mg) in N,N-dimethylformamide was added 3-mercapto-4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine (816 mg). After being stirred for 45 minutes at room temperature, the reaction mixture was poured into water. The resulting precipitates were collected by filtration and dissolved in ethyl acetate. The solution was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried and evaporated under reduced pressure. The residue was triturated in diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.25 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O.[CH3:12][N:13]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2=[CH:17][CH:18]=[C:19]3[C:23]([NH:22][CH2:21][CH2:20]3)=[C:15]2[CH2:14]1>C1(C)C=CC=CC=1.C(Cl)Cl>[N:6]1([N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16]4[CH:24]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:25][N:13]([CH3:12])[CH2:14][C:15]4=3)[CH2:20][CH2:21]2)[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: CN1Cc2c(ccc3c2NCC3)C(c2ccccc2)C1
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1Cc2c(ccc3c2N(N2C=CCC2)CC3)C(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of 1.9 ml (0.02 mol) of phosphorus oxychloride in 6 ml of toluene is added dropwise to a solution of 3.4 g (0.04 mol) of pyrrolid-2-one in 8 ml of toluene at a temperature between 2° and 0° C., with stirring and cooling. The mixture is stirred at room temperature for 11/2 hours and left to stand overnight. A solution of 5.2 g (0.02 mol) of 8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole in 10 ml of toluene and 20 ml of CH2Cl2 is then added. The CH2Cl2 is distilled off and the reaction mixture is stirred at a temperature between 75° and 80° C. for 8 hours, with stirring. The solid which has precipitated is filtered off with suction, and 2N NaOH and H2O are added in order to convert it into the free base. The aqueous phase is extracted with CH2Cl2, the CH2Cl2 phase is dried and the solvent is removed. The residue is chromatographed on silica gel 60 from E. Merck, Darmstadt) using an eluent mixture of CH2Cl2 /MeOH (2:1), and on aluminum oxide (aluminum oxide 90 from E. Merck, Darmstadt) using an eluent mixture of CH2Cl2 and MeOH (20:0.25). The product is dried in a desiccator over P2O5 under a water pump vacuum.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17](C3C=CC4N(C)N=NC=4C=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[C:44]2[CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1>>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:46]3[CH:47]=[CH:48][C:43]4[N:42]=[N:41][N:40]([CH3:39])[C:44]=4[CH:45]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nnn(C)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate, but using 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H), 7.60-7.45 (m, 4H), 5.18 (s, 1H), 4.39 (s, 3H), 4.28-4.17 (m, 2H), 2.63 (s, 3H), 1.26 (t, J=8 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:16][CH:15]=2)[C:5]1=[O:27].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]Cl.O>CN(C)C=O>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][C:6]1([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:18][CH:19]=2)[C:5](=[O:27])[N:4]([CH3:3])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7]1
Reactant: CN1C(=O)C(c2ccc(OC3CCCCO3)cc2)Sc2ccccc21
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCC1(c2ccc(OC3CCCCO3)cc2)Sc2ccccc2N(C)C1=O
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of 60% sodium hydride (3.1 g) in dimethylformamide (30 ml), 3,4-dihydro-4-methyl-3-oxo-2-[4-(tetrahydropyran-2-yloxy)phenyl]-2H-1,4-benzothiazine (25.0 g) dissolved in dimethylformamide (60 ml) is added under nitrogen atmosphere, and the mixture is stirred for 30 minutes. A solution of 3-dimethylaminopropyl chloride in dimethylformamide [prepared by mixing of 3-dimethylaminopropyl chloride hydrochloride (13.3 g) and triethylamine (11.8 ml) in dimethylformamide (50 ml) and followed by filtration to remove precipitate] is added to the reaction mixture, and the mixture is stirred for 1 hour at 65°-75° C. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 25.1 g (81.0%) of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1OCc1ccccc1
Yield: 91.3 %

Procedure:
To a solution of methyl 3-(benzyloxy)-2-thiophenecarboxylate (7.85 g, 31.61 mmol) in MeOH (32 mL) and THF (16 mL) was added 2 N NaOH (21 mL), and the mixture was stirred at reflux for 10 hrs, and then concentrated under reduced pressure. The residue was diluted with water, washed with ether. The separated aqueous phase was acidified with 5N HCl. The precipitated solid was collected by filtration, washed with hexane, and dried under reduced pressure at 60° C. to give 3-(benzyloxy)-2-thiophenecarboxylic acid as a yellow solid (6.76 g, yield; 91%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36].O>CN(C)C=O>[Cl:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
1.01 g (2.59 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 20 ml of dimethylformamide under argon atmosphere, 228 mg of sodium hydride (60% oil dispersion) and 1.5 ml of 1-bromo-4-chlorobutane were added under ice-cooling and the mixture was stirred at room temperature for 3 hours. 228 mg of sodium hydride (60% oil dispersion) and 1.5 ml of 1-bromo-4-chlorobutane were further added and the mixture was stirred for additional 1 hour. Water was added to the reaction solution and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to give 396 mg (32%) of 5-(4-chlorobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:22][CH2:23][CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(F)cccc2c1-c1ccc(OC)cc1
Yield: 4.2 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.096 mL, 1.0 mmol) to give the title compound (0.006 g).
Reaction SMILES: Cl.C[NH:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>C(Cl)(Cl)Cl>[C:9]([NH:3][CH2:4][CH2:5][NH2:6])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: CNCCN
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.2 %

Procedure:
The intermediate N-t-BOC, N-methyl-ethylenediamine monohydrochloride prepared in example 5 (10 mmol, 2.1 g) was stirred with 2M NaOH (11 cm3) at room temperature for 10 min. The solution was then cooled to 0° C., and to this, was added a solution of methacryloyl chloride (11 mmol, 1.1 cm3) in chloroform (30 cm3), dropwise. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 1 h. The organic and aqueous phases were then separated, and the aqueous phase extracted with chloroform. The organic extracts were combined, dried (MgSO4), filtered and conc. in vacuo, to give the crude product. The crude product was stirred at room temperature over a slurry of basic alumina in chloroform for 18 hr. Removal of the alumina and concentration of the filtrate then gave a pale yellow oil. Purification by flash chromatography (silica gel, diethyl ether: hexane : methanol elution) afforded N-t-BOC, N-methyl, N′-methacryloyl-ethylenediamine (Rf0.51) as a yellow oil (1.63 g, 67%). δH (400 MHz; CDCl3) 6.94 (1H, br s), HNOC(H3C)C═CHaHb; 5.74 (1H, br m), (H3C)C═CHaHb; 5.30 (1H, br m), (H3C)C═CHaHb; 3.43 (4H, br m), 2×CH2; 2.87 (3H, s), N(CH3); 1.93 (3H, br m), CH3; 1.44 (9H, s), C(CH3)3. δC (75.4 MHz; CDCl3) 168.52, NHOC(H3C)C═CH2; 157.33, NHCO2C(CH3)3; 139.36, (H3C)C═CH2; 119.81, (H3C)C═CH2; 80.85 C(CH3)3; 47.32, CH2N(CH3)OC(H3C)C═CH2; 39.32, CH2NHCO2C(CH3)3; 34.68, N(CH3); 28.33, C(CH3)3; 18.47, CH3. Found: (HM+.) 243.17178.
Reaction SMILES: [C:1]1([S:7](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].[CH3:13][C@H:14]1[C@H:19]([CH2:20][CH:21]=[CH2:22])[CH2:18][CH2:17][C:16](=[O:23])[CH2:15]1.Cl>C(COC)OC>[CH3:13][CH:14]1[CH2:15][C:16](=[O:23])[CH:17]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH:19]1[CH2:20][CH:21]=[CH2:22]
Reactant: COS(=O)c1ccccc1
Reactant: C=CC[C@@H]1CCC(=O)C[C@H]1C
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Product: C=CCC1CC(Sc2ccccc2)C(=O)CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. mixture of 16.9 g. (0.109 mole) of methyl benzenesulfinate and 8.68 g. (0.217 mole) of potassium hydride in 100 ml. of dimethoxyethane was slowly added a solution of 15.0 g. (0.0987 mole) of trans-3-methyl-4-(2-propenyl)cyclohexanone in 50 ml. of dimethoxyethane. The reaction was stirred 30 minutes longer at 0° C. and then cautiously added to 500 ml. of ice-saturated sodium chloride and 45 ml. 6 N hydrochloric acid. The quenched reaction mixture was extracted once with 300 ml. ether and once with 200 ml. dichloromethane. The organic extract was dried over magnesium sulfate and evaporated to give a quantitative yield of the title compound as a semisolid mixture of axial and equatorial sulfenates. Crystallization from ether yields 7.8 g. of pure axial sulfenate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6]([CH3:13])[CH:5]=[C:4]([CH3:14])[C:3]=1[NH2:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH:15][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:2]=1[CH3:1])=[O:26]
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Reactant: COc1ccccc1N=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1NC(=O)Nc1c(C)cc(C)c(N2CCCC2)c1C
Temperature: 25 °C
Yield: 25.5 %

Procedure:
A solution of 2 (0.25 g, 1.22 mmol) and 2-methoxyphenyl isocyanate (0.18 g, 1.22 mmol) in toluene (5 mL) was heated at 80° C. overnight. The mixture was allowed to cool to room temperature and then diluted with EtOAc. The organic layer was washed with water (50 mL) and brine (50 mL) before it was dried (MgSO4) and concentrated on a rotavap. The residue was chromatographed on silica gel to give the title compound (0.11 g) as a solid. ESI [M+H+]=354.22.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](OCC)=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][N:32]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C@@H:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[C:24]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=6)[CH:34]=[CH:33][N:32]=5)[CH:25]=4)=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2ccncc2)n1
Reactant: CCOC(=O)c1ccc2c(c1)CC[C@@H]2N1CCN(C)CC1
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CC[C@@H]3N2CCN(C)CC2)cc1Nc1nccc(-c2ccncc2)n1

Procedure:
The title compound was prepared by condensation reaction between ethyl (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylate and 4-methyl-N(3)-(4-pyridin-4-ylpyrimidin-2-yl)benzene-1,3-diamine, according to the procedure described in Step C of EXAMPLE 11. MS (M+1)=520.27. 1HNMR (DMSO-d6, ppm): δ 10.14 (s, 1H); 9.04 (s, 1H); 8.07 (d, J=4.4 Hz, 2H); 8.55 (d, J=4.8 Hz, 1H); 8.06 (s, 1H); 8.04 (d, J=4.4 Hz, 2H); 7.78 (s, 1H); 7.75 (d, J=8.8 Hz, 1H); 7.45 (d, J=7.6 Hz, 1H); 7.44 (d, J=4.8 Hz, 1H); 7.35 (d, J=7.6 Hz, 1H); 7.18 (d, J=8.8 Hz, 1H); 4.31 (t, J=7.2 Hz, 1H); 2.0-3.0 (m, 10H); 2.19 (s, 3H); 2.12 (s, 3H); 2.04 (m, 2H).
Reaction SMILES: C([O:4][CH:5]([CH2:26][O:27]C(=O)C)[C:6]([NH:8][C:9]1[C:10]([I:25])=[C:11]([CH2:20][O:21]C(=O)C)[C:12]([I:19])=[C:13]([C:17]=1[I:18])[C:14](Cl)=[O:15])=[O:7])(=O)C.[OH:31][CH:32]([CH2:35][OH:36])[CH2:33][NH2:34].[Br-].[Li+].C(N(CC)CC)C>O1CCCC1>[OH:4][CH:5]([CH2:26][OH:27])[C:6]([NH:8][C:9]1[C:10]([I:25])=[C:11]([CH2:20][OH:21])[C:12]([I:19])=[C:13]([C:17]=1[I:18])[C:14]([NH:34][CH2:33][CH:32]([OH:31])[CH2:35][OH:36])=[O:15])=[O:7]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: NCC(O)CO
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(NC(=O)C(O)CO)c1I
Temperature: 65 °C
Reaction time: 26 h
Yield: 83 %

Procedure:
5-[N-(2,3-Diacetoxypropionyl)amino]-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (7.71 g, 9.9 mmol), 2,3-dihydroxypropylamine (1.48 g, 16.2 mmol), lithium bromide (90 mg, 1 mmol) and triethylamine (2.27 ml, 16.2 mmol) were mixed in tetrahydro-furan (55 ml) at ambient temperature. The temperature was increased to 65° C. and held there for 26 h with efficient stirring, and the mixture was then evaporated to dryness. The residue was dissolved in a mixture of water and methanol (6:1, 70 ml) and treated with a strongly basic anion exchange resin (Dowex 1×8) for 2.5 h. The resin was filtered off, the solution diluted with further water (50 ml) and treated with a strongly acidic cation exchange resin (Amberlyst 15) to bring the pH of the solution to 5.5-6.0. The resin was filtered off and the solution was treated with activated charcoal (0.35 g), filtered and evaporated to a light yellow to white solid residue. This was triturated with acetonitrile (20 ml) for 12 h, giving 5.8 g (70%) of a white crystalline residue.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>>[Si:1]([O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
4-[[t-Butyl(dimethyl)silyl]oxymethyl]benzoic acid (1.44 g) was suspended in thionyl chloride and the mixture was heated to 80° C. for 45 minutes. The resulting solution was concentrated in vacuo. Residual thionyl chloride and HCl were removed by subsequent concentration from toluene (twice). The crude residue was carried on to the next reaction step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:23]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([Br:23])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCC(=O)C(Br)C(=O)OCC
Reaction time: 0.08 h

Procedure:
3-Oxo-hexanoic acid ethyl ester (4.0 mL, 25 mmol) and magnesium perchlorate (1.7 g, 7.6 mmol) was placed in 500 mL of ethyl acetate and allowed to stir for 5 minutes. N-Bromosuccinimide (4.7 g, 26 mmol) was added and the reaction mixture was allowed to stir for 15 minutes, at which time thin-layer chromatography (10% ethyl acetate in hexanes, SiO2, 254 nm irradiation) indicated the reaction was complete. The reaction mixture was diluted with 500 mL of ethyl ether and washed three times with an equal volume of saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. This material was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[C:12]1([N:18]2[C:22]([SH:23])=[N:21][N:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]1([N:18]2[C:22]([S:23][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:8]=[O:9])[CH:10]=3)=[N:21][N:20]=[N:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cc(CCl)ccc1O
Reactant: Sc1nnnn1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=Cc1cc(CSc2nnnn2-c2ccccc2)ccc1O
Temperature: 0 °C

Procedure:
25.6 g of 5-chloromethylsalicylaldehyde and 26.7 g of 1-phenyl-5-mercaptotetrazole were dissolved in 250 ml of dioxane. Then, internal temperature of the solution was lowered to 20° C. or less with ice water and thereto was added dropwise 20.8 ml of triethylamine with stirring followed by stirring at room temperature for 2 hours. After completion of the reaction, the precipitated salt was filtered off and the filtrate was concentrated under reduced pressure. Thus obtained residue was dissolved in 500 ml of ethyl acetate and then washed with water and the organic layer was dried over anhydrous sodium sulfate. Thereafter sodium sulfate was filtered off and the solvent was distilled out under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and cyclohexane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([CH2:13][CH2:12][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: ClCCN1CCOCC1
Product: O=[N+]([O-])c1ccc(SCCN2CCOCC2)cc1

Procedure:
Following the procedures of Example 1, the title compound is prepared from 4-nitrothiophenol and 4-(2-chloroethyl)morpholine.
Reaction SMILES: [F:1][CH:2]([F:54])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N:48]2[CH2:52][CH2:51][O:50][C:49]2=[O:53])[CH:43]=1.[ClH:55]>O1CCOCC1>[ClH:55].[F:54][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[N:23][CH:22]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH2:40][O:41][C:42]1[CH:43]=[C:44]([N:48]2[CH2:52][CH2:51][O:50][C:49]2=[O:53])[CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(COc5cccc(N6CCOC6=O)c5)nc4cc3F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCCN1c1cccc(OCc2nc3cc(F)c(-c4cnc(N5CCNCC5)nc4)cn3c2Cc2ccccc2OC(F)F)c1
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of Example 257 (50 mg, 0.067 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (5 mL, 20 mmol), and the reaction mixture was stirred for 3 h. The solvent was removed in vacuo, and the residue was freeze-dried, to afford the title compound (25 mg, 58%). δH (300 MHz, DMSO-d6) 9.23 (m, 2H), 8.68 (m, 1H), 8.63 (d, 2H, J 1.4 Hz), 7.86 (d, 1H, J 10.2 Hz), 7.29 (m, 4H), 7.19 (m, 1H), 7.12 (dd, 1H, J 7.8, 1.5 Hz), 7.08 (m, 2H), 6.77 (dd, 1H, J 8.0, 2.0 Hz), 5.25 (s, 2H), 4.56 (s, 2H), 4.43 (m, 2H), 4.02 (m, 6H), 3.19 (m, 4H). LCMS (ES+) 647 (M+H)+, RT 1.90 minutes.