Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][C:31](OC)=O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:30][C:31]1[NH:19][C:17](=[O:18])[C:3]2[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nc21
Yield: 47.5 %

Procedure:
10 mg (0.036 mmol) of 5-amino-3-methyl-(3-nonyl)-1H-pyrazole-4-carboxamide and 57 mg (0.274 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 7.3 mg (48%) of a solid, Rf=0.57 (dichloromethane/methanol=15:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](C=O)[C:5]([Cl:10])=[CH:4][N:3]=1.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: O=Cc1cc(Br)ncc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1cc(Br)ncc1Cl
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g, 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and this mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (51.7 g, 97%). LC-MS: tR=0.92 min; ES+: 309.06.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].II.[F:11]F.C(=O)(O)[O-].[Na+]>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:11][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=1
Reactant: CCc1ccncc1
Reactant: FF
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Product: CCc1ccnc(F)c1

Procedure:
A solution containing 4-ethylpyridine (12.8 g, 120 mmol) and iodine (30.5 g, 120 mmol) in CF2ClCFCl2 (150 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (165 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 40 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (300 ml), neutralised with solid sodium bicarbonate and extracted with dichloromethane. The organic extracts were dried and evaporated to a yellow oil (9.54 g) which contained ethlpyridine (78 % conversion), 2-fluoropyridine and other minor products by GC/MS. The oil redissolved in dichloromethane and washed with 2N HCI solution, dried (MgSO4) and evaporated to a clear oil to give 2-fluoro-4-ethylpyridine in >95% purity (6.3 g, 54% based on 78% conversion); δH (200 MHz, CDCl3, Me4Si) 1.26 ppm (3H, t, J 7.6, CH3), 2.69 (2H, q, J 7.6, CH2), 6.75 (1H, s, H-3), 7.02 (1H, d m, J 5.1, H-5), 8.09 (1H, d, J 5.1, H-6); δC (50 MHz, CDCl3, Me4Si) 14.1 ppm (s, CH3), 28.2 (d, 4JC-F 2.7, CH2), 108.5 (d, 2JC-F 36.5, C-3), 121.3 (d, 4JC-F 3.9, C-5), 147.3 (d, 3JC-F 15.2, C-6), 159.3 (d, 3JC-F 7.8, C-4), 164.2 (d, 1JC-F 236.3, C-2); δF (235 MHz, CDCl3, CFC13) 69.9 ppm (s); m/z (E1+125 (M+, 100%), 110 (47), 97 (15), 83 (13).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][C:20]4[CH:35]=[CH:34][C:23]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:22][CH:21]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:42]>>[ClH:1].[ClH:42].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:24][NH:25][CH3:26])=[CH:34][CH:35]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the compound (0.18 g) obtained in Example 3 and 4N hydrogen chloride-ethyl acetate solution was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (0.17 g) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=O)=[CH:12]1)(=[O:10])=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:12]1)(=[O:10])=[O:9]
Reactant: CN1CCN(C(=O)c2cn(S(=O)(=O)c3ccccc3Br)c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2cn(S(=O)(=O)c3ccccc3Br)c3ccccc23)CC1
Temperature: 0 °C

Procedure:
(1-(2-Bromobenzenesulfonyl)-1H-indol-3-yl)-(4-methylpiperazin-1-yl)methanone (0.93 g, 0.002 moles) in THF (10 mL) was treated with cooled and stirred suspension of LAH (0.04 g, 0.001 moles) in THF (10 mL) slowly over the period of 2 to 5 hours, the reaction mixture was heated to reflux for 2-4 hours. After the completion of reaction, the reaction mixture was poured on to the ice and the compound was extracted with ethyl acetate. The residue obtained was purified by flash chromatography (silica gel, EtOAc/Hexanes, 2/8) to afford the compound, which was identified by IR, NMR and mass spectral analyses as the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[OH:12])[N:7]([CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([O:27][CH3:28])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:12][CH2:23][CH2:22][CH2:21][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Yield: 31.6 %

Procedure:
A solution of methyl 4-chloro-2-[(2,4-dichlorophenyl)(hydroxy)methyl]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 215, 703 mg, 1.58 mmol) and cyanomethylenetributylphosphorane (763 mg, 3.16 mmol) in toluene (32 mL) was stirred for 12 h at 110° C. The reaction mixture was concentrated in vacuo and purified by column chromatography on NH silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to afford the desired product as pale yellow oil (212 mg, 0.499 mmol, 32%).
Reaction SMILES: [NH2:1][CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([NH:5][CH:6]1[C:24](=[O:25])[N:8]2[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH:13]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4].[O:32]=[C:33]1[N:37]([C:38](Cl)=[O:39])[C:36]2[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=2[NH:34]1.Cl>C(#N)C>[O:32]=[C:33]1[N:37]([C:38]([NH:1][CH:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]([NH:5][CH:6]2[C:24](=[O:25])[N:8]3[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH:13]([S:15][C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH3:14])[CH2:11][S:12][C@H:7]23)=[O:4])=[O:39])[C:36]2[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=2[NH:34]1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Reactant: O=C(Cl)n1c(=O)[nH]c2ccccc21
Agent: Cl
Solvent: CC#N
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)[nH]c4ccccc43)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To 15 ml. of dry acetonitrile were added 923 mg. (2 mmoles of 7-(α-aminophenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1.62 grams (8 mmoles) of N,O-bis-trimethylsilylacetamide. Solution was complete within 5 minutes. To the mixture then were added 452 mg. (2.3 mmoles) of 2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride. The temperature of the mixture rose about 4°and solution was complete within 5 minutes. After 20 minutes, a sample of the reaction mixture, analyzed by TLC, indicated that the reaction was complete. After two hours, the mixture (containing some solid) was slowly dropped into rapidly stirred ice water. A gummy solid deposited and was changed to particulate solid upon further stirring of the mixture. The suspension (pH 1.9) was adjusted to pH 1.7 by addition of concentrated hydrochloric acid. The mixture was filtered, and the solid was washed with dilute hydrochloric acid and air-dried to give 1.16 grams of the title compound as a buff-colored powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:22](=[O:23])[C:21]3[S:20][C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13]=3[CH:12]=[N:11]2)[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)[C:26]1=[O:58].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].C(#N)C>[CH3:24][N:25]1[C:26](=[O:58])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]3[C:22](=[O:23])[C:21]4[S:20][C:19]5[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=5[C:13]=4[CH:12]=[N:11]3)[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: O=Cc1c(Br)cccc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cccc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 130a (160 mg, 0.40 mmol), (S)-1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronic acid 113f (160 mg, 0.40 mmol), Pd(dppf)Cl2 (32 mg, 0.040 mmol), sodium acetate (66 mg, 0.80 mmol), K3PO4 (170 mg, 0.80 mmol), and acetonitrile (6 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 130b (123 mg, 46%) as a yellow solid. LCMS: [M+H]+ 664.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[NH:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C@H:22]2[CH2:26][CH2:25][N:24](C(OCC3C=CC=CC=3)=O)[CH2:23]2)[CH:12]=1)=[O:10].Cl>[Pd].CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[NH:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C@H:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1cn([C@H]2CCN(C(=O)OCc3ccccc3)C2)c2ncccc2c1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(Nc1c(Cl)cncc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 193.9 %

Procedure:
To a 4 ml methanol solution of 60 mg (0.11 mmol) of the compound obtained in Example 10, 20 μl (0.12 mmol) of 6N-hydrochloric acid and 30 mg of 10% palladium activated carbon were added and stirred at room temperature for 21 hours under hydrogen atmosphere. Then, after the catalyst was removed by filtration, the mother liquor was concentrated to obtain 47 mg of (S)-N-(3,5-dichloropyridin-4-yl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide hydrochloride, as a colorless oily substance.
Reaction SMILES: [C:1]([C@@H:7]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C(Cl)Cl.FC(F)(F)C(O)=O.C(N(CC)CC)C.[N+:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45](Cl)(=[O:47])=[O:46])([O-:38])=[O:37]>C(=O)(O)[O-].[Na+]>[N+:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([N:9]1[CH2:10][CH2:11][C@@H:7]([C:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:8]1)(=[O:47])=[O:46])([O-:38])=[O:37]
Reactant: C=CCCC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(=O)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of (R)-tert-butyl 3-pent-4-enoylpyrrolidine-1-carboxylate (300 mg, 1 mmol) in methylene chloride (5 mL, 80 mmol) was added trifluoroacetic acid (2 mL, 20 mmol) and the resultant mixture was stirred at room temperature for 1 h. The crude reaction mixture was then concentrated to obtain a crude oil which was re-dissolved in methylene chloride (5 mL, 80 mmol) prior to the addition of triethylamine (1 mL, 7 mmol). This solution was cooled to 0° C. before adding 2-nitrobenzenesulfonyl chloride (450 mg, 2.0 mmol) in a single portion. The reaction mixture, which immediately turned blue in color, was stirred overnight at room temperature. At the end of the reaction, the solution was diluted with saturated aqueous sodium bicarbonate (50 mL) to give two layers which were separated. The aqueous layer was further extracted with methylene chloride (2×20 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give a blue oil, which was purified by flash column chromatography (silica gel, eluting with 0-100% ethyl acetate in hexanes) to give (R)-1-(1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)pent-4-en-1-one (305 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 7.76-7.70 (m, 2H), 7.66-7.62 (m, 1H), 5.78 (ddt, J1=17.0 Hz, J2=10.4 Hz, J3=6.5 Hz, 1H), 5.07-4.97 (m, 2H), 3.70 (dd, J1=12.0 Hz, J2=8.0 Hz, 1H) 3.61 (dd, J1=12.0 Hz, J2=8.1 Hz, 1H), 3.52 (t, J=8.1 Hz, 2H), 3.24 (p, J=8.0 Hz, 1H), 2.59 (td, J1=7.3 Hz, J2=3.6 Hz, 2H), 2.32 (q, J=6.8 Hz, 2H), 2.24-2.16 (m, 1H), 2.14-2.05 (m, 1H), 1.28 (ddd, J1=17.8 Hz, J2=10.6 Hz, J3=7.3 Hz, 1H); ESI MS found for C15H18N2O5S m/z 339.3 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.[S:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=O)=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[O:20][CH2:31][C:30]2[CH:34]=[CH:35][C:27]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:28][CH:29]=2)[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OCc3ccc(S(N)(=O)=O)cc3)[C@@]1(C)C[C@@H]2F
Reaction time: 8.5 h
Yield: 38.9 %

Procedure:
A solution of 500 mg of 11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one in 7.5 ml of pyridine was mixed at room temperature with 750 mg of 4-sulfamoylbenzoic acid, 800 mg of N,N-dicyclohexylcarbodiimide as well as 125 mg of p-toluenesulfonic acid and stirred for 8.5 hours. Then, it was added to sodium bicarbonate solution, extracted four times with dichloromethane, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum, and chromatographed on silica gel with dichloromethane/acetone. 302 mg of 11β-fluoro-17β-(4-sulfamoylbenzoxy)-7α-methylestr-4-en-3-one with a melting point of 232° C. was obtained. [α]D=+100.5° (CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH:16][CH2:15][CH2:13][OH:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: NCCO
Product: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Yield: 57.8 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.6 g, 6 mmol, synthesized according to J. Am. Chem. Soc., 1940, 62, 511-514) and ethanolamine (1.0 mL, 17 mmol) to give the title compound (1.02 g, 58%) as a pale-yellow solid. MS (ISP) 294.1 [(M+H)+], 296.2 [(M+2+H)+].
Reaction SMILES: O1CCCC1.[CH:6]1([O:9][C:10]2[CH:11]=[C:12]([C:20]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]4[CH:24]=[N:25][NH:26][C:27](=[O:28])[C:22]=4[C:21]=3[CH:38]=[O:39])[CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[CH2:8][CH2:7]1.[BH4-].[Na+]>O>[CH:6]1([O:9][C:10]2[CH:11]=[C:12]([C:20]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:23]4[CH:24]=[N:25][NH:26][C:27](=[O:28])[C:22]=4[C:21]=3[CH2:38][OH:39])[CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(C=O)c2c(=O)[nH]ncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(CO)c2c(=O)[nH]ncc21
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To 3 ml of tetrahydrofuran solution containing 221 mg (0.450 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 10-(a) was added 58 mg (1.53 mmol) of sodium borohydride under ice-cooling, and the reaction mixture was raised to room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 155 mg of the title compound as a pale yellowish foam. (Yield: 70%)
Reaction SMILES: [P:1]([O-:41])([O:32][CH:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N+:35]1([CH3:40])[CH3:39])([O:3][CH2:4][CH:5]([O:24]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[H][H]>C(O)C.[Pd]>[P:1]([O-:41])([O:32][CH:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N+:35]1([CH3:40])[CH3:39])([O:3][CH2:4][CH:5]([OH:24])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OC=C1CCC[N+]1(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OC=C1CCC[N+]1(C)C
Yield: 80.7 %

Procedure:
In 20 ml of ethanol was dissolved 162 mg of 2-Benzyloxy-3-hexadecyloxypropyl 1,1-dimethylpyrrolidinio-2-ylmethyl phosphate prepared in Example 7, and 20 mg of palladium(5%)-carbon (catalyst) was added to the resulting solution. The mixture was stirred overnight at 50° C. in a stream of hydrogen. The reaction liquid was cooled, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give 111 mg of 3-hexadecyloxy-2-hydroxypropyl 1,1-dimethylpyrrolidinio-2-ylmethyl phosphate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C=CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Yield: 91.6 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 157 (4.2 g), 1 mol/L of an aqueous sodium hydroxide solution (17 mL), and methanol (170 mL), to give the captioned compound (3.7 g, 92%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 75.5 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.203 g, 0.448 mmol) and 4-chorosulphonyl-2-hydroxybenzoic acid (0.319 g,1.34 mmol). Purification on Dynamax C18 (85% CH3CN/H2O) gave 0.221 g (49%) of the title compound as a brown solid, mp 188-192° C. 1H NMR (DMSO-d6) δ1.26-1.32 (m, 2H), 1.49-1.57 (m, 2H), 1.64-1.74 (m, 4H), 1.77 (s, 3H), 2.18 (s, 3H), 2.96 (quintet, 1H), 3,79 (s, 2H), 6.96 (d, 2H), 7.23 (d, 1H), 7.36-7.43 (m, 4H), 7.53-7.56 (m, 2H), 8.00 (d, 1H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 651 (M−H). Anal. Calcd. for C32H29BrOS: C, 58.81; H, 4.47; N, 0.00. Found: C, 58.45; H, 4.54; N, 0.07.