Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:32][C:33]([O:35]CC)=[O:34])[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=3)=[N:17][C:16]=2[CH:31]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:32][C:33]([OH:35])=[O:34])[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=3)=[N:17][C:16]=2[CH:31]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)O)c4ccccn4)ccc3s2)cc1
Yield: 90 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide dihydrochloride and sodium hydroxide solution. Yield: 90% of theory, C23H20N6O3S (460.52); EKA mass spectrum: (M+H)+=461; (M+Na)+=483; (M+2Na)++=253.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.C(=O)(O)[O-].[Na+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].CN(C=O)C>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1ccc(Br)cc1I
Reactant: C=CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(Br)ccc1N
Temperature: 80 °C
Yield: 55.8 %

Procedure:
To a microwave vial was added, 4-bromo-2-iodoaniline (1.70 g, 5.71 mmol), PdOAc2 (0.064 g, 0.285 mmol), sodium bicarbonate (1.198 g, 14.27 mmol), ethyl acrylate (0.651 ml, 5.99 mmol) and DMF (1.902 ml). The reaction was heated in microwave for 1 hour at 80° C. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.860 g of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate. m/z (ESI) 270.1 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([OH:9])[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][C:4]=1S(O)(=O)=O.I[CH3:23].[C:24](=[O:27])([O-])[O-].[K+].[K+]>>[CH3:24][O:27][C:8]1[C:7]([O:9][CH3:23])=[C:6]([CH:5]=[CH:4][CH:3]=1)[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(C(=O)c2ccccc2)c1OC

Procedure:
In Scheme II, benzophenone 4 was treated with iodomethane in the presence of potassium carbonate to produce the dimethoxy-benzophenone 7. Bromination of 7 with bromine in chloroform furnished bromo-benzophenone 8, which was converted to benizisoxazole 9 according to Scheme I.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.N12CCC(CC1)N(C1N=CC(N)=CN=1)CC2.[C:35]([Cl:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[Pd].C(O)C>[ClH:43].[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[N:10]([C:7]1[N:6]=[CH:5][C:4]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:9][N:8]=1)[CH2:11][CH2:12]2
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cnc(N2CCN3CCC2CC3)nc1
Agent: [Pd]
Agent: Nc1cnc(N2CCN3CCC2CC3)nc1
Solvent: CCO
Product: Cl
Product: O=C(Nc1cnc(N2CCN3CCC2CC3)nc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 4-(5-nitro-pyrimidin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (0.86 g, 2.9 mmol), palladium (0.25 g, 10% on activated carbon) and ethanol (50 ml) was stirred under hydrogen for 10 min (200 ml of hydrogen consumed). The rection-mixture of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylamine was filtered through celite and was washed with ethanol (50 ml). The ethanolic solution of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylamine was mixed with benzoylchloride 0.41 g, 2.90 mmol) and was stirred for 15 h at room-temperature. The title product precipitated as hydrochloric acid salt by addition of hydrochloric acid in ethanol. Yield 0.38 g (36%). LC-ESI-HRMS of [M+H]+ shows 324.1817 Da. Calc. 324.182435 Da, dev. −2.3 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][C:40]([NH2:46])=[C:39]2[NH:47][CH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:55]([O:57][CH2:58][C:59](Cl)=O)[CH3:56]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:29]([CH2:28][O:35][CH2:36][CH3:45])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:28]([O:35][C:36]1[CH:45]=[CH:44][C:43]2[N:42]=[CH:41][C:40]3[N:46]=[C:56]([CH2:55][O:57][CH2:58][CH3:59])[N:47]([CH2:48][CH:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[C:39]=3[C:38]=2[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccc(OCc3ccccc3)cc2c1NCC1CCOCC1
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC1CCOCC1

Procedure:
For Examples 228 and 230, 7-benzyloxy-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (Example 228) or 6-benzyloxy-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (Example 230) can be treated with ethoxyacetyl chloride according to the method described in Part C of Example 50 to provide 7-benzyloxy-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (Example 228) or 8-benzyloxy-2-ethoxymethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (Example 230).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][C:12]#[N:13].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][C:12]#[N:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: N#CC[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1CC#N
Temperature: 0 °C
Yield: 60.2 %

Procedure:
Acetyl chloride (8.6 g) was added dropwise to a stirred, cooled solution of ((S)-pyrrolidin-2-yl)acetonitrile hydrochloride (Intermediate 138, 8.0 g) and triethylamine (16.5 g) in DCM (80 mL) while maintaining the temperature at 0° C. The resultant solution was stirred at 0° C. for 30 minutes. Water was added and the layers were separated. The aqueous layer was further extracted with DCM and the combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by HPLC (C18) to give ((S)-1-acetylpyrrolidin-2-yl)acetonitrile (5.0 g) as a light yellow oil which was used directly without further characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=O)[C:6](Cl)=[N:5]2.[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C[OH:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([N:8]([CH3:12])[CH:7]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:6](=[O:25])[NH:5]2)=[CH:10][CH:11]=1
Reactant: CO
Reactant: N#Cc1ccc(N)cc1
Reactant: Cn1c(=O)c(Cl)nc2cc(Br)ccc21
Product: CN1c2ccc(Br)cc2NC(=O)C1Nc1ccc(C#N)cc1
Temperature: 40 °C

Procedure:
270 mg (1 mmol) of 6-bromo-3-chloro-1-methyl-1H-quinoxalin-2-one and 240 mg (2 mmol) of 4-aminobenzonitrile are heated to 100° C. in 3 ml methanol. The precipitate is cooled to 40° C., diluted with methanol and suction filtered.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
Cyclopropylmethylamine (1.62 g, 22.8 mmol) and triethylamine (3 ml) were dissolved in THF (40 ml) and 4-bromobenzoylchloride (5 g, 22.8 mmol) added over 5 min at 0° C. The reaction was stirred at room temperature for 16 h, reduced to dryness under vacuum and the residue partitioned between DCM (75 ml) and water (75 ml). The aqueous was extracted with DCM (2×50 ml). The combined organic phases were washed with brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica eluting with cyclohexane/ethyl acetate (8:2). The solvent was evaporated from the product fractions under vacuum to give 4-bromo-N-cyclopropylmethylbenzamide (4.3 g, 74%). LCMS: retention time 3.00 min, MH+255.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([C:11]2[C:19]3[O:18][C:17]([F:21])([F:20])[O:16][C:15]=3[C:14](SC)=[CH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:25]1C=CC=C(C(OO)=O)C=1.[S:35](S([O-])=O)([O-:38])(=O)=[O:36].[Na+].[Na+]>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([C:11]2[C:19]3[O:18][C:17]([F:21])([F:20])[O:16][C:15]=3[C:14]([S:35]([CH3:25])(=[O:38])=[O:36])=[CH:13][CH:12]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: CSc1ccc(C(=O)c2cnoc2C2CC2)c2c1OC(F)(F)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)c2cnoc2C2CC2)c2c1OC(F)(F)O2
Temperature: 1 °C

Procedure:
A solution of 5-cyclopropyl-4-(2,2-difluoro-7-methylsulphenyl-1,3-benzodioxol-4-oyl)isoxazole (0.64 g) in dichloromethane was treated with m-chloroperbenzoic acid (55%, 1.5 g). After 2 hours the mixture was cooled to 1° C., and 1M sodium metabisulphite solution added. The filtered solution was separated and the organic phase washed with sodium acetate solution, brine, dried over anhydrous sodium sulphate and evaporated to give 5-cyclopropyl-4-(2,2-difluoro-7-methylsulphonyl-1,3-benzodioxol-4-oyl)isoxazole (compound 5, 0.35 g) as a white solid, m.p. 164°-165° C.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>COCCOC.O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:29]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:28]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][C:12]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(C=O)cc1OCCc1ccccc1
Reactant: CCOC(C)=O
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCC(=Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride (oily)(0.847 mg) in 25 ml of 1,2-dimethoxyethane, 4.20 ml of triethyl phosphonoacetate was added dropwise over 10 minutes and stirred at room temperature for 1 hour. To this reaction solution, 2.65 ml of pentyl bromide was added, and then refluxed by heating for 3 hours under stirring. Thereafter, the reaction solution was cooled to room temperature and 0.857 mg of 60% sodium hydride (oily) was added thereto. After stirring at room temperature for 30 minutes, 5.15 g of 4-methoxy-3-(2-phenylethoxy)-benzaldehyde was added and refluxed by heating for 2 hours under stirring. Then, the reaction solution was cooled to room temperature, and ethyl acetate and water was added thereto to separate the solution into layers. The organic layer separated was washed with water, an aqueous solution of saturated sodium hydrogencarbonate and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30:1) to thereby obtain 5.39 g of ethyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-pentylacrylate as a mixture of E- and Z-isomers (E-isomer:Z-isomer=7.0:1).
Reaction SMILES: [OH:1][CH:2]([CH3:25])[CH2:3][NH:4][C:5]([C:7]1[C:8]([C:21]([F:24])([F:23])[F:22])=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[N:11][CH:12]=1)=[O:6].C(N(CC)CC)C>CS(C)=O.ClCCl>[O:1]=[C:2]([CH3:25])[CH2:3][NH:4][C:5]([C:7]1[C:8]([C:21]([F:22])([F:24])[F:23])=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[N:11][CH:12]=1)=[O:6]
Reactant: CC(O)CNC(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a stirred solution of 2-(3-chloro-phenylamino)-trifluoromethyl-pyrimidine-5-carboxylic acid (2-hydroxy-propyl)-amide (200 mg) in dimethylsulfoxide (6.0 ml) and triethylamine (324 mg) at 0° C. was added a solution of sulphur trioxide-pyridine complex (250 mg) in dimethylsulfoxide (6.0 ml). This was allowed to warm to room temperature and after 2 hours the mixture was diluted with dichloromethane and washed twice with 0.1N hydrochloric acid. The organic layer was dried (Na2SO4) and evaporated. The sample was purified by mass directed auto-purification to afford the title compound (91 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CC1C=CC(S(O[CH2:32][CH2:33][F:34])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:33][F:34])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCF)C(=O)C1
Reaction time: 0.5 h

Procedure:
1-t-Butoxycarbonyl-3-oxopiperazine (21.6 g) is dissolved in dry DMF (500 ml) and potassium t-butoxide (24.2 g) is added. The mixture is stirred at 20-25° for 30 minutes, then 1-(4-methylphenylsulfonyloxy)-2-fluoroethane (J. Med. Chem., 23(9), 985-90 (1980), 25.9 g) is added and stirring continued at the same temperature for 24 hours. The solvent is removed and the residue partitioned between ethyl acetate and water. The organic phase is washed with water and concentrated. The residue is dissolved in isopropanol and diluted with iso-hexane forming a precipitate which is removed by filtration. The mixture is chromatographed (silica; eluting with a gradient increasing in polarity from 0 to 50% isopropanol in iso-hexane) to give 1-t-butoxycarbonyl-4-(2-fluoroethyl)-3-oxopiperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Mg+2].[Cl-].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[O:11]
Reactant: CC(C)(C(=O)O)c1ccccc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1F
Reaction time: 16 h

Procedure:
To a solution of 2-(2-fluorophenyl)-2-methylpropanoic acid (3.98 g, 22 mmol), IPAc (31 mL) and DMF (0.017 mL), was slowly added oxalyl chloride (2.0 mL, 23 mmol) over 10 minutes. The resulting solution was stirred for 16 hours and then concentrated in vacuo to afford an oil. In a separate flask, IPAc (30.0 mL) and diethyl malonate (4.2 mL, 27 mmol) were combined. To this mixture was added anhydrous MgCl2 (2.6 g, 27 mmol). The resulting white slurry was stirred at room temperature for 30 minutes, and then TEA (10 mL, 73 mmol) was added. After stirring for an additional 2.5 hours, the reaction was chilled in an ice water bath for 10 minutes, and then the crude acid chloride (previously prepared above) was added to the white mixture via syringe over 10 minutes. The ice bath was removed, and the reaction was stirred for 1.5 hours at room temperature. The mixture was acidified with 5N HCl and added IPAc (50 mL) was added. The aqueous layer was separated and set aside. The organic layer was sequentially washed with saturated NaHCO3 solution and then water. The separated organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. MS (m/z)=325 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([SH:12])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([S:12][CH3:14])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nnc(S)nc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc(SC)nc1O
Reaction time: 1 h

Procedure:
To a 0° C. solution of 29.0 g (144.1 mmol) of 5-hydroxy-3-mercapto-1,2,4-triazine-6-carboxylic acid ethyl ester in 75 mL of DMF was added 14.4 g (144.1 mmol) of potassium carbonate. The reaction mixture was stirred for 1 hour, and 24.2 mL (389.2 mmol) of methyl iodide was added as fast as the effervescence would allow. The ice bath was removed, and the reaction was covered with a nitrogen filled balloon and stirred at room temperature overnight.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][N:11]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([C:20](=[O:21])[C:19]4[CH:30]=[CH:31][C:16]([C:15]([F:14])([F:32])[F:33])=[CH:17][CH:18]=4)=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (755 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 3 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-brown powder (436 mg, yield 53%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:44][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CO)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 210.1 %

Procedure:
The hydroxymethyl derivative produced in Example 30 (5.0 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) were dissolved in 100 ml of benzene and the resulting solution put under a nitrogen atmosphere. N-Bromosuccinimide (2.7 g, 15 mmol) was added in portions to the above solution and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 12.3 g of a brown oil. Purification of this oil by chromatography on 600 g of silica gel (230-400 mesh) using ethyl acetate-hexane as the eluent gave 4.52 g of a white solid. Recrystallization of this solid from diisopropyl ether gave the title compound as a white crystalline solid (4.12 g, 68%), mp 76°-78° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[NH3:24]>CO.[Cu-]=O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH2:24])=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: N
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: O=[Cu-]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N)nc3C)c(C)nc12
Temperature: 130 °C
Yield: 54 %

Procedure:
50 mg of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.13 mmol) and 10 mg of copper (I) oxide are added to 3 ml of 2 M NH3 in MeOH and vial is capped with a Teflon® lined cap, heated at 130° C. for overnight. The reaction mixture is concentrated under N2 gas and applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:20:1) to give 22 mg of the title compound. Yield 54%: mass spectrum (m/e): 330 (M+1); 1H-NMR (CDCl3): 6.72 (s, 1H), 5.24 (br, 2H), 3.40 (m, 1H), 2.56 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.4 Hz).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O: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>C(#N)C.C(OCC)(=O)C.[Cu](Br)Br>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH3:21]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: Br[Cu]Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Yield: 56.4 %

Procedure:
A solution of 500 mg of 11β-fluoro-7α-methylestr-4-ene-3,17-dione in 16.5 ml of acetonitrile was stirred with 400 mg of copper(II) bromide for 6.5 hours at 25° C. Then, it was diluted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 280 mg of pure 11β-fluoro-3-hydroxy-7α-methylestra-1,3,5(10)-trien-17-one with a melting point of 185-186° C. was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of methylbenzoic acid (I-1) (0.41 mol, 1 eq) and DMF (0.5 mL) in DCM (500 mL) at RT, oxalyl chloride (0.45 mol, 1.1 eq) is added slowly over 5 min. The resulting mixture is stirred at RT for 2 h and then concentrated in vacuo to afford the product, methylbenzoyl chloride. The product is used directly in the next step.