Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18].Br[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:20][CH2:21][CH3:22])[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18]
Reactant: Cc1cc2ccccc2n1Nc1ccncc1F
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccncc1F)n1c(C)cc2ccccc21

Procedure:
The title compound was prepared from N-(3-fluoro-4-pyridinyl)-2-methyl-1H-indol-1-amine and 1-bromopropane with the aid of NaH in substantially the same manner as in Example 4, m.p. 5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:23]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[N:7][CH:6]=[CH:5]2>C(O)C.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:23]
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinolin-l-amine (0.28 g, 0.81 mmol) was disolved in ethanol (20 mL) and 10% palladium on carbon (0.086 g, 0.81 mmol) was added to the solution. The reaction stirred overnight at RT under a hydrogen atmosphere. The reaction was filtered through celite and concentrated to give the title compound as a pink film (0.25 g, 98%). MS (M+H)+ 318.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].Cl>O1CCOCC1.C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC1CC1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1nc(C(=NOC2CC2)C(=O)O)cs1
Temperature: 33 °C
Reaction time: 1.5 h
Yield: 157.2 %

Procedure:
To a solution of ethyl 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(1.88 g) in 1,4-dioxane (16.7 ml) was added 1N sodium hydroxide (16.7 ml). The mixture was stirred for 1.5 hours at 33° C. After the mixture was cooled under ice-bath, 1N hydrochloric acid (16.7 ml) was added to the mixture. The mixture was concentrated in vacuo to give a residue. The residue was suspended in ethanol, concentrated in vacuo and triturated with ethyl acetate to give crude 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetic acid (syn isomer)(2.63 g). This compound was used for Preparation 33 without further purification.
Reaction SMILES: N1CCOCC1.C([O:10][C:11]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[C:20]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48])=[CH:43][N:44]([CH3:46])[CH3:45])=[C:38]([F:53])[CH:37]=3)=[CH:32][CH:31]=2)[C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C=C.O>O1CCCC1.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]>[OH:10][C:11]1[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:21]=[C:20]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48])=[CH:43][N:44]([CH3:45])[CH3:46])=[C:38]([F:53])[CH:37]=3)=[CH:32][CH:31]=2)[C:12]=1[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: C=CCOC(=O)C(=CN(C)C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: O
Product: C=CCOC(=O)C(=CN(C)C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
Morpholine (0.02 ml, 0.23 mmol) and tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) were successively added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{1-[(allyloxy)carbonyl]-2-(dimethylamino)vinyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (67 mg, 0.10 mmol) obtained in Example (93-1) in tetrahydrofuran (1 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-1/>99) to give crude tert-butyl 2-hydroxy-6-{[(4′-{1-[(allyloxy)carbonyl]-2-(dimethylamino)vinyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (42 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH3:21])[CH:23]=2)[NH:27][C:26]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: Cc1ccc2c(c1)CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 95 °C
Yield: 70.3 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (560 mg), 5-methyl-2-oxindole (300 mg), and piperidine (4 drops) in ethanol (4 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for an additional hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 496 mg of 4-(2-carboxyethyl)-3-methyl-5-(5-methyl -2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([N:11]1[CH2:14][C:13]([CH3:30])([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@@H:24]([CH2:26][NH2:27])[O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[F:29][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][NH:27][C:37](=[O:39])[CH3:38])[O:23][C:22]2=[O:28])[CH:19]=[CH:20][C:15]=1[C:13]1([CH3:30])[CH2:14][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1
Reactant: CC1(c2ccc(N3C[C@@H](CN)OC3=O)cc2F)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(C)CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Temperature: 0 °C
Yield: 84 %

Procedure:
The title compound was prepared as follows: (R)-(-)-N-carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine was diluted with 220 mL dichloromethane, cooled to 0° C., and successively treated with 3.7 mL pyridine (46 mmol) and 1.8 mL acetic anhydride (19 mmol) with no observable change. The cooling bath was removed and the reaction mixture was warmed to room temperature for 16 hours. The visually unchanged solution was concentrated to a yellow foam, rediluted with 50 mL dichloromethane, and filtered to remove the remaining insoluble precipitate. The filtrate was purified by LC on 340 g (230-400) silica gel eluting with 2.5% methanol/ethyl acetate to afford 5.85 g (84%) of (S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-(3-methyl)-3-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide as a colorless glass. Rf 0.24 (2.5% methanol/ethyl acetate); [α]D −19°(c 0.9971, methanol); IR (mull) 1754, 1706, 1676, 1516, 1430, 1415, 1357, 1227, 1194, 1075, cm−1, 1H NMR (300 MHz, CDCl3) δ 7.42 (dd, 1H, J=2.1 Hz, J=12.9 Hz, aromatic), 7.33 (m, 5H, aromatic), 7.13 (dd, 1H, J=2.2 Hz, J=8.5 Hz, aromatic), 7.04 (t, 1H, J=8.5 Hz, aromatic), 6.56 (bt, 1H, J=6.2 Hz, NH), 5.10 (s, 2H, Ph—CH2), 4.79 (m, 1H, methine), 4.30 (d, 2H, J=8.2 Hz, Ph—C—CH2as), 4.01 (m, 3H, Ph—C—CH2bs, Ph—N—CH2a), 3.78 (dd, 1H, J=6.7 Hz, J=9.1 Hz, Ph—N—CH2b),3.64 (m, 2H, NH—CH2s), 2.02 (s, 3H, O═C—CH3), 1.60 (s, 3H, Ph—C—CH3); 13C NMR (75 MHz, CDCl3) 171.2, 160.3 (d, JCF=246 Hz), 156.6, 154.2, 137.9 (d, JCF=11 Hz), 136.5, 128.9 (d, JCF=14 Hz), 128.4, 127.9, 127.2 (d, JCF=7 Hz) 113.2 (d, JCF=2 Hz), 106.4 (d, JCF=28 Hz), 72.0, 66.6, 60.7, 60.3, 47.3, 41.7, 36.1, 28.1, 22.9; Anal. Calcd for C24H26N3O5F1: C, 63.29; H, 5.75; N, 9.23. Found: C,62.98; H, 5.96; N, 8.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:26]([NH:20][C:19]2[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[CH3:24])=[O:28])=[C:40]([CH3:45])[CH:39]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4ccc(Cl)cc4C)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (92 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 4-chloro-2-methylaniline (44 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution to precipitate a crystal which was then collected by filtration to give 118 mg (yield 78%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>CO.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[CH:13]=[C:4]([C:3]([OH:30])=[O:2])[C:5](=[CH:10][C:11]=2[NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:6]([OH:8])=[O:7])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C

Procedure:
A steady stream of argon is passed through a suspension of 5.0 g (12.12 mmol) of 4,5-bis-(4-fluoroanilino)phthalic acid dimethylester in 40 ml of methanol, and a solution of 2.04 g (48.6 mmol, 2 eq) of lithium hydroxide monohydrate in 20 ml of water is added. The reaction mixture is heated to reflux for 1 hour, cooled to RT and diluted with 50 ml water. Methanol is removed by evaporation, the resulting solution is cooled to 0°, and 12 ml 4N hydrochloric acid and thereafter 100 ml of water are added. After 15 rain at 0°, the gray crystals are filtered off, washed with water and resuspended twice in 100 ml toluene with removal of the toluene by distillation to yield the title compound in the form of gray crystals, FAB-MS: 385 [M+ +H].
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]([OH:13])(=O)[C@@H:6]([CH2:8][C:9]([OH:11])=[O:10])[OH:7].[CH3:14][OH:15]>>[CH3:14][O:15][C:5](=[O:13])[C@H:6]([OH:7])[CH2:8][C:9]([O:11][CH3:1])=[O:10]
Reactant: CC(=O)Cl
Reactant: CO
Reactant: O=C(O)C[C@@H](O)C(=O)O
Product: COC(=O)C[C@@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cooled solution of methanol (250 mL) was added acetyl chloride (12.5 mL), and the solution was stirred for 1 hour at 0° C. (R)-Malic acid (20.0 g) was added, and the solution was stirred for 16 hours at room temperature. Solvent was removed by evaporation in vacuo leaving a quantitative yield of (R)-2-hydroxysuccinic acid dimethyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)(O)[O-:27].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:16])[CH2:17][OH:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3cccnc3)CO2)CCN(C)C1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CO)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,8-dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.3 mmol) in 20% aq. TFA (2 mL) was stirred at RT overnight. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with EtOAc (2×30 mL) to remove the impurities. The aqueous layer was lyophilized to obtain the crude product that was purified by reverse phase HPLC to obtain 5 mg of 3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propane-1,2-diol as the TFA salt. 1H NMR (CD3OD, TFA) δ (ppm): 8.75 (s, 1H), 8.6 (m, 2H), 7.83 (m, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 4.62 (d, 1H), 4.45 (dd, 2H), 4.3 (t, 1H), 4.05 (t, 1H), 3.8 (m, 2H), 3.5 (m, 3H), 3.1 (s, 3H), 2.3 (s, 3H). Separation by chiral HPLC provides enantiomers II-257a-b.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[C:27](Cl)=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:24]([O:23][CH3:22])[CH:25]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)cc(OC)c3)sc2Cc2ccccc2)cc1
Yield: 65.7 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 3,5-dimethoxy-benzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 65.7%, mp: 152-153 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.78 (6H, s, 2×OCH3), 3.80 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.55 (1H, t, J=2.12 Hz, ArH), 6.83 (2H, d, J=8.68 Hz, ArH), 6.90 (2H, t, J=2.12 Hz, ArH), 7.25˜7.33 (5H, m, ArH), 7.39 (2H, d, J=8.68 Hz, ArH), 10.75 (1H, br, CONH); EI-MS m/e (%): 460.2 (M+, 100), 165.0 (84); HREI-MS Calcd. for C26H24N2O4S: 460.1457. found: 460.1464.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[N:7][N:8]([CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:9]3=[O:12])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=c1c2cc(Br)ccc2cnn1Cc1cccnc1
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2cnn1Cc1cccnc1

Procedure:
The titled compound was prepared from 7-bromo-2-(3-pyridylmethyl)-1 (2H)-phthalazinone and 4-chlorophenol in the same manner as in Example 1 (1) c).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2].[ClH:16].[CH2:17]([OH:19])[CH3:18]>C(Cl)(Cl)Cl>[ClH:16].[CH2:17]([O:19][C:1](=[NH:2])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)[CH3:18]
Reactant: CCO
Reactant: CS(=O)(=O)Nc1cccc(OCC#N)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)COc1cccc(NS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
N-(3-Cyanomethoxyphenyl)-methanesulfonamide (1.0 g) was dissolved in a mixture of 20 ml of chloroform and 0.25 ml of absolute ethanol (EtOH). The reaction mixture was cooled in an ice bath and saturated with hydrogen chloride gas. The mixture was slowly allowed to come to room temperature and stirred for 16 hours. The solvent was evaporated leaving 1.1 g of 2-(3-methanesulfonylaminophenoxy)-acetimidic acid ethyl ester hydrochloride. ##STR67##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:28](=[O:30])[CH3:29])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])(C)(C)C.FC(F)(F)C(O)=O>O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH2:16][N:14]([CH3:15])[S:13]([C:12]2[CH:11]=[C:10]([C:28](=[O:30])[CH3:29])[S:9][C:8]=2[NH2:7])(=[O:27])=[O:26])=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
(5-Acetyl-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamo yl}-thiophene-2-yl)carbamic acid t-butyl ester (1.3 g) was added to trifluoroacetic acid (10 mL). After stirred for 10 minutes at room temperature, water was added to the residue that was evaporated in vacuo, and the pH of saturated sodium bicarbonate was adjusted to 11. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride water, whereafter this solution was dried with anhydrous magnesium sulfate. The solid obtained by passing through a short column of NH-silica gel and evaporating the solvent at reduced pressure was washed with ethyl acetate, and the title compound (713 mg) was obtained as an ocher solid.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[OH:2][CH2:1][C@@H:33]1[CH2:32][CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@@H:34]1[C@H:35]1[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7α-Hydroxymethylandrostane-3,17-dione (II-bx) was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.30 (t, 1H), 3.48 (m, 2H), 2.46-0.95 (m, 21H), 1.00 (s, 3H), 0.78 (s, 3H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Br[CH2:12][C:13]#[CH:14].C1(C)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:14][C:13]#[CH:12]
Reactant: C#CCBr
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CCOCCOCCOC
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution under N2 of 2-(2-methoxy-ethoxy)ethanol (4.9 ml, 41.61 mmoles) in dry THF (50 ml) was portionwise added at room temperature under stirring with 60% NaH in oil (1.66 g, 41.61 mmoles). The mixture was stirred for 30 minutes then dropped into a solution of 80% 3-bromo-propyne in toluene (5.1 ml, 45.77 mmoles), and stirred for 1 hour, then diluted with ethyl ether, thrice washed with water, anhydrified over Na2SO4 and dried to give 5 g of the title compound as an oil (yield: 76%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH2:19][C:20]2[N:21]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:22]=[C:23]([CH2:25][C:26]4([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]4)[N:24]=2)([OH:18])[CH2:13][CH2:12]3)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][N:61]=1>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:66][C:63]1[CH:64]=[CH:65][C:60]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH2:19][C:20]2[N:21]([C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:22]=[C:23]([CH2:25][C:26]4([C:29]([F:31])([F:30])[F:32])[CH2:28][CH2:27]4)[N:24]=2)([OH:18])[CH2:13][CH2:12]3)=[N:61][CH:62]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3(O)Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1(Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2cc(-c3ccc(F)cn3)ccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (264 mg, 0.23 mmol) was added to a degassed solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol (1.61 g, 2.29 mmol), potassium carbonate (411 mg, 2.97 mmol), and 2-bromo-5-fluoropyridine (483 mg, 2.74 mmol) in methanol/toluene (5 mL/50 mL). The solution was stirred at 90° C. for 2 h. The solvent was removed in vacuo and the residue was redissolved in EtOAc (200 mL). The solution was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography eluting with 0-100% EtOAc/hexanes to give 5-(5-fluoropyridin-2-yl)-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[N:24][OH:25])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.N1C=CC=CC=1>O1CCCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:15]([N:16]2[N+:24]([O-:25])=[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]3=[N:17]2)=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NNC3CCCCC3=NO)cc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C#CCN1C(=O)COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Temperature: 80 °C

Procedure:
To a solution of 2-[2-(7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)hydrazino]cyclohexanone oxime (0.4 g) in tetrahydrofuran (6 ml), 15% aqueous pyridine (7 g) was added, and a solution of copper sulfate (0.7 g) in water (1.5 ml) was added thereto, followed by heating at 80° C. for 2 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous copper sulfate solution, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give Compound No. 1 (0.2 g). m.p., 186°-187° C.