Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(N)cc1C
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-3-methylaniline (5 g, TCI) in triethylamine (50 ml) was added with methyl acrylate (3.6 ml, TCI), tris(2-methylphenyl)phosphine (2.5 g, TCI), and palladium acetate (606 mg, WAKO), and stirred at 90° C. for 18 hours. The reaction mixture was added with water (30 ml) and ethyl acetate (30 ml×2) for extraction, and then successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (yield: 4.0 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21])(=O)=O.[Na+].[I-:26]>CCOC(C)=O>[I:26][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21]
Reactant: [I-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1I
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (2) (5.0 g, 13.7 mmol) and NaI (7.0 g) in EtOAc (200 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature and washed with sat. aq. Na2S2O3. The organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel. Elution with CH2Cl2, gave 1-iodo-2,4-dinitronaphthalene (3) (4.3 g 91%) as yellow needle: mp (EtOAc/CH2Cl2) 194–195° C.; 1H NMR [(CD3)2SO] δ 8.76 (s, 1H, H-3), 8.54 (m, 1H), 8.33 (m, 1H), 8.00(m, 2H); 13C NMR δ 151.81, 147.05, 134.97, 132.18, 131.24, 123.88, 123.26, 117.50, 102.66. Anal. (C10H5IN2O4) C, H, N.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[Cl:25]C1C=C(NN)C=CC=1.C(N(CC)CC)C>C1(C)C=CC=C(C)C=1>[Cl:25][C:20]1[CH:19]=[C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)[CH:23]=[CH:22][CH:21]=1
Reactant: NNc1cccc(Cl)c1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Agent: Cl
Solvent: Cc1cccc(C)c1
Solvent: CCN(CC)CC
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(Cl)c1

Procedure:
A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.3 grams 3-chlorophenylhydrazine hydrochloride in the presence of 1.3 grams triethylamine in about 50 ml. meta-xylene. The mixture was then stirred at reflux overnight, and the reaction mixture evaporated to dryness under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with ethyl acetate as the eluant. The product containing fractions were combined and evaporated to dryness to produce a crude product, which was recrystallized from methanol to produce 2 grams 1-(3-chlorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 182°-184° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](/[CH:13]=[CH:14]/[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[C:11]([C:20]([N:22]([CH2:44][CH:45]([CH3:47])[CH3:46])[C@H:23]2[CH2:28][C@@H:27]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:24]2)=[O:21])[N:10]=[N:9]1>CO.[C].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[C:11]([C:20]([N:22]([CH2:44][CH:45]([CH3:47])[CH3:46])[C@H:23]2[CH2:28][C@@H:27]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:24]2)=[O:21])[N:10]=[N:9]1
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1/C=C/c1nccs1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CCc1nccs1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
tert-Butyl (3S,5R)-3-[({1-(2-fluorophenyl)-5-[(E)-2-(1,3-thiazol-2-yl)ethenyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (200 mg) and 5% palladium-carbon (20 mg) were suspended in methanol (4 ml), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atom) for 3 days. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (200 mg).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.Cl.[N+]([O-])([O-])=O.[Na+].[I-:42].[K+]>C(O)(=O)C.O.II>[I:42][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(N)cc21
Agent: Cl
Agent: II
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(I)cc21
Temperature: 0 °C
Yield: 52 %

Procedure:
A solution of 6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole (500 mg, 0.98 mmol) in acetic acid (15 mL) was diluted with H2O (1.0 mL) and stirred at 0° C. Concentrated HCl (250 μL, ˜3 mmol) in H2O (250 μL) was added. Sodium nitrate (90 mg, 1.3 mmol) in H2O (300 μL) was added, and the reaction stirred for 8 min. Iodine (10 mg) and a solution of potassium iodide (250 mg, 1.3 mmol) in H2O (250 μL) were added, and the frothing reaction stirred for 30 min at 23° C. The reaction was diluted with H2O (25 mL) and extracted with ethyl acetate (2×20 mL). Organics were washed with saturated sodium metabisulfite solution (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (8% ethyl acetate/hexanes) gave 316 mg (52%) of 6-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a faintly yellow oil, which slowly crystallized to a white solid. 1H NMR (300 MHz, CDCl3) δ 8.45 (d, 1H, J=9.0 Hz), 8.05 (s, 1H), 7.91-7.88 (m, 1H), 7.67-7.62 (m, 2H), 7.38-7.34 (m, 2H), 6.24 (s, 2H), 5.77 (s, 2H), 3.65-3.57 (m, 4H), 0.93 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.1 Hz), -0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H37N4O2Si2) C, H, N. Calculated: C, 50.31; H, 6.01; N, 9.03. Found: C, 50.55; H, 6.08; N, 9.00.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C([O-])(O)=O.[Na+]>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[C:3]([NH2:16])=[C:2]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1c(Nc2ccc(Cl)cc2)ncnc1N1CCCC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-Chloro-N4-(4-chlorophenyl)-pyrimidine-4,5-diamine I-(1A-1)a (114 mg, 0.45 mmol) and pyrrolidine (1 ml, excess) were combined and heated with stirring at 100° C. for 2 hours. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to dryness to yield the desired compound I-(17A-1)a (131 mg, quantitative) as an orange-brown solid: +ESI MS (M+1) 290.3; 1H NMR (500 MHz, CD3OD) δ 7.85 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 3.63 (m, 4H), 1.96 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Brc1cnc2c(c1)CCN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Brc1cnc2[nH]ccc2c1
Yield: 78.7 %

Procedure:
A mixture of 5-bromo-7-azaindoline (15.6 g, 78 mmol) and precipitated, active manganese (IV) oxide (21.9 g, 252 mmol) in toluene (300 mls) was heated at 90° C. for 1 hour and the hot solution filtered through a pad of diatomaceous earth. The diatomaceous earth and manganese residues were washed with acetone and these washings added to the toluene filtrate. Evaporation of the filtrate under vacuum gave 5-bromo-7-azaindole (12.1 g, 78%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](O)=[O:18])[CH2:12][CH2:11]1)=[O:7].[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH:29]1([NH:34][C:17](=[O:18])[CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=3)[CH2:15][CH2:14]2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)CN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1)NC1CCCC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)acetic acid (73 mg, 0.18 mmol), TEA (123 μL, 0.88 mmol), and cyclopentylamine (30 mg, 0.35 mmol) in DMF (1 mL) was treated with a solution of HATU (100 mg, 0.26 mmol) in DMF (1 mL). The reaction mixture was stirred overnight then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigourously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs.
Reaction SMILES: [N:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[N:1]=[C:2]([CH:9]=[O:10])[CH:3]=[CH:4][CH:5]=1
Reactant: OCCO
Reactant: O=Cc1cccc(C=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=Cc1cccc(C2OCCO2)n1
Yield: 60.3 %

Procedure:
To a solution of pyridine-2,6-dicarbaldehyde (5 g, 37.4 mmol) in benzene (100 mL) was added ethylene glycol (1.1 g, 18.5 mmol) and p-toluenesulfonic acid (0.3 g, 1.8 mmol). The reaction mixture was equipped with a dean stark condenser and refluxed for 15 min. The reaction mixture was concentrated under reduced pressure and the resulting crude was purified via column chromatography to afford 6-(1,3-dioxolan-2-yl)picolinaldehyde (2 g, 30%). MS (ES+) (M+H) 180.0495
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[C:13]([O:18][CH3:19])[CH:12]=[C:11]([F:20])[C:10]=2[F:21])=[C:4]([F:22])[CH:3]=1.Cl>[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[C:13]([O:18][CH3:19])[CH:12]=[C:11]([F:20])[C:10]=2[F:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Product: COc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1N
Yield: 85 %

Procedure:
Intermediate I-6a was prepared from (4-bromo-2-fluoro-phenyl)-(2,3-difluoro-5-methoxy-6-nitro-phenyl)-amine (I-4a: 16 g, 0.0425 mol), zinc powder (19.6 g, 0.298 mmol) and concentrated HCl (45 mL) using procedures analogous the preparation of Intermediate (I-5a) above to afford the product (85% yield). H1NMR (CDCl3, 300 MHz): δ 7.24 (dd, 1H), 7.06 (dt, 1H), 6.66-6.58 (m, 1H), 6.36 (t, 1H), 5.36 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:17]=[O:18])[CH3:9]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-ethylbenzene (25 g) in dry tetrahydrofuran (350 ml) at −70° C. was treated dropwise with n-butyllithium (59 ml of a 2.5M solution in hexanes) and stirred for 1 hour. N,N-Dimethylformamide (30 ml) was added and the solution was stirred at −70° C. for 1 hour and allowed to warm to room temperature. The reaction mixture was partitioned between saturated ammonium chloride solution and ethyl acetate. The organic phase was washed with 1N hydrochloric acid, dried (MgSO4) and evaporated.
Reaction SMILES: P(N)([O-])[O-].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:11][C@@:12]12[C@H:22]3[CH2:23][CH2:24][C@:25]4([CH3:35])[C@@:29]5([O:34]C(=O)CC5)[CH2:28][CH2:27][C@H:26]4[C@@H:21]3[CH:20]=[CH:19][C:18]1=[CH:17][C:15](=[O:16])[CH2:14][CH2:13]2.C[Si](Cl)(C)C>CCOCC.C(Cl)Cl.[Cu].C1C=CC=CC=1>[CH2:5]([C@@H:13]1[C@@:12]2([CH3:11])[C:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:35])[C@H:26]3[CH2:27][CH2:28][C:29]2=[O:34])=[CH:17][C:15](=[O:16])[CH2:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCC
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]21CCC(=O)O1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: NP([O-])[O-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCCCC[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
(C6H6) (10.1 mg, 0.02 mmol, 0.05 eq.) and the phosphoramidite ligand (21.6 mg, 0.040 mmol, 0.10 eq.) were dissolved in Et2O (2.0 mL) under an argon atmosphere and allowed to stir for 1 h at room temperature. In another flask, Cp2ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 1-hexene (0.13 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for 40 min, the resulting clear yellow solution was transferred via syringe over about 1 min to the stirred solution containing the copper and ligand under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before Canrenone (136.0 mg, 0.40 mmol, 1.0 eq.) and TMSCl (0.26 mL, 2.00 mmol, 5.0 eq.) were added sequentially dropwise via syringe. Stirring at room temperature was continued arbitrarily for 15 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and NH4Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the former phase was extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (sat. aq., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the yellow residue (30:70 EtOAc/petrol; SiO2) gave major diastereomer (2) (+)-7α-hexyl-17α-hydroxy-3-oxo-pregn-4-ene-21-carboxylic acid γ-lactone (101 mg, 0.24 mmol, 59%) and minor diastereomer (2a) (+)-1α-hexyl-4-androstene-3,17-dione (35 mg, 0.082 mmol, 21%). Diastereomeric ratio (4.8:1) was determined by integration of 1H NMR spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:34]4[C:30](=[O:40])[C:31]5[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:33]4=[O:35])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 4/500 mg, 1.21 mmol), phthalimide (534 mg, 3.63 mmol) and triphenylphosphine were dissolved in a 1:1 mixture of THF and DMF (10 ml). Ditertbutyl azodicarboxylate (698 mg, 3.03 mmol) was added at 0° C. and mixture was stirred at room temperature for 4 hours. After evaporation, the crude mixture was purified by silica gel chromatography (6% methanol/CH2Cl2) to give the title compound (33% yield); NMR Spectrum: 4.09 (t, 2H), 4.50 (t, 2H), 5.31 (s, 2H), 7.31 (d, 1H), 7.38 (t, 1H), 7.60 (d, 1H), 7.77 (dd, 1H), 7.83-7.90 (m, 4H), 7.99 (s, 1H), 8.05 (d, 1H), 8.31 (s, 1H), 8.61 (d, 1H); Mass Spectrum: 542 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Li+]>C1COCC1>[CH3:1][O:2][N:3]=[C:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(=NOC)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CON=C(CC(=O)O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 3-(methoxyimino)-3-(4-methoxyphenyl)propanoate from Step A in THF (5 mL) was added 1 N lithium hydroxide (5 mL), and the resulting solution was stirred at room temperature for 12 h. Most of the solvents were removed in vacuo, and 1N hydrochloric acid (5 mL) was added. The aqueous layer was extrated with ethyl acetate (x4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a white solid (350 mg). 1H NMR (400 MHz, CDCl3) δ 7.58 (m), 6.89 (m), 4.00 (s), 3.96 (3), 3.81 (s), and 3.78 (s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.Cl.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>O>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:15][C:14]([OH:18])([CH3:17])[CH3:16])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: Cl
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Reaction time: 72 h
Yield: 3 %

Procedure:
A solution of 5.2 g (30 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 20 mL of water and a solution of 7.8 g (61 mmol) of 70% aqueous tert-butyl hydroxperoxide are added simultaneously over one hour at 35-50° C. to a mixture of 0.33 g (1.2 mmol) of ferric chloride hexahydrate, 8 mL of water, 0.2 mL of 37% hydrochloric acid, and 60 mL of tert-butyl alcohol. The reaction mixture is maintained at 45° C. for one hour after the addition and is then stirred at room temperature for three days. Gas chromatography shows 3% of the title compound is present in the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([C:17](O)=[O:18])=[C:5]2[O:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:6]([CH2:17][OH:18])=[C:5]2[O:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1c(C(=O)O)n(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCCCOc1c(CO)n(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (6.31 g, 16 mmol) in tetrahydrofuran (50 mL were added oxalyl chloride (1.7 mL, 19.2 mmol) and N,N-dimethylformamide (2 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (2.11 g, 56 mmol) in 1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-bromo-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone (5.87 g, 96.5%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O>[Ni].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)cc([N+](=O)[O-])c1Cl
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(-c2ccccc2)cc(N)c1Cl

Procedure:
A solution of 2.79 g. (0.01 mole) of 4-chloro-3,5-dinitrobiphenyl [R. C. Hall and C. S. Giam, J. Agr. Food Chem 20 (3) 546-52 (1972)] in 200 ml. of dioxane is hydrogenated at 3 atmospheres using Raney Nickel Catalyst. The catalyst is removed by filtration and the residue concentrated under reduced pressure. The residue is recrystallized from ethanol-water. There is obtained 1.12 g. (51%) of material melting point at 142°-144.5°. Additional recrystallization raises the melting point to 146.7°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22]>CC#N>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(OCCN(C)C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a stirred mixture of methyl 3-hydroxybenzoate (200 mg, 1.32 mmol), and K2CO3 (169 mg, 1.58 mmol) in MeCN (50 mL) was added 2-chloro-N,N-dimethylethanamine (137 mg, 1.58 mmol). The mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound that was used without further purification (300 mg, Yield 98%). 1H NMR (CDCl3, 400 MHz): δ 7.61-7.53 (m, 1H), 7.53-7.47 (m, 1H), 7.26-7.23 (m, 1H), 7.06-7.04 (m, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.84 (s, 3H), 2.69 (t, J=5.6 Hz, 2H), 2.28 (s, 6H). LCMS (m/z): 224.2 (M+1).