Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([O:18][CH3:19])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[C:28]([F:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:35][C:28]1[C:29]([OH:34])=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[NH:26][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:2]=1[F:1]
Reactant: COc1cc(C(=O)O)c(F)c(-c2cccc(F)c2)c1
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 2-fluoro-3-(3-fluorophenyl)-5-methoxybenzoic acid (402 mg, 1.52 mmol, 1.1 eq) in CH2Cl2 (20 mL) at 0° C. was added oxalylchloride (525 mg, 4.14 mmol, 3.0 eq) and DMF (5 drops). The solution was stirred at 0° C. for 2 h then the solvent removed in vacuo. The residue was taken up in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-difluorophenol (intermediate X(a)) (200 mg, 1.38 mmol, 1.0 eq) and NaHCO3 (348 mg, 4.14 mmol, 3.0 eq) in THF (10 mL) at 0° C. The mixture was stirred at 0° C. for 4 h then poured into water and extracted with EtOAc. The organic extract was washed with water, brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:3) to give the title compound as a white solid (300 mg, 50%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[N:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH2:11][CH2:12][OH:13])[N:6]=[CH:5]4)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: OCCn1ncc2cc(I)ccc21
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: OCCn1ncc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(5-iodoindazol-1-yl)ethanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 1.60 g (73% of theoretical); C22H16ClN3O (M=373.835); calc.: molpeak (M+H)+: 374/376 (Cl); found: molpeak (M+H)+: 374/376 (Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)=[O:13]
Reactant: Cc1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccc(C)cc2[nH]1

Procedure:
A solution of 6-methylindole-2-carboxylic acid (38.2 g.) in methanol (400 ml.) containing phosphorus oxychloride (5 ml.) was heated under reflux for 4 hours and then evaporated. The residue was dissolved in chloroform and the solution was washed successively with water and sodium bicarbonate solution and then dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from methanol to give 6-methylindole-2-carboxylic acid methyl ester (28.1 g.), m.p. 128°-131° C.
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)[C:4]([CH3:6])=O)[CH3:2].Cl.O.[NH2:28][NH2:29].[OH-].[Na+]>O.CO.C(O)(=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[C:8]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:7]=2[CH:3]([CH2:1][CH3:2])[C:4]([CH3:6])=[N:29][N:28]=1
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1ccccc1Cl
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(C)=NN=C(c2ccccc2Cl)c2cc(OC)c(OC)cc21
Temperature: 95 °C

Procedure:
A mixture of 10.37 g (28.9 mmoles) of 2-(1-ethylacetonyl)-4,5-dimethoxy-2'-chlorobenzophenone, 10.5 ml of glacial acetic acid and 2.65 ml of concentrated hydrochloric acid is heated to 95° C. under stirring. The mixture is cooled to 60° C., and 2.14 ml of 98% hydrazine hydrate are added to the mixture in portions, whereupon the temperature of the mixture raises to 85° C. After 30 minutes a solution of 1.44 g of sodium hydroxide in 4.5 ml of water is added to the mixture, followed by 10 ml of methanol. The resulting solution is poured into 130 ml of water, and the separated 5H-2,3-benzodiazepine derivative is isolated. 9.04 g (88%) of the title compound are obtained; m.p.: 129°-131° C. C20H21ClN2O2 =356.9. The crude product can be recrystallized e.g. from ethanol. The product with the highest purity grade melts at 147°-149° C. The rhodanide salt of the title compound ([C20H22ClN2O2 ]SCN=425.95) melts at 169°-171° C. after recrystallization from isopropanol.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][CH:25]([CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][NH2:44]>>[CH3:42][O:43][N:44]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][CH:25]([CH2:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C(CCc1ccccc1)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(CCc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine. The two (Z) and (E) compounds are not separated.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[CH3:20][O-:21].[Na+].Cl>CN(C=O)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([O:21][CH3:20])=[C:3]([OH:19])[CH:4]=[CH:5]3)=[CH:13][CH:14]=1
Reactant: C[O-]
Reactant: Oc1ccc(-c2ccc3c(Br)c(O)ccc3c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(O)ccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 1-bromo-6-(4-hydroxyphenyl)-2-naphthol (0.41 g, 1.30 mmoles), CuBr (0.19 g, 0.13 mmoles), sodium methoxide (3 ml of 4.4 N in methanol), and DMF (6 ml) was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into HCl (50 ml of 1 N aqueous solution), and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, stripped of solvent, and purified by silica column chromatgraphy (40% ethyl acetate—hexanes) to yield 0.31 g (89%) of the title compound as a white solid: mp 204-206° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.47 Hz), 7.19 (1H, d, J=8.81 Hz), 7.57-7.60 (3H, m), 7.71 (1H, dd, J=1.41 Hz, J=8.78 Hz), 7.94-7.98 (2H, m), 9.54 (2H, s); MS m/z (M−H)— =265;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 55 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=95:5 to 50:50, 170 mg, 55%) which was obtained as a white foam. MS: m/e=334.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1)=O.[BH4-].[Na+].Cl>O1CCCC1>[OH:2][CH2:3][CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1
Reactant: COC(=O)Cc1n[nH]c(=O)c2c1CCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCO)c2c1CCCC2
Temperature: 0 °C

Procedure:
The compound prepared in Example 15 (350 mg) was dissolved in tetrahydrofuran (8.0 mL). Under an atmosphere of argon, sodium borohydride (239 mg) was added thereto at 0° C. and the mixture was refluxed for 13 hours. After cooling to 0° C., 1N hydrochloric acid was added to the reaction mixture, which was adjusted to pH 5. The deposited solid was collected by filtration. The filtrate was concentrated and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated to give the title compound having the following physical data.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]([F:39])([F:38])[C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28](F)[CH:27]=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[F:38][C:11]([F:10])([F:39])[C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:27]=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH:19]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCOCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tetrahydro-2H-pyran-4-ol (220 mg, 2.11 mmol, 3.00 equiv, 98%) in N,N-dimethylformamide (5 mL). This was followed by the addition of sodium hydride (86 mg, 3.58 mmol, 5.00 equiv), in portions at room temperature. The resulting solution was stirred for 10 min at room temperature. To this was added N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide (300 mg, 0.70 mmol, 1.00 equiv, 98%). Then the resulting solution was stirred for an additional 2 h at 80° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate, and washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/methanol (20/1). The product was obtained as 400 mg (97%) of a brown oil.
Reaction SMILES: CO[C:3]1([CH3:11])[CH:7]=[CH:6][C:5]([O:9]C)([CH3:8])[O:4]1.CC(=O)/C=C\C(=O)C.[C:20](O)(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.O>[C:20]([CH:6]([CH2:7][C:3](=[O:4])[CH3:11])[C:5](=[O:9])[CH3:8])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(=S)c1ccccc1
Reactant: COC1(C)C=CC(C)(OC)O1
Agent: CC(=O)/C=C\C(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CC(C(C)=O)C(=S)c1ccccc1
Yield: 69.8 %

Procedure:
In a 50 ml three-necked flask equipped with thermometer, 10 ml addition funnel and magnetic stirrer is placed 6 g of 2,5-dimethoxy-2,5-dimethyl-2,5-dihydrofuran, 24 ml H2O and 1 drop of glacial acetic acid. The mixture (which is crude cis-3-hexene-2,5-dione) is stirred for one hour until homogeneous. Then 5.25 g thiobenzoic acid is added over a five-minute period. The mixture is allowed to stand for eighteen more minutes and is then extracted with 35 ml of methylene chloride. After drying over anhydrous sodium sulfate and subsequent solvent removal, 7.55 g of crude 3-thiobenzoyl-2,5-hexanedione is recovered. The crude material is purified by column chromatography on 108 g silicic acid packed in ether:hexane (1:9) mixture. Elution with 630 ml ether:hexane (1:9) solvent mixture; followed by elution with 500 ml ether:hexane (1:4) solvent mixture; followed by elution with 850 ml ether:hexane (1:3) solvent mixture gives 6.2 g of 3-thiobenzoyl-2,5-hexanedione, having the following analyses:
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([O:15][C:16]([CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:33][CH:34]([CH3:47])[C:35](=[O:46])[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].C(O)(=O)C>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Si:26]([O:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([CH:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[C:35]([OH:46])([CH:34]([CH3:33])[CH3:47])[C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:20][CH2:21]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)C(O)(C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropylamine (418 mg, 4.15 mmol) in anhydrous tetrahydrofuran (6 mL) under the atmosphere of argon was added a 1.58 M n-butyl lithium-hexane solution (2.5 mL, 5.4 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min, and then at −78° C. for 5 min. A solution of trans-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexan (1.36 g, 3.76 mmol) in anhydrous tetrahydrofuran (7 mL) was added dropwise at the same temperature over 7 min, and the reaction mixture was further stirred for 15 min. The cold enolate solution thus prepared was added dropwise via canula to a solution of benzyl 3-methyl-2-ketobutyrate (776 mg, 3.76 mmol) in anhydrous tetrahydrofuran (4 mL) having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was adjusted to pH 4 with acetic acid, and the temperature was raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases for extraction. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 20:1) to give dibenzyl 3-(trans-4-t-butyldimethylsilyloxycyclohexyl)-2-hydroxy-2-isopropylsuccinate as oil in amounts of 629 mg (low polar diastereomer, yield: 29%) and 801 mg (high polar diastereomer, yield: 37%), respectively.
Reaction SMILES: [Cl:1][CH:2]([Cl:37])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:27]C(=O)OC(C)(C)C)([CH3:26])[CH3:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:27][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@@H:8]([OH:7])[C@H:9]([NH:5][C:3](=[O:4])[CH:2]([Cl:37])[Cl:1])[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a solution of the product of Step 1 (50 mg. 0.09 mmol) in DCM (1 mL) is added TFA (0.25 mL) and stirred at room temperature for 1 hour. Reaction is diluted with toluene (5 mL) and concentrated. Crude product is dissolved in DCM (0.5 mL) and DIPEA (200 μL), adsorbed on celite and purified on silica gel column eluting from 5 to 20% MeOH/DCM. The combined fractions are concentrated to give an oil, which is basified using saturated aqueous NaHCO3 (0.5 mL), and extracted with ethyl acetate (3×2 mL). The combined extracts are dried over Na2SO4 and concentrated to give the title compound (3 mg). 1H NMR (400 MHz, CD3OD) δ 1.52 (s, 6H), 4.2-4.29 (m, 1.5H), 4.32-4.38 (m, 0.5H) 4.4-4.51 m, 1.5H), 4.55-4.61 (m, 0.5H), 4.89 (d, 1H, J=4.0 Hz) 6.19 (s, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.45-7.50 (m, 3H), 7.51-7.56 (m, 3H). m/z (Cl) 396 [M-OH].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCOC(C)=O.O>C(Cl)Cl>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[S:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: CN(C)C1CCNCC1
Reactant: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(C)C1CCN(S(=O)(=O)c2cc(C#N)ccc2Sc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of compound 29 (0.100 g, 0.26 mmol) in DCM (8.00 mL) was added 4-dimethylaminopiperidine (0.044 g, 0.34 mmol) and TEA (0.034 g, 0.34 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.0). After stirring at room temperature for 2 hrs, the reaction was complete as indicated by the absence of the starting material (TLC). Water was added and aqueous layer was extracted twice with DCM. Combined extracts were washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to form a clear oil. The oil was dissolved in DCM and purified with chromatography with a gradient from 0 to 30% MeOH in DCM. Pure fractions were combined, evaporated in vacuo, triturated with DCM and hexanes, and then filtered to yield compound 83 as a white powder (0.068 g, 100% HPLC purity, 56% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.26 (d, J=2 Hz, 1H), 7.89 (m, 2H), 7.78 (d, J=9 Hz, 1H), 7.71 (dd, J1=3 Hz, J2=9 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 3.79 (d, J=12 Hz, 2H), 2.85 (t, J=13 Hz, 2H), 2.22 (m, 1H), 2.12 (s, 6H), 1.79 (m, 2H), 1.40 (m, 2H); MS (ESI, EI+): m/z=470 (MH+); melting point: 140-143° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].O.O.C([N+]([O-:23])(CC)CC)C.O>CS(C)=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC[N+]([O-])(CC)CC
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0° C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48%) as a white solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M+, 100%).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]2O[C@@H:13]32)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[FH:29].[K].CS(C)=O>O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([F:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: F
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(F)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 140 °C
Yield: 19.9 %

Procedure:
A mixture of 100 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione, 200 mg of potassium hydrogen fluoride and 1 ml of dimethyl sulfoxide was heated at 140° C. for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (50/1)] to give 20 mg of 17α-acetoxy-6-fluoro-2-oxapregna-4,6-diene-3,20-dione.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.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]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Cn1cc(-c2nnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2N)cn1
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 160 mg (0.767 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. The reaction mixture was again stirred for 15 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). 66 mg of the target compound were obtained (47% of theory).