Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][C:16]=1[O:23][CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32].[C:33]([O:38][CH2:39][CH3:40])(=[O:37])[C:34]#[C:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:39]([O:38][C:33]([C:34]1[C:35]([CH3:36])=[N:14][N:15]2[C:16]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][C:20]=12)=[O:37])[CH3:40]
Reactant: CCc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A solution of 1.88 g (1.54 mmol, 38% purity) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-ethylpyridinium 2,4,6-trimethylbenzenesulphonate (Example 166A) in 12 ml of N,N-Dimethylformamide was admixed with 0.35 g (3.08 mmol) of ethyl 2-butynoate (CAS: 4341-76-8) and 0.64 g (4.61 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated and the residue was partitioned between water and ethyl acetate. The organic phase was removed, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane/ethyl acetate, gradient 0% to 10%), which gave 0.29 g (35% yield, 70% purity) of product.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:10]=3[N:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]OC(OC)N(C)C>>[CH:1]1([N:7]2[CH:29]=[CH:17][S:14](=[O:15])(=[O:16])[C:13]3[CH:12]=[N:11][C:10]4[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:9]=4[C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(OC)N(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(S(C)(=O)=O)cnc21
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)S(=O)(=O)C=CN3C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Cyclohexyl-5-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (6.1 mg, 0.014 mmol) in N,N-dimethylformamide dimethyl acetal (2.5 mL) was stirred at 170° C. for 3 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (1 mL) and stirred with 1 M hydrochloric acid (1 mL) at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting pale yellow oil (8.5 mg) containing the title compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl.[NH:11]([C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CCC>[NH:11]([C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CCCCO
Product: NCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
4-Aminobenzylamine (122 mg, 1.0 mmol) and ethereal hydrogen chloride (1.0M; 1.0 ml, 1.0 mmol) were added to a solution of 4-anilino-5-bromo-2-chloropyrimidine (256 mg, 0.9 mmol) in n-butanol (4 ml) and the mixture was heated at 100° C. for 16 hours. The insoluble solid was filtered off and dissolved in methanol (5 ml). Silica (2 g) was added and volatile material was removed by evaporation. The residue was purified by bond elute chromatography, eluting with 0-4% 2.0M methanolic ammonia solution in DCM, to give the product (163 mg, 49%): LCMS (MH+): 370, 372; HPLC (RT, System A): 2.04.
Reaction SMILES: Cl.[I:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][C@H:19]([C:26](O)=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([O:15][C:16]([NH:18][C@H:19]([C:26]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([I:2])=[CH:4][CH:5]=1)=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:13])([CH3:11])[CH3:14]
Reactant: NCc1ccc(I)cc1
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of 4-iodobenzylamine hydrochloride (2.965 g, 11.0 mmol), Boc-Glu(OMe)-OH.DCHA (4.426 g, 10.0 mmol), EDCI (2.301 g, 10.0 mmol), HOBt (1.351 g, 10.0 mmol) in DCM (100 mL) containing DIPEA (5.23 mL) was stirred at room temperature under nitrogen for 20 h. The reaction mixture was diluted with DCM, washed with 1N HCl, sat. NaHCO3 solution, and brine. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting with hexane/ethyl acetate (3:1) to give (S)-methyl 4-(tert-butoxycarbonylamino)-5-(4-iodobenzylamino)-5-oxopentanoate (3.653 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 5.24 (brs, 1H), 4.39 (t, J=5.4 Hz, 2H), 4.15 (m, 1H), 3.70 (s, 3H), 2.57-2.37 (m, 2H), 2.20-2.11 (m, 1H), 1.99-1.90 (m, 1H), 1.44 (s, 9H); MS (ESI), 499 (M+Na)+.
Reaction SMILES: [C:1]1([NH:12][C:13](=[O:15])[CH3:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O-:16]S([O-])(=O)=O.[Mg+2].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[O:16]=[C:7]1[C:6]2[C:1]([NH:12][C:13](=[O:15])[CH3:14])=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)Nc1cccc2c1CCCCC2
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product from Example 132B (1 g, 4.92 mmol) in acetone (150 ml) was added 15% MgSO4 (15 mL). To the solution was added KMnO4 (1.944 g, 12.30 mmol) and stirred at ambient temperature for 2 hours. Then heated at slightly reflux for 40 hours. The mixture was filtered through diatomaceous earth, and washed with CH2Cl2. The organic was separated, diluted with CH2Cl2, washed with saturated Na2S2O3, dried and concentrated. The residue was purified by chromatography on silica gel column eluting with 20% EtOAc/hexanes to provide the title product. 1H NMR (DMSO-d6) δ 1.68-1.74 (m, 4H), 1.94 (s, 3H), 2.55-2.59 (m, 2H), 2.70 (t, J=6.04 Hz, 2H), 6.98 (d, J=7.34 Hz, 1H), 7.22 (d, J=7.34 Hz, 1H), 7.32 (t, J=7.70 Hz, 1H), 9.90 (s, 1H). MS (M+H)+ m/z 218.
Reaction SMILES: [CH3:1][C:2]([C:17]#[N:18])([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:12][C:11]([CH3:13])([CH2:14][NH2:15])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([CH3:1])([CH3:16])[CH2:17][NH2:18])=[CH:5][CH:6]=1
Reactant: CC(C)(C#N)Cc1ccc(CC(C)(C)C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(CN)Cc1ccc(CC(C)(C)CN)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
In a 2-liter flask, equipped with a magnetic stirrer, a reflux condenser capped with a nigrogen bubbler, and an additional funnel, was placed 7.50 g (0.0312 M) of 1,4-bis(2-methyl-2-cyanopropyl)benzene and 300 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 107 ml of a 24.1% solution (0.150 M) of diisobutylaluminum hydride in toluene was added from the addition funnel in 28 min. The mixture was then refluxed for 16 hrs. After the mixture had been cooled in an ice-water bath, a solution of 6 ml of water in 30 ml of methanol was added dropwise with stirring. This was followed by the dropwise addition of a solution of 30 ml of water in 60 ml of methanol. The mixture was stirred vigorously for 1 hr while being cooled in the ice-water bath, and then for an additional hour at room temperature. The mixture was filtered under nitrogen, the solid was washed thoroughly on the filter with toluene, and the combined filtrate and rinsings were distilled on the water pump. The resulting residue crystallized on cooling to room temperature. Further drying on the oil pump gave 5.28 g (68%) of crude 1,4-bis(2,2-dimethyl-3-aminopropyl)benzene melting at 53°-56° to a cloudy melt. Distillation of this material through a small Vigreux still gave the product as a colorless liquid boiling at 131°-132°/0.60 mm. The solidified material melted to a clear melt at 53.5-54.75°.
Reaction SMILES: [Br-].O=[C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[N+](C)C.Br.C(C1C2C(=CC=CC=2)CCC=1N(C)C)C(C1C=CC=CC=1)=O.[NH2:47][C:48]1[CH:56]=[C:52]([C:53]([OH:55])=[O:54])[C:51]([OH:57])=[CH:50][CH:49]=1>C(O)(=O)C>[C:53]([C:52]1[CH:56]=[C:48]([N:47]2[C:6]3[CH2:7][CH2:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[CH:4]=[C:3]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:49]=[CH:50][C:51]=1[OH:57])([OH:55])=[O:54]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: C[N+](C)=C1CCc2ccccc2C1CC(=O)c1ccccc1
Agent: Br
Agent: CN(C)C1=C(CC(=O)c2ccccc2)c2ccccc2CC1
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Temperature: 75 °C
Reaction time: 4.5 h

Procedure:
A mixture of 10.0 g of tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-methylmethanaminium bromide in equilibrium with 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide and 4.1 g of 5-aminosalicylic acid in 50 ml of acetic acid is vigorously stirred at 75° C. for 4.5 hours. The reaction mixture is then cooled to 20° C., filtered and the precipitate collected, washed successively with one 20 ml portion of acetic acid and five 20 ml portions of hexane and then dried for 20 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[Cr](O)(O)(=O)=[O:15].C(O)(C)C>CC(C)=O>[CH:1](/[CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([OH:15])=[O:13])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/C1CCC(C=O)CC1
Reactant: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCC/C=C/C1CCC(C(=O)O)CC1
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A solution of 1.6 g of 4-(trans-1-pentenyl)cyclohexanecarboxaldehyde in 120 ml of acetone was cooled to -10° C., treated dropwise with 8N chromic acid (about 10 ml) until the colour of the mixture remained brown-orange and stirred for 1 hour. Excess chromic acid was reduced by the addition of isopropanol. The green solution was subsequently partitioned three times in water/methylene chloride. The organic extracts were washed twice with water and the wash-water was back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. The pale brown crystalline residue (2.01 g) was dissolved partially in 20 ml of petroleum ether. Undissolved residue was filtered off and the filtrate was evaporated. Recrystallization of the resulting residue from 60 ml of petroleum ether at -78° C. gave 866 mg (49.5%) of 4-(trans-1-pentenyl)cyclohexanecarboxylic acid as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][CH:24]=[C:25]4[C:28]([O:30]CC)=[O:29])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7].[Li+].[OH-]>CCO.C1COCC1>[Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][CH:24]=[C:25]4[C:28]([OH:30])=[O:29])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(C(=O)OCC)c4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(C(=O)O)c4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of ethyl 7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-1-naphthoate (Example 9, 9.4 mg, 0.012 mmol) in EtOH (0.5 mL) and THF (0.5 mL) was added 2N LiOH (58 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 30 min and then at 40° C. for 2 h. The reaction mixture was quenched with 6N HCl, and then extracted with CHCl3 (4×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (9.0 mg, 94%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 9.90 (s, 1H), 8.40 (d, J=7.3 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.17 (d, J=1.1 Hz, 1H), 8.08 (dd, J=8.4, 1.8 Hz, 1H), 7.98 (t, J=2.2 Hz, 1H), 7.79-7.74 (m, 1H), 7.71-7.64 (m, 1H), 7.24-7.04 (m, 4.5H), 6.90-6.88 (m, 0.5H), 4.53 (br s, 2H), 3.58-3.39 (m, 4H), 3.13 (d, J=1.3 Hz, 1H), 3.05-2.94 (m, 1H), 2.82 (br s, 1H), 2.79-2.66 (m, 1H), 2.33 (s, 2H), 2.28 (s, 1H), 1.49-1.20 (m, 6H), 1.13-0.98 (m, 2H), 0.96-0.84 (m, 3H), 0.80-0.64 (m, 3H); MS(ESI−) m/z 782.5 (M−H)−.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[O:29]=[C:28]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][N:9]2[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc2c1cnn2CCN1CCCCC1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(2-piperidin-1-yl-ethyl)-1H-indazol-4-ylamine (mmol), tert-butoxycarbonylamino-acetic acid (mmol), ethyldimethylpropylcarbodiimide hydrochloride (mmol), N-hydroxybenzotriazole (mmol) and N-methyl morpholine (mmol) were dissolved in 15 mL of DMF and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.34 (m, J=4.41 Hz, 6 H), 1.41 (s, 9 H), 2.37 (m, 4 H), 2.69 (t, J=6.78 Hz, 2 H), 3.86 (d, J=6.10 Hz, 2 H), 4.46 (t, J=6.78 Hz, 2 H), 7.08 (s, 1 H), 7.32 (m, 2 H), 7.64 (m, 1 H), 8.23 (s, 1 H), 9.96 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][S:29]([C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=3)(=[O:31])=[O:30])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1sc(Cc2ccccc2)c(-c2ccc(-c3ccc(O)cc3)cc2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1sc(Cc2ccccc2)c(-c2ccc(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)cc3)cc2)c1C

Procedure:
The title compound was prepared from 4′-(2-benzyl-4,5-dimethyl-thiophen-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 173-175° C.; MS m/e 570 (M−H)+;
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:46]N(C=O)C.[H-].[Na+].IC>O>[CH3:46][N:16]1[C:14]2=[N:15][C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=[C:13]2[C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:17]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3n2)c(OC)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2nc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.75 h
Yield: 84 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (Intermediate J) (77.2 mg, 0.118 mmol) and DMF (1 mL) to give a clear solution. Sodium hydride (60% in mineral oil) (7.06 mg, 0.177 mmol) was added in one portion to give a bright yellow mixture. The mixture was stirred for 45 min, then iodomethane (14.72 μl, 0.235 mmol) was added. After stirring for an additional 1 h, the mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM (0.9 mL) and TFA (0.18 mL), and the resulting mixture was stirred for 1.5 h. The mixture was diluted with MeOH (5 mL), then filtered through Celite® (diatomaceous earth) with the aid of methanol. The filtrate was concentrated, and the crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to afford 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (51.42 mg, 0.099 mmol, 84% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.48 (s, 1 H), 7.97-7.85 (m, 3 H), 7.83-7.78 (m, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.53 (s, 1 H), 7.38 (d, J=1.9 Hz, 1 H), 6.35 (d, J=1.9 Hz, 1 H), 3.75 (s, 3 H), 3.28 (s, 3 H). m/z (ESI) 520.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CC(C)=O>[CH:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11])([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C#N)ccc1OC(C)C
Temperature: 25 °C

Procedure:
25 g 4-Hydroxy-3-methoxy-benzonitrile, 27.8 g potassium carbonate and 33.5 mL isopropyl iodide were placed in 250 mL acetone and heated to reflux where they were maintained for 22 h. After this time the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude product was partitioned between ethyl acetate and water and the aqueous phase was separated and extracted with additional ethyl acetate. The combined organic fractions were dried, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(OC)C=CC=CC=1.C([NH:35][C:36]1[S:37][CH:38]=[C:39](/[C:41](=[N:69]/[O:70][CH2:71][C:72]([O:74]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:73])/[C:42]([NH:44][C@@H:45]2[C:67](=[O:68])[N:47]3[C:48]([C:55]([O:57]CC4C=CC(OC)=CC=4)=[S:56])=[C:49]([CH2:52][CH2:53][OH:54])[CH2:50][S:51][C@H:46]23)=[O:43])[N:40]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:35][C:36]1[S:37][CH:38]=[C:39](/[C:41](=[N:69]/[O:70][CH2:71][C:72]([OH:74])=[O:73])/[C:42]([NH:44][C@@H:45]2[C:67](=[O:68])[N:47]3[C:48]([C:55]([OH:57])=[S:56])=[C:49]([CH2:52][CH2:53][OH:54])[CH2:50][S:51][C@H:46]23)=[O:43])[N:40]=1
Reactant: COc1ccc(COC(=S)C2=C(CCO)CS[C@@H]3[C@H](NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CCO)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
(d-2) To a mixture of trifluoroacetic acid (4 ml) and anisole (0.8 ml) was added under ice-cooling 360 mg (0.349 mM) of p-methoxybenzyl 7β-{α-(2-tritylaminothiazole-4-yl)-α-[(Z)-benzhydryloxycarbonylmethoxyimino]acetamido}-3-(2-hydroxy)ethylthio-3-cephem-4-carboxylate, and the mixture was stirred for one hour. The reaction mixture was added slowly dropwise to a mixture of diethyl ether and petroleum ether (1:2, 50 ml), thecrystals which formed were collected by filtration to give 188 mg of 7β-{α-(2-aminothiazole-4-yl)-α-[(Z)-carboxymethoxyimino]acetamido}-3-(2-hydroxy)ethylthio-3-cephem-4-carboxylic acid trifluoroacetate. The crystals and 77 mg (0.917 mM) of sodium bicarbonate were dissolved in 5 ml of water, and the solution was applied to a Sephadex HL-20 column chromatography (eluent: water) to give 164 mg of 7β-{α-(2-aminothiazole-4-yl)-α-[(Z)-carboxymethoxyimino]acetamido}-3-2-hydroxy)ethylthio-3-cephem-4-carboxylic acid sodium salt.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=[C:6]1[C:13]([O:15][CH3:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl>C(Cl)Cl.O>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:11]2[S:10][C:9]3[S:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=3[CH:12]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc2ccsc2s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2cc(C(=O)c3ccc(F)cc3)sc2s1
Temperature: 20 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
Anhydrous aluminium chloride (136 g) is added in small portions, over a period of 30 minutes, to a mixture of methyl thieno[2,3-b]thiophene-2-carboxylate (40.3 g) and 4-fluorobenzoyl chloride (32.3 g) in methylene chloride (1000 cc) at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and then hydrolysed, with care, by the addition over a period of 30 minutes of 0.5 N aqueous hydrochloric acid (500 cc), the internal temperature being maintained at about 20° C. by external cooling with a bath of cold water. The methylene chloride solution is diluted with methylene chloride (5000 cc), decanted off, washed three times with distilled water (total 3000 cc), three times with a saturated aqueous sodium bicarbonate solution (total 1000 cc), and again three times with distilled water (total 3000 cc), then dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (1 g), filtered and evaporated. The residue is triturated in diethyl ether (250 cc), the resulting crystals are filtered off, washed three times with diethyl ether (total 375 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. Methyl 5-(4-fluorobenzoyl)-thieno[2,3-b]thiophene-2-carboxylate (51.8 g), melting at 220° C., is thus obtained.