Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@@H:20]([CH:22]=[O:23])[CH3:21])[CH2:18][CH:17]=4)[C:11]1([CH3:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@H:20]([CH3:21])[CH:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[OH:23])[CH2:18][CH:17]=4)[C:11]1([CH3:33])[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](C(O)c1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
ix)—A solution of the aldehyde 10 (2.0 g), obtained in the previous step, in dry tetrahydrofuran (17 ml) was added dropwise to a 1 M solution of phenylmagnesium bromide (13 ml) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 h. A saturated aqueous solution of ammonium chloride was added and the product was extracted into ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-4,4,20-trimethyl-21-phenylpregna-8,14-diene-3,21-diol 3-benzoate (11) (3.0 g) which was used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2](=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH:21][CH2:22][CH:23]([CH2:25]O)[OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOC1>C1(C)C=CC=CC=1.O>[CH2:3]([C:2]1([CH3:1])[O:24][CH:23]([CH2:22][OH:21])[CH2:25][O:20]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCC(C)=O
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCO1
Product: CCCCCCCCCCCCCCCCCC1(C)OCC(CO)O1
Reaction time: 12 h

Procedure:
In an appropriate reactor were poured 11.1 g (40 mmol) of 2-nonadecanone, 6 g--which represents an excess with regard to the stoichiometric proportions--of twice distilled glycerol and 0.6 g of p-toluenesulphonic acid dissolved in 120 ml of dry toluene. The reaction mixture was refluxed under stirring for 12 hours and the resulting water was eliminated using a Dean Stark apparatus. After cooling, the organic phase was washed with 30 ml of 5% by weight aqueous solution of potassium hydroxide and then three times with the minimum amount of water. After drying over anhydrous sodium sulphate, the solvent was removed under reduced pressure. The residue was then purified by chromatography on a silica gel column. There were successively eluted the fraction of the ketone not involved in the reaction (petroleum ether : diethyl ether, 95:5 by volume), and then the dioxolan a (petroleum ether/diethyl ether 85:15 by volume). the dioxolan is a viscous product, partially crystallized.
Reaction SMILES: I[CH3:2].CSC.[CH3:6][C:7]([CH3:24])([CH3:23])[C:8](=[O:22])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:13][CH:12]=1.O>CS(C)=O.O1CCCC1>[O:21]1[CH2:20][CH2:19][O:18][CH:17]1[C:14]1[CH:15]=[CH:16][C:11]([CH:10]=[CH:9][C:8]2([C:7]([CH3:24])([CH3:23])[CH3:6])[CH2:2][O:22]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(C2OCCO2)cc1
Reactant: CI
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C1(C=Cc2ccc(C3OCCO3)cc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
8.1 g (0.13 mol) of iodomethane are slowly added dropwise to a solution of 9.9 ml (0.135 mol) of dimethyl sulphide in 75 ml of absolute dimethylsulphoxide and 35 ml of absolute tetrahydrofuran, during which the internal temperature must not rise above 35° C. This suspension is subsequently stirred at room temperature overnight, and 15.7 g (0.14 mol) of potassium tert.-butylate are then added in portions. The mixture is subsequently stirred at room temperature for 30 minutes and cooled to 0° C., and 26 g (0.1 mol) of 4,4-dimethyl-1-[4-(1,3-dioxolan-2-yl)-phenyl]-1-penten-3-one are added in portions. The reaction mixture is subsequently stirred at room temperature overnight, water is then added and the mixture is extracted three times with toluene. The combined toluene phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. 25.6 g of crude 2-{2-[4-(1,3-dioxolan-2-yl)-phenyl]-ethenyl} -2-tert.-butyl-oxirane are obtained as an oil, which is further reacted directly. ##STR24##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:14]([CH:38]([OH:40])[CH3:39])[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:53][C:54](OC(C)=O)=[O:55]>CN(C1C=CN=CC=1)C.CCOCC>[C:54]([O:40][CH:38]([C:14]1[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][C:17]2[C:12]([C:13]=1[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)[CH3:39])(=[O:55])[CH3:53]
Reactant: CC(O)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reaction time: 2 h

Procedure:
To a solution alcohol (300 mg) from Step 4 in Ac2O (2 mL) was added pyridine (300 mL) and DMAP (2 mg). After 2 hr, the reaction mixture was diluted with Et2O, washed with H2O, a solution of CuSO4, and the solvent evaporated to give the title product which was used as such for the next step.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2].[CH2:25]([Li])CCC.IC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:25])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: COc1ccc(Nc2cc3c(c(C(C)C)c2C)OCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A stirred solution of 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.2 g, 0.615 mmol) in 5 mL of anhydrous tetrahydrofuran under argon, was cooled to -78° C. and treated with 1.6M solution of n-butyllithium in hexanes (0.77 mL, 1.23 mmol). The resulting green reaction mixture was stirred for 0.5 hour at -78° C. and then treated drop wise with iodomethane (0.5 mL, 6.15 mmol) that was passed through a bed of potassium carbonate. The yellow reaction mixture was allowed to warm to room temperature, recooled to 0° C., quenched with saturated ammonium chloride solution and extracted with diethylether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography to afford the title compound (0.11 5 g, 51%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.80 (d, 2H, J=9.1 Hz), 6.74 (s, 1H), 6.45 (d, 2H, J=9.1 Hz), 4.24 (s, 2H), 3.77 (s, 3H), 3.60 (br m, 2H), 3.25 (heptet, 1H, J=7.0 Hz), 2.12 (s, 3H), 1.38 (d, 6H, J=7.0 Hz), 1.32 (s, 6H), 1.24 (t, 6H, J=7.0 Hz).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O.C1C=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.COCCOC>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
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: [Na+]
Solvent: COCCOC
Solvent: c1ccccc1
Product: O=C1Nc2cccc(-c3ccc(Cl)cc3Cl)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (70 mg, 0.208 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (210 μL, 0.420 mmol), (Ph3P)4Pd (10 mg, 0.009 mmol) (Aldrich), and 2,4-dichlorophenylboronic acid (44 mg, 0.231 mmol) (Lancaster) in 6 mL of a 5:1 mixture of benzene:1,2-dimethoxyethane was heated at reflux under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60% ethyl acetate-hexanes elution) to yield pure (Z)-4-(2,4-dichlorophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 52 mg, 69%) as a yellow-brown solid (mp 185-187° C.).
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:52]2[N:56]([CH2:57][CH:58]=[C:59]([CH3:61])[CH3:60])[C:55]([C:62]([NH:64][CH2:65][C:66]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH:69]=[CH:68][CH:67]=3)=[O:63])=[N:54][N:53]=2)[CH2:47]1>O1CCCC1>[NH2:5][CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:52]2[N:56]([CH2:57][CH:58]=[C:59]([CH3:61])[CH3:60])[C:55]([C:62]([NH:64][CH2:65][C:66]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH:69]=[CH:68][CH:67]=3)=[O:63])=[N:54][N:53]=2)[CH2:47]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCCC(N)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
14 mg phthalimide, 65 mg triphenylphosphine and finally 50 μl of diisopropyl azodicarboxylate are added to a solution of 39 mg 3-(3-hydroxy-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole in 1 ml dry tetrahydrofuran. The solution is stirred for 14 h at ambient temperature and then evaporated to dryness. The residue is taken up in 2 ml of toluene and combined with 50 μl ethanolamine. After 4 h stirring at 80° C. the mixture is cooled to ambient temperature and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 95:5:1->80:20:1).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][N:11]([CH3:22])[C:12](=[O:21])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CS(C)=O.[NH4+].[Cl-]>[CH3:9][O:10][N:11]([CH3:22])[C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:21]
Reactant: CON(C)C(=O)/C=C/c1ccccn1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CON(C)C(=O)[C@@H]1C[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution under N2 of trimethylsulfoxonium iodide (3.89 g, 17.7 mmol, 2 eq.) in DMSO (10 mL) cooled at r.t. with a water bath, sodium hydride 60% dispersion in mineral oil (707 mg, 17.7 mmol, 2 eq.) was added portionwise over 10 min. The resulting mixture was stirred at r.t. for 1 hour. A solution of (E)-N-methoxy-N-methyl-3-(pyridin-2-yl)acrylamide (1.70 g, 8.8 mmol, 1 eq.) in DMSO (5 mL) was added and the reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in sat. aq. NH4Cl soln. (50 mL) and extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+20% AcOEt to Heptane+80% AcOEt) to yield (±)-(trans)-2-pyridin-2-yl-cyclopropanecarboxylic acid methoxy-methyl-amide as an yellow oil.
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[C:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[C:17]1([NH:27][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Product: O=C(Nc1cccc2ccccc12)C1C(=O)c2ccncc2C1=O

Procedure:
In a similar manner to Example 1a, 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid naphthalen-1-ylamide was obtained starting from 5,7-Dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester and naphthalen-1-ylamine. The desired product was obtained as a light brownish powder. ESI−MS: m/z 317 (MH+); 1H-NMR (DMSO-d6): δ7.38-7.67 (5H, m), 7.91 (1H, d, J=8.1 Hz), 8.38 (1H, d, J=8.7 Hz), 8.54 (1H, dd, J=1.1 Hz, 7.6 Hz), 8.57 (1H, d, J=1.1 Hz), 8.75 (1H, d, J=4.9 Hz), 11.61 (1H, brs).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)C.[OH-].[K+].CO.O>CO>[S:11]1[C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2
Reactant: CCOC(=O)CCc1cc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To a solution of benzo[b]thiophene-2-propanoic acid ethyl ester (3.52 g, 15.0 mmol) in MeOH (200 mL) was added at 0° C. 10% KOH/MeOH (70 mL, 144 mmol) and H2O (30 mL). The solution was stirred at 25° C. for 6 h then kept in a refrigerator (0° C.) overnight. After addition of H2O (20 mL), the mixture was concentrated under reduced pressure to remove most of MeOH then acidified carefully with 3N HCl to pH 2. The resultant turbid mixture was extracted with Et2O (3×500 mL). The combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated to dryness to give benzo[b]thiophene-2-propanoic acid (3.04 g, 14.7 mmol) in 98% yield as a solid, mp 140°-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]OS(C)(=O)=O)=[CH:19][N:18]=2)=[O:16])=[CH:11][S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].C(OCC)(=O)C.O>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[CH:19][N:18]=2)=[O:16])=[CH:11][S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(COS(C)(=O)=O)cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)CCNCc1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
N-(4-t-Butoxycarbonylaminothiophen-3-yl)-5-methanesulfonyloxymethylpyridine-2-carboxylic acid amide (Reference Compound No. 4-1, 0.36 g, 0.83 mmol) and N,N-dimethylethylenediamine (0.46 mL, 4.2 mmol) were dissolved in anhydrous dichloromethane (5.0 mL)-anhydrous acetonitrile (5.0 mL), and then the reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (0.10 L) and water (0.10 L) were added to the reaction solution, and then the mixture was partitioned. The organic layer was washed with brine (0.10 L), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give 98 mg of the title reference compound as a brown amorphous product. (Yield 28%)
Reaction SMILES: C(C1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#N.Cl.[C:24]([OH:27])(=[O:26])[CH3:25]>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:25]([CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:9])=[O:10])[C:24]([OH:27])=[O:26]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Reactant: CC(=O)O
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1Oc1ccc(F)cc1F

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.3 g) and concentrated hydrochloric acid (13 ml) in acetic acid (8 ml) was refluxed for 8 hours. The precipitates were filtered, washed with water, dried, and recrystallized from a mixture of ethyl acetate and hexane to give crystals of 3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzoic acid (0.72 g).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[Li]CCCC.[CH:47](=[O:49])[CH3:48].Cl>C1COCC1>[Si:24]([O:23][C@@H:15]1[CH2:16][CH2:17][C@@:18]2([CH3:19])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@@H:20]2[CH2:21][CH2:22][C@@:5]2([CH3:6])[C@H:7]3[CH2:8][CH2:9][C@@H:4]2[C:3]#[C:2][CH:47]([OH:49])[CH3:48])[CH2:14]1)([C:37]([CH3:38])([CH3:40])[CH3:39])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC=O
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C(Br)Br)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dibromo-2-[3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-yl]-ethylene (308 mg, 0.44 mmol) in THF (11 mL) was added at −78° C. a solution of n-BuLi 1.6 M in hexanes (2.76 mL, 4.4 mmol) and the mixture was stirred for 2 h. Acetaldehyde (0.032 mL, 0.57 mmol) was added at −78° C. and the temperature was let to rise to 25° C. Addition of HCl solution 2N at 0° C. was followed by extraction with ethyl acetate. The organic layer was washed with NaHCO3 brine and dried with (Na2SO4) and the solvent was evaporated in vacuo. Subsequent purification of the residue with flash column chromatography using petroleum etherlethyl acetate 90/10 as eluent afforded the desired compound named above.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[Br:18][C:19]([Br:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)C#N>ClCCl>[Br:18][C:19]([Br:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#CC(Br)(Br)c1ccccn1
Solvent: ClCCl
Product: BrC(Br)(c1ccccn1)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (2.0 g, 8.1 mmol) and dibromo(2-pyridyl)acetonitrile (4.91 g, 17.8 mmol) in 50 mL of dichloromethane was heated to reflux for 16 h. After cooling to room temperature, the precipitate was filtered, washed with dichloromethane and dried to give 2.76 g (80%) of the title compound as a light-brown solid: mp 195° C. (dec); 1H NMR (CDCl3) δ8.25 (m, 2H), 7.96 (dt, 1H), 7.76 (d, 1H), 7.32 (m, 2H), 6.95 (t, 1H), 6.92 (s, 1H) ppm; 13C NMR (CDCl3) δ166.08, 157.95, 150.34, 148.28, 147.71, 38.31, 128.76, 124.79, 124.58, 122.94, 121.68, 119.49, 13.97, 54.37 ppm; HRMS calcd for C14H8Br2N4S: 421. 8836, found: 421.8850.
Reaction SMILES: [Si]([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4=[N:26][S:27](=[O:31])(=[O:30])[CH2:28][CH2:29][N:24]4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:31]=[S:27]1(=[O:30])[CH2:28][CH2:29][N:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C:12]4[CH:32]=[CH:33][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:15][CH:16]=3)[C:25]2=[N:26]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(O)cc4)cc3)C2=N1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 9-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (1.82 g) in THF (dry) (55 mL) was added to tetrabutylammonium fluoride(1 M in THF) (6.79 mL) at room temperature. After stirring for 0.5 hr, the mixture was added with sat.NH4Cl aq. and silica gel, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane then MeOH in EtOAc), recrystallized from THF-IPE, then preparative HPLC (C18, eluent; H2O/MeCN with 0.1% TFA). The collected fraction was concentrated in vacuo. The residue was recrystallized from MeCN—H2O to give the title compound (492 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH2:28][CH3:29])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH2:28][CH3:29])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1C
Temperature: 78 °C
Yield: 79 %

Procedure:
1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.235 g, 0.605 mmol) and ethyl formate (0.145 mL, 1.80 mmol) were dissolved in anhydrous ethanol (5 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.13 mL, 3.02 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.199 g, 0.478 mmol, 79%).