Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C@H:19]([NH:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:30]([O:32][CH3:33])=[O:31])[CH2:7][C@@H:6]1[OH:34])(=[O:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C@H:19]([NH:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:30]([O:32][CH3:33])=[O:31])[CH2:7][C@@H:6]1[O:34][C:46](=[O:48])[CH3:47])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 2β-acetoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (3.069 g) in chloroform (33 ml) containing dry PTSA (2.64 g) was stirred for 20 min then treated with acetic anhydride (6.5 ml) and the mixture left for 5 h. The mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, washed with aqueous ammonia solution (2×) and water (1×), dried and evaporated to give an oil (2.867 g). This was purified by preparative t.l.c. in chloroform/methanol (9:1) to give the title compound [α]D +48.6°, νmax 1730 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH:23]=[O:24].O>C1COCC1.CCOC(C)=O>[CH2:10]([O:9][CH:8]([O:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([CH:23]([OH:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH3:20])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CC(C)(C)CC=O
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: -78 °C
Yield: 57.5 %

Procedure:
Dissolve 1-bromo-4-(diethoxymethyl)-benzene (6.1 g, 23.55 mmol) in anhydrous THF (150 mL) and cool the solution to −78° C. Add n-butyllithium (11.3 mL, 28.26 mmol, 2.5M solution in hexane) and stir the mixture for 30 min. Add 3,3-dimethylbutyraldehyde (4.7 mL, 35.33 mmol) and stir the mixture for 1 h. Add water and EtOAc. Warm the solution to room temperature and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts with Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (93:7) to give the desired intermediate as a colorless oil (3.8 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH:13]=[CH:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.F[B-](F)(F)F.[C:26]1([N+]#N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NC1C=CC=CC=1.O.O.O.C([O-])(=O)C.[Na+]>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C=CC(c2cc(F)ccc2Cl)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Reaction time: 16 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (20 mg, 022 mmol, 0.020 equiv) was added to a deoxygenated mixture of tert-butyl 3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (1-2, 330 mg, 1.11 mmol, 1 equiv), benzenediazonium tetrafluoroborate (1-3, prepared from aniline by the method described for 1-1, 213 mg, 1.11 mmol, 1.00 equiv), and sodium acetate trihydrate (459 mg, 3.32 mmol, 3.00 equiv) in acetonitrile (20 mL) at 23° C. The reaction mixture was stirred for 16 hours, then partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (2×70 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% hexanes in EtOAc) to provide tert-butyl 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (14) as a dark orange oil. LRMS m/z (M+H—CH3) 359.0 found, 359.1 required.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[CH3:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 68.1 %

Procedure:
To a suspension of potassium carbonate (9.73 g, 70.0 mmol, 1.10 equiv) and 2-amino-5-chloro-N-(diisopropyl-λ4-sulfanylidene)-3-methyl-benzamide (18.7 g, 62.4 mmol, 1.00 equiv) in toluene (80 mL) a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (20.1 g, 64.1 mmol, 1.03 equiv.) in toluene (40 mL) was added at 60° C. After 35 minutes at 60° C., the reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (50 mL), 0.1 M HCl (50 mL), dried over Na2SO4 and concentrated. The crude product was recrystallized from methyl tert-butyl ether to yield the title compound (24.4 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]=C)[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+]>ClCCl.O.C(OCC)(=O)C.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]=[O:23])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(C=O)c1
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of 5-vinylthiophene-3-sulfonic acid[2-(4-fluorophenyl)ethyl]-methyl-amide (328 mg) in dichloromethane (2 mL) was added sodium meta periodate (863 mg) and ruthenium trichloride monohydrate (5 mg) at room temperature. After stirring for 2 hours, this solution was diluted with water and ethyl acetate, and Celite filtration was carried out. The organic layer was separated, after drying with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation were purified by silica gel column chromatography (hexane/ethyl acetate) and the title compound (138 mg) was obtained as a yellow oily substance.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[Cl:33])[NH:29][CH:28]=[C:27]2[C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1COCC1.C1(C)C=CC=CC=1>[Cl:33][C:32]1[CH:31]=[C:30]2[C:26]([C:27]([C:34]([O:36][CH3:37])=[O:35])=[CH:28][NH:29]2)=[CH:25][C:24]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])=[CH:13][CH:14]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)OB(c2ccc(-c3ccccc3O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 115 °C
Yield: 73 %

Procedure:
A glass tube was charged with 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-ol (86.2 mg, 0.29 mmol), methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (84 mg, 0.29 mmol), toluene (1.2 mL), THF (0.6 mL), EtOH (0.6 mL), and 2.0M potassium carbonate solution (0.6 mL, 1.2 mmol). Nitrogen was then bubbled through the mixture for 5 minutes then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg, 0.032 mmol) was added. The tube was sealed and heated to 115° C. for 2 hours. The reaction was cooled to room temperature, opened, and neutralized with 1.0M sodium hydrogensulfate then diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (x2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash column chromatography (20% to 100% ethyl acetate/heptane) was then used to to provide the title compound as a white solid (80 mg, 73% yield). MS (ES−) 376.1 (M−H). 1H NMR (500 MHz, DMSO-d6) δ 12.09 (br. s., 1H), 9.60 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 7.65 (d, 2H), 7.47 (d, 2H), 7.34 (dd, 1H), 7.19 (dt, 1H), 6.98 (d, 1H), 6.91 (dt, 1H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][C:25]([NH:27][NH2:28])=[O:26].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:28][NH:27][C:25](=[O:26])[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CC(=O)NN
Solvent: CO
Solvent: O
Product: CC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 109 mg, 0.29 mmol) was dissolved in MeOH (5 mL) to which was added acethydrazine (85 mg, 1.1 mmol). The resulting solution was heated on a 45 C oil bath for 16 h, then cooled to room temperature and poured into 15 mL of water. The resulting suspension was cooled to 4C, then filtered and the solids rinsed with cold water (25 mL). The solids were dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white crystalline solid, which was recrystallized from acetone/MeOH to yield 70 mg (56%) of 4.32 as a white microcrystalline solid which is an inseparable mixture of isomers in a ratio of 60:40: mp 270-271 C; Rf 0.2 (10% MeOH/CHCI3); 1H-NMR (500 MHz, DMSO-d6): (major isomer) δ 11.25 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70(s, 2H), 2.24 (s, 3H); (minor isomer) δ 11.41 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70(s, 2H), 1.95 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): (major isomer) δ 171.39, 135.98, 133.15, 129.73, 126.01, 124.96, 123.86, 121.69, 115.41, 108.31, 88.78, 86.09, 71.41, 69.66, 61.10, 20.36; (minor isomer) δ 165.24, 138.70, 133.12, 129.82, 126.06, 124.96, 123.99, 122.17, 115.33, 108.51, 88.78, 86.09, 71.41, 69.66, 61.10, 21.67. HRMS (ES) m/z calcd. for C16H16Cl3N3O5·Na 458.0053, found 458.0043. Anal calcd for C16H16Cl3N3O5: C, 44.01; H, 3.69; N, 9.62. Found: C, 43.76; H, 3.75; N, 9.67.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:26][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1
Yield: 88.7 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.99 g, 7.08 mmol), 4-methoxybenzyl chloride (1.30 mL, 9.6 mmol), potassium iodide (0.17 g, 0.99 mmol) and cesium carbonate (4.68 g, 14.4 mmol) in 2-butanone (45 mL) was stirred at reflux under nitrogen for 16 h. The reaction was cooled, diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography with hexanes/ethyl acetate (4:1) to afford 1′-(4-methoxybenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.52 g, 89%) as a colorless solid: mp 147-148° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=8.7 Hz, 2H), 7.21 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.16 (dd, J=7.5, 0.6 Hz, 1H), 7.02 (ddd, J=7.7, 7.4, 1.0 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.13 (s, 1H), 5.88 (d, J=1.2 Hz, 1H), 5.87 (d, J=1.2 Hz, 1H), 5.02 (d, J=15.3 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.76 (d, J=15.3 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 3.79 (s, 3H); MS (ES+) m/z 402.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 24.4 g (200 mmol) of 4-hydroxybenzaldehyde in 100 ml of dimethylformamide is treated with 97.75 g (300 mmol) of caesium carbonate and stirred at 90° C. for 1 h. A solution of 66.93 g (300 mmol) of tert-butyl 2-bromisobutyrate in 100 ml of dimethylformamide is then added dropwise, and the mixture is stirred at 90° C. overnight. The dimethylformamide is distilled off under reduced pressure and the residue is then taken up in ethyl acetate, washed 2× with water, 2× with 1 N aqueous sodium hydroxide solution and 1× with sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. This gives 16.6 g (31%) of tert-butyl 2-(4-formylphenoxy)-2-methylpropionate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[C:29]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(OCOCC)C>[C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C:13](=[CH2:29])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCOCC
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Yield: 86.3 %

Procedure:
Analogously to Example 35, 1.0 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione is stirred with a suspension of 1.0 g of sodium acetate in 30 ml of chloroform, 30 ml of formaldehyde diethylacetal, and 3.8 ml of phosphorus oxychloride for 7 hours at 65° C., and then worked up. The crude product is purified on 220 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone), thus obtaining 890 mg of 21-acetoxy-17α-hydroxy-6-methylene-4-pregnene-3,20-dione, mp 194.5°-196° C.
Reaction SMILES: [C:1]([C:6]1[CH:19]=[C:18]2[C:9]([S:10][C:11]3[CH:12]=[CH:13][C:14]([C:20](=[O:24])[CH:21]=[CH:22][CH3:23])=[CH:15][C:16]=3[CH2:17]2)=[CH:8][CH:7]=1)(=[O:5])[CH:2]=[CH:3][CH3:4].C1C2CC3C(=CC=CC=3)SC=2C=CC=1.C(Cl)(=[O:43])/C=C/C.[Cl-].[Al+3].[Cl-].[Cl-].BrBr>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:6]1[CH:7]=[CH:8][C:9]2[S:10][C:11]3[C:16](=[CH:15][C:14]([C:20](=[O:24])[CH:21]=[CH:22][CH3:23])=[CH:13][CH:12]=3)[C:17](=[O:43])[C:18]=2[CH:19]=1)(=[O:5])[CH:2]=[CH:3][CH3:4]
Reactant: C/C=C/C(=O)Cl
Reactant: CC=CC(=O)c1ccc2c(c1)Cc1cc(C(=O)C=CC)ccc1S2
Agent: BrBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Al+3]
Solvent: ClCCl
Product: CC=CC(=O)c1ccc2sc3ccc(C(=O)C=CC)cc3c(=O)c2c1
Temperature: 25 °C

Procedure:
To 1-[7-(but-2-enoyl)-9H-thioxanthen-2-yl]-but-2-en-1-one, which is synthesized by thioxanthene and crotonoyl chloride in the presence of aluminium chloride as described in WO2005-080337A1, dissolved in dichloromethane are added bromine (2.0 equiv.) and aqueous tetra-n-butylammonium bromide (0.5 equiv.). Stirring the reaction mixture at room temperature and succeeding extractive work-up and purification give 2,7-bis-(but-2-enoyl)-thioxanthen-9-one, which is transformed into the compound of example 9 as described in example 4.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10]N1C2C=CC=CC=2N=N1.[CH3:20][C:21]1[C:29]([CH3:30])=[CH:28][C:24]2[NH:25][N:26]=[N:27][C:23]=2[CH:22]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:27]1[C:23]2[CH:22]=[C:21]([CH3:20])[C:29]([CH3:30])=[CH:28][C:24]=2[N:25]=[N:26]1
Reactant: Cc1cc2nn[nH]c2cc1C
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Product: Cc1cc2nnn(Cc3nc4ccccc4[nH]3)c2cc1C

Procedure:
The same procedure described in the preparation of 1-(1H-benzimidazol-2-ylmethyl)-1H-benzotriazole was used, except that 5,6-dimethylbenzotriazole was used instead of benzotriazole. 1-(1H-benzimidazol-2-ylmethyl)-5,6-dimethyl-1H-benzotriazole was isolated as an intermediate:
Reaction SMILES: CC(OCC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O)=O.[OH-].[Na+].[S:21]([CH:25]([C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)[C:26](O)=[O:27])([OH:24])(=[O:23])=[O:22].S(Cl)([Cl:36])=O>CN(C)C=O.CCOCC.O>[S:21]([CH:25]([C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)[C:26]([Cl:36])=[O:27])([OH:24])(=[O:23])=[O:22]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(c1ccsc1)S(=O)(=O)O
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)C(c1ccsc1)S(=O)(=O)O

Procedure:
With cooling and stirring, 1.84 g. (0.0068 mole) of 7-ACA was suspended in 25 ml. of water and to the suspension was added dropwise 6.8 ml. of a 1N-aqueous solution of sodium hydroxide to dissolve 7-ACA. On the other hand, to a suspension of 1.5 g. (0.0068 mole) of α-sulfo-3-thienylacetic acid in 10 ml. of ether were added 5.5 ml. of thionyl chloride dropwise and 3 drops of dimethylformamide, then the resulting solution was stirred for 5 hours at room temperature. The reaction solution was subjected to the evaporation to dryness under reduced pressure to give α-sulfo-3-thienylacetyl chloride as a residue. The residue was dissolved in 10 ml. of ethyl acetate and the solution was added dropwise to the 7-ACA solution mentioned above, followed by stirring for 30 minutes. The aqueous layer was separated from the reaction solution and adjusted it pH to 6.5 by adding a saturated aqueous solution of NaHCO3. The resulting solution was freeze-dried to obtain 3.6 g. of a crude product. The product was purified according to column chromatography using Amberlite XAD-2 to obtain 1.6 g. (42%) of 7-(α-sulfo-3'-thienylacetamido)cephalosporanic acid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][CH2:42]Br>CN(C=O)C.O>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][C:18]([CH3:19])=[C:9]([O:8][CH:5]4[CH2:4][CH2:3][CH:2]([N:1]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[CH2:7][CH2:6]4)[CH:10]=3)[C:15]2=[O:20])=[CH:27][CH:26]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](N)CC4)c(C)cc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(OC4CCC(N5CCCC5)CC4)c(C)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.8 %

Procedure:
To a solution of 0.4 g (1 mmol) of 6-(cis-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one (26, step b), 0.31 g (2 mmol) sodium iodide and 0.35 g (2.5 mmol) potassium carbonate in 40 ml DMF were added dropwise 0.24 g (1.1 mmol) 1,4-dibromobutane. After stirring at room temperature for 2 days the mixture was diluted with water and extracted with ethyl acetate. After drying and evaporation the residue was purified by chromatography to yield 182 mg of 2-(4-methoxy-benzyl)-7-methyl-6-(4-pyrrolidin-1-yl-cyclohexyloxy)-2H-isoquinolin-1-one.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][C:5]=1[O:12][CH3:13])([O-:3])=[O:2].C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:8][Br:15]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a 250 mL round bottomed flask containing 10 g (54.6 mmol) of 4-nitro-3-methoxybenzyl alcohol in 30 mL THF was added, 36 g (109 mmol, 2 eq ) of carbon tetrabromide followed by 15.9 g (60 mmol, 1.1 eq.) triphenylphosphine at 0° C. The mixture was stirred at 0° C. for 3 hours. Upon removal of the solvent, the residue was purified by flash chromatography, eluting with 10:90 EtOAc-Hexane, to give 11 g (82%) of the product as a yellow solid. 1H NMR (400 MHz, CDCl3): δ7.86 (s, 1H), 7.84 (m, 1H), 7.12 (s, 1H), 7.07 (m, 1H), 4.47 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20]COC)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C(#N)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:41]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[O:42])=[CH:3][CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Yield: 68 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyethoxyquinoline (150 mg) was added to 5.0 ml of toluene and 2.5 ml of acetonitrile, and the mixture was heated to reflux. After then adding 4-fluorophenyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 150 mg of the title compound as light brown crystals (68% yield).