Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[C:14]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[CH:15]=[CH:16][CH:17]=2)[N:9]=[C:8]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[N:24]=2)[CH:7]=1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43]>ClCCl.C(OCC)(=O)C>[CH3:39][N:40]([CH3:45])[CH2:41][C:42]([O:22][CH:20]1[CH2:21][N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:10]3[C:6]([CH3:5])=[CH:7][C:8]([C:23]4[O:27][N:26]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:30][CH:29]=5)[N:24]=4)=[N:9]3)[CH:13]=2)[CH2:19]1)=[O:43]
Reactant: CN(C)CC(=O)O
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(OC(=O)CN(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
86 mg (0.70 mmol) of 4-N,N-dimethylaminopyridine and 671 mg (3.50 mmol) of EDC were added to a solution of 550 mg (1.17 mmol) of the compound from Example 1 and 361 mg (3.50 mmol) of N,N-dimethylglycine in 11 ml of dichloromethane. After the reaction mixture had been stirred at RT for 8 h, all volatile constituents were removed on a rotary evaporator. The residue obtained was taken up in 200 ml of ethyl acetate and washed once with approx. 100 ml of water. After drying over anhydrous magnesium sulphate, filtration and concentration, the product was isolated by means of MPLC (approx. 30 g of silica gel, eluent: 25:25:1 cyclohexane/ethyl acetate/triethylamine) A first fraction of 328 mg of the title compound was obtained. A further 115 mg of the title compound were obtained from a second, still-contaminated fraction by recrystallization from cyclopentyl methyl ether. A total of 443 mg (68% of theory) of the title compound was thus obtained. Another crystallization from diisopropyl ether/cyclopentyl methyl ether (2:1, 1.5 ml per 100 mg) gave the title compound with a melting point of 117° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(N(CC)CC)C.[CH2:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26].S(Cl)(Cl)=O>ClCCl>[CH2:25]([N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[C:11]([C:2]=1[OH:1])=[C:10]([Br:12])[CH:9]=[CH:8][CH:7]=2)=[O:17])[CH3:26]
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Br)cccc21
Reactant: CCNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)c1c(O)c2c(Br)cccc2n(C)c1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To an ice-cold solution of 1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid (9.6 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and N-ethylaniline (4.2 g, 0.035 mol) in 150 ml of dichloromethane was added dropwise during 0.5 hours a solution of thionyl chloride (3.0 ml, 0.042 mol) in 10 ml of dichloromethane. The stirring was continued at 4° C. for 24 hours. The solvents were evaporated. The residue was dissolved in ethyl acetate, filtered through celite and extracted with 2 M sodium hydroxide. The aqueous phase was washed with ethyl acetate and then acidified with hydrochloric acid to pH 5. On standing a crystalline precipitate was formed which was filtered off, washed with water and dried to give the title compound (8.5 g), yield 69%.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1.O.Cl>C(O)(=O)C>[Cl:11][C:6]1[C:5]([O:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)=[C:4]([CH:9]=[C:8]([Cl:10])[CH:7]=1)[CH:3]=[O:2]
Reactant: COc1cc(OC)nc(Oc2c(Cl)cc(Cl)cc2C(OC)OC)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)nc(Oc2c(Cl)cc(Cl)cc2C=O)n1

Procedure:
3,5-Dichloro-2-(4,6-dimethoxypyrimidin-2-yl)oxy benzaldehyde dimethylacetal (2.1 g) was dissolved in acetic acid (50 ml), and then water (10 ml) and 35% hydrochloric acid (1 ml) were added thereto. The mixture was reacted at room temperature for 6 hours. The reaction mixture was poured into water, and extracted with toluene. The extract was washed with a 2% sodium hydroxide aqueous solution, and further washed 3 times with water. The toluene phase was dried, and concentrated under reduced pressure. The crystal thus obtained was recrystallized from a mixture of carbontetrachloride and hexane to obtain the above identified compound as a white crystal (1.0 g). (Melting point: 132°-133° C.)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=1>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:17]2[C:22]([O:23][CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cccnc1Br
Reactant: CNC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCOc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of N-(1-benzylpiperidin-4-yl)-N-methylamine (XXVII, 4.80 g) and 2-bromo-3-ethoxypyridine (XXVIIIa, 2.3805 g) is placed in a metal, screw cap reaction vessel using dichloromethane as the transfer solvent. Reduced pressure is applied to the vessel with heating at 50° to 60° for 45 min to remove dichloromethane. The vessel is then sealed and heated at 160 to 165° for 2 days. After cooling, the resulting solids are dissolved in dichloromethane and washed with water and saline. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give the product, which is chromatographed (silica gel; eluting with ethyl acetate/hexane (30/70) followed by ethyl acetate/hexane (50/50)), to give N-(1-benzylpiperidin-4-yl)-N-(3-ethoxypyridin-2-yl)-methylamine (XXVIII, Chart G); MS (m/z) 325; IR (neat) 1462, 1211, 1481, 1589 and 1450 cm-1.
Reaction SMILES: C([O:4][C:5]1([CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])C(=O)C)[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1)(=O)C.CO.[OH-].[Na+]>O>[OH:4][C:5]1([CH2:21][NH:22][CH:26]([CH3:28])[CH3:27])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: CC(=O)OC1(CN(C(C)=O)C(C)C)COc2ccc(NS(C)(=O)=O)cc2OC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)NCC1(O)COc2ccc(NS(C)(=O)=O)cc2OC1

Procedure:
3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7-methanesulfonamido-3,4-dihydro-2H-1,5-benzodioxepin (4.2 g., 10 millimole) in 20 ml. methanol is treated with 2 g. (50 millimoles) of sodium hydroxide in 20 ml. of methanol. The mixture is refluxed for 3 hours, cooled, and diluted with 400 mls. of water, neutralized with acid and extracted with ether. The combined ethereal solutions are washed with water, dried over anhydrous sodium sulfate, and evaporated to give 3-hydroxy-3-isopropylaminomethyl-7-methanesulfonamido-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH3:16][N:17]1C(=O)O[C:20](=[O:21])[C:19]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:18]12.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:17]([CH3:16])[C:18]2[C:19]([C:20]=1[OH:21])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Temperature: 90 °C
Yield: 67.2 %

Procedure:
A solution of diethyl malonate (8.16 g, 51 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 2.24 g, 56 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then heated to 90° C. for 30 min. and cooled to room temperature. A solution of N-methylisatoic anhydride (10 g, 56 mmol) in dimethylacetamide was added slowly and the mixture was heated overnight at 120° C. The mixture was then cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 8.47 g (67%) of white solids. M.P. 67° C. 1H NMR (DMSO-d6): δ 1.30 (t, J=7.0 Hz, 3H), 3.53 (s, 3H), 4.32 (q, J=7.0 Hz, 2H), 7.30 (t, J=7.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.75 (t, J=8.4 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 13.03 (s, 1H). EIMS m/z 248 (M+1), 270 (M+23). Anal. (C13H13NO4) C, H, N.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 51 %

Procedure:
The title compound was prepared from 4-methoxyphenylhydrazine hydrochloride (1.39 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.24 g, 4.08 mmol, 63%). 1H NMR (300 MHz, DMSO-d6) δ 7.42 (d, 2H), 7.00 (d, 2H), 5.33 (s, 1H), 5.05 (s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Yield: 96.1 %

Procedure:
A sol. of compound E3 (1.23 g, 1.50 mmol) and TBAF (1.0 M in THF, 1.88 mL, 1.88 mmol) in THF (20 mL) was stirred at 0° C. for 3.5 h. The mixture was diluted with EtOAc and was then washed with brine (4×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→1:2→1.1→EtOAc) yielded the title compound (1.02 g, 96%). LC-MS: tR=1.11 min, ES+: 707.33.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@@H:38]([C:52]4[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:69]([C@:76](N)([C:82]([O:84][CH:85]([C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)=[O:83])[CH2:77][O:78][C:79](Cl)=[O:80])([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70].[N:99]1C=CC=CC=1>O1CCCC1>[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@@H:38]([C:52]4[CH:53]=[CH:54][C:55]([N:58]([NH2:99])[C:79]([O:78][CH2:77][C@@H:76]([C:69]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:70])[C:82]([O:84][CH:85]([C:86]5[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=5)[C:92]5[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=5)=[O:83])=[O:80])=[CH:56][CH:57]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)[C@@](N)(COC(=O)Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(N(N)C(=O)OC[C@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)C)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 12, 3.2 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate are reacted with 2.65 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride and 0.67 ml of pyridine in 65 ml of tetrahydrofuran and worked up. The resulting crude product is chromatographed over 400 g of silica gel, and 500 ml fractions are taken. The fractions are eluted with toluene/ethyl acetate (1:1). By reprecipitating fractions 7-28 from CH2Cl2 /ether/hexane, 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-{(2R)-2-[4-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. [α]D20 =-69°±1° (1.00% in CDCl3).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:18])=[N:13][CH:14]=2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[C:1]([O:4][CH2:5][CH:6]([CH2:19][OH:20])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:18])=[N:13][CH:14]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OCC(CO)CCn1cnc2cnc(N)nc21
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (0.48 g, 1.5 mmol) in methanol (9 ml) was added anhydrous potassium carbonate (14 mg, 0.1 mmol) and the solution was stirred for 20 minutes. Two drops of glacial acetic acid were added, the solution was filtered and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (15:1, 10:1) to afford 9-(4-acetoxy-3-hydroxymethylbut-1-yl)-2-aminopurine as a white crystalline solid (124 mg, 30%), m.p. 166°-168°; νmax (KBr) 3440, 3220, 1720, 1650, 1615, and 1580 cm-1 ; δH [(CD3)2SO]1.68 (1H, m, 3'-H), 1.82 (2H, m, 2'-H), 1.98 (3H, s, CH3), 3.41 (2H, t, J4.8 Hz, D2O exchange gives d, CH 2 OH), 3.9-4.05 (2H, AB part of ABX, JAB 10.9 Hz and JAX =JBX 5.8 Hz, CH2OCO), 4.12 (2H, t, J 7.2 Hz, 1'-H), 4.62 (1H, t, J 5.0 Hz, D2O exchangeable, OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 8.07 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Observed M+, 279.1326. C12H17N5O3 requires 279.1331).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>C(Cl)Cl>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(-c2ccc3nc(NS(C)(=O)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a solution of the product from Example 83 (0.35 g, 0.83 mmol) in anhydrous CH2Cl2 (50 mL) was added methanesulfonyl chloride (194 μL, 2.49 mmol) and pyridine (1.34 mL, 16.6 mmol). The resulting mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude product was purified by C-18 reverse-phase HPLC using an acetonitrile:H2O (0.1% TFA) gradient to give the title compound (19 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H) 11.41 (d, J=1.84 Hz, 1H) 7.96 (d, J=1.47 Hz, 1H) 7.77 (d, J=8.09 Hz, 1H) 7.57 (dd, 1H) 7.42 (d, J=8.09 Hz, 1H) 7.25-7.32 (m, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.25 (s, 3H) 3.02 (s, 3H) 1.40 (s, 9H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:25][CH:26]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Clc1ccc(OCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1ccc(OCCSc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 2-sulfanylbenzimidazole (159 mg, 1.06 mmol) and DIPEA (150 mg, 200 μl, 1.16 mmol) in dry THF (3 ml) is refluxed for half an hour. After cooling to rt, 1-(2-bromo-ethoxy)-4-chloro-benzene (250 mg, 1.06 mmol) is added. After a further 4 h of reflux, the solvents are removed in vacuo and the residue purified by flash chromatography on silica gel (AcOEt/heptane, 1:9 to 3:7), yielding the title compound (285 mg) in 88% as a white solid: tR=5.40 min (LC-1), ESI-MS (neg.): m/z 303.0 [M−H]+; 1H-NMR (CDCl3): δ 3.76 (t, 2H, SCH2), 4.31 (t, 2H, OCH2), 6.76 (d, 2Harom), 7.18 (d, 2Harom), 7.22-7.32 (m, 3Harom), 7.57 (m, 1Harom).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:19]4[S:18][N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:20]([OH:22])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CC1(C)[O:38][C@@H:37]([CH2:39][O:40][NH2:41])[CH2:36][O:35]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[OH:38][C@H:37]([CH2:36][OH:35])[CH2:39][O:40][NH:41][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]=[N:17][S:18][C:19]=2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:22]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NOC[C@H](O)CO)c1ccc2cnsc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (155 mg, 0.47 mmol) and diisopropylethylamine (0.10 mL, 0.61 mmol) in DMF (5 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (97 mg, 0.66 mmol), EDCI (117 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken in MeOH (10 mL) and a 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour before being diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to reverse-phase HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 15 to 95%, ramp time 20 minutes) to afford the title compound as a yellow solid (115 mg, 59%). LCMS (method A): RT=9.02 min, [M+H]+=418. 1H NMR (DMSO-d6, 400 MHz) 9.98 (1 H, s), 8.97 (1 H, s), 7.72 (1 H, s), 7.61 (1 H, d, J=8.35 Hz), 7.09-6.90 (3 H, m), 3.95 (1 H, dd, J=9.94, 3.81 Hz), 3.79 (2 H, d, J=16.92 Hz), 3.40 (2 H, d, J=5.46 Hz), 2.03-1.94 (1 H, m), 1.03-0.97 (2 H, m), 0.77-0.71 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:43])([O:40][CH2:41][I:42])[O:37][CH2:38][CH3:39]>C(#N)C>[I-:42].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:41][O:40][C:36]([O:37][CH2:38][CH3:39])=[O:43])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)OCI
Solvent: CC#N
Product: CCOC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [I-]
Temperature: 60 °C
Reaction time: 14 h
Yield: 56.7 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone(1.31 g) and ethyl iodomethyl carbonate (1.25 g) was added acetonitrile (20 ml) and the mixture was stirred for 14 hours at 60° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was submitted to silica gel flush chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=4/1). The fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-ethoxycarbonyloxymethyl-1H-1,2,4-triazolium iodide (Compound 17, 1.1 g) as a pale yellow powder.
Reaction SMILES: Cl.[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:30])[CH3:29].C1C[O:35][CH2:34][CH2:33]1>>[C:28]([O:26][CH2:25][C:22]([NH:21][CH2:20][C:9]1[CH:8]=[C:7]2[C:16](=[C:15]3[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:17]=[CH:18][C:19]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=1)([CH3:27])[CH2:23][O:24][C:34](=[O:35])[CH3:33])(=[O:30])[CH3:29]
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)OCC(C)(COC(C)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Yield: 65.2 %

Procedure:
A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride (1B, 5.0 g, 13.1 mmol) and acetylchloride (Aldrich, 5.0 mL, 70.3 mmol) was refluxed in dry THF (200 mL) under N2 for 12 h. The reaction mixture was poured into a satd. NaHCO3 solution (500 mL) and extracted with EtOAc (3×500 mL). The EtOAc layes were combined, dried (K2CO3) and filtered to give a slightly yellow liquid. The solvent was removed to give an off-white solid. This was recrystallized 3× from PhCH3 /hexane (1:1). After filtration and drying, 3.67 g (65.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol diacetate was obtained mp 136°-137.5°, (C, H, N).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].CO>[CH2:1]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC(Cc2ccccc2)CC1
Agent: [Ni]
Solvent: CO
Product: O[C@H]1CC[C@@H](Cc2ccccc2)CC1
Product: O[C@H]1CC[C@H](Cc2ccccc2)CC1

Procedure:
Besides, 30 g of the above-obtained 4-benzyl-2-cyclohexen-1-one were hydrogenated at room temperature for 6 hours using 5 g of Raney nickel in methanol under hydrogen pressure (3 kg/cm2) until the absorption of hydrogen was stopped. After an organic layer was collected by decantation and concentrated, the residue was purified by column chromatography, thereby obtaining 13 g of cis-4-benzylcyclo-hexanol and 14 g of trans-4-benzylcyclohexanol (yield: 90% in total).