Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([OH:14])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[CH:2]=C.C([O:17]CC)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[OH:14][C:4]1([CH2:1][CH:2]=[O:17])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1
Reactant: C=CCC1(O)CCC2(CC1)OCCO2
Reactant: CCOCC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: O=CCC1(O)CCC2(CC1)OCCO2
Reaction time: 0.75 h

Procedure:
NalO4 (18.13 g) followed by OsO4 (4% in water, 0.96 mL) is added to a mixture of 8-allyl-1,4-dioxa-spiro[4.5]decan-8-ol (12.59 g), diethyl ether (65 ml), and water (85 mL) at room temperature. The mixture is vigorously stirred at room temperature overnight, before aqueous Na2S2O3 solution (50 mL) is added and stirring is continued for another 45 min. The combined organic phases are washed with water, dried (MgSO4), and concentrated. The crude product is used without further purification. Yield: 2.68 g (ca. 70% pure); Mass spectrum (ESI+): m/z=201 [M+H]+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CO>CN(C=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:11]1[CH2:12][C:13]2[C:22](=[O:23])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:15][C:14]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncccn1)C2

Procedure:
1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (100 mg, 0.3265 mmol) (prepared as in Example 5) and 2-chloropyrimidine (38 mg, 0.3265 mmol) were stirred in DMF (2.5 mL) at 100° C. for 16 h. The solvent was removed under vacuum and the residue purified by column chromatography (silica gel, 5% CH3OH/CH3Cl) to yield a yellow oil. Trituration of the oil with MeOH afforded the product as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[Br-].[CH:22]1([Zn+])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:22]1([C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:19][CH3:20])[CH:4]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: [Zn+]C1CCCCC1
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Agent: [Pd]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1O
Reaction time: 18 h

Procedure:
Intermediate 1 (850 mg) and tetrakis(triphenylphosphine)-palladium (0) (250 mg) are dissolved in tetrahydrofuran (16 ml), and thereto is added a 0.5 M tetrahydrofuran solution (20 ml) of cyclohexylzinc bromide under argon atmosphere at room temperature, and the mixture is stirred for 18 hours. A saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (120 mg).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:10][CH2:11][CH2:12][CH2:13][OH:14].CC([OH:22])C>CC(C)=O.O.[O-2].[Cr+6].[O-2].[O-2]>[F:6][C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:10][CH2:11][CH2:12][C:13]([OH:22])=[O:14]
Reactant: CC(C)O
Reactant: OCCCOc1cc(F)cc(F)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCOc1cc(F)cc(F)c1
Reaction time: 0.17 h

Procedure:
At about −20° C., 17.22 g (172.18 mmol) of chromium(VI) oxide were taken up in 1.2 l of acetone and 38 ml of water, and 19 ml of conc. sulfuric acid were slowly added to the mixture. The mixture was stirred for 10 min and then 8.10 g (43.05 mmol) of the compound from Example 168A in 400 ml of acetone were added dropwise over the course of 1 h. The mixture was stirred at 0° C. for 1.5 h. After addition of 90 ml of propan-2-ol, the reaction mixture was filtered through kieselguhr, the solvents were removed from the filtrate in vacuo, and the residue was taken up in 500 ml of diethyl ether. The solution was washed twice with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvents were removed in vacuo. 11.36 g of the title compound were obtained and were reacted further in the next stage without further purification.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[CH:31]1([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:11])[N:5]=[CH:4][C:3]=2[NH:20][C@@H:21]2[CH2:26][C@@H:25]3[CH2:27][C@@H:23]([C:24]3([CH3:29])[CH3:28])[C@H:22]2[CH3:30])[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1C1CC1)C2(C)C
Yield: 73.6 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (62 mg, 0.131 mmol), cyclopropylboronic acid (45 mg, 0.524 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (13 mg, 0.013 mmol) and potassium carbonate (72 mg, 0.524 mmol) in 1,4-dioxane-water (9/1, 0.7 mL) were stirred in a nitrogen stream at 100° C. for 6 hours. After cooling the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (chloroform/methanol=8/1) to give the desired product (42 mg, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7](C(F)(F)F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:28])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[Cl:29]C1C=C(Cl)C=CC=1CN>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:29])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:28])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1cccnc1
Product: O=C(NCc1ccc(Cl)cc1Cl)[C@@H]1CCC(=O)N1Cc1cccnc1

Procedure:
N-[(2,4-dichlorophenyl)methyl]-5-oxo-1-(3-pyridinylmethyl)prolinamide was prepared in a manner analogous to that described above for the synthesis of N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(3-pyridinylmethyl)prolinamide (E120) but using [(2,4-dichlorophenyl)methyl]amine in the place of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)C=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1C(=O)C=CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2-Maleimido)ethylcarbamic acid tert-butyl ester (48 mg, 0.2 mmol) was dissolved in a mixed solvent of trifluoroacetic acid and dichloromethane (30:70, 5 ml), followed by stirring at 0° C. for 2 hours, and then the reaction solution was concentrated. The thus obtained residue was dissolved in dichloromethane (20 ml), and a saturated aqueous sodium hydrogencarbonate solution (10 ml) was added thereto to separate the layers. The organic layer was dried over potassium hydrogencarbonate and filtered. The solvent was evaporated under reduced pressure to give 1-(2-aminoethyl)-3-pyrroline-2,5-dione (28 mg, 0.2 mmol, yield 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2cc(-c3ccc4[nH]ccc4c3)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
5-bromo-1H-indole (31.4 mg, 0.160 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (114 mg, 0.301 mmol), Fibercat palladium catalyst (Johnson-Matthey, 31 mg), and K2CO3 (2 M in water, 0.45 ml, 0.90 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on silica gel (5:1->4:1->2:1 hexanes/EtOAc) to afford crude product. This crude material was then purified two times via HPLC (10%->95% MeCN/water with 0.1% TFA) afford title compound (12.2 mg, 21%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:23]=[C:24]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]([CH3:22])([OH:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[N:7]=1.O.O.Cl[Sn]Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([N:23]=[C:24]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]([CH3:22])([OH:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:7]=1
Reactant: CC(O)(C#Cc1cn2nc(-c3ccco3)nc2c(N)n1)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)(C#Cc1cn2nc(-c3ccco3)nc2c(N)n1)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-methyl-1-(4-nitro-phenyl)-but-3-yn-2-ol-(17.7 mg, 0.044 mmol;. see Ex. 72 below which was prepared according to Example 24 above) in DMF (3 mL) was added SnCl2.2H2O (98 mg, 0.43 mmol) and the reaction was stirred at room temperature for overnight. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC eluting with a water/acetonitrile gradient to yield the title compound (6.5 mg, 39%) as yellow solid. 1H NMR (300 MHz, DMSO) δ 8.25 (s, 1H), 7.93 (br s, 1 H), 7.60 (s, 2H), 7.33 (m, 2H), 7.14 (br s, 1H), 7.04 (m, 2H), 6.72 (br s, 1H), 2.82 (s, 2H), 1.38 (s,3 H). MS: m/z=375 amu (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-])=O>CO.C1CCCCC1.[Pd]>[NH2:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a solution of methyl 4-amino-3,5-dinitrobenzoate (D203) (3.0 g, 12.4 mmol, 1 equiv) in MeOH (40 ml) and cyclohexane (80 ml) was added 10% palladium on charcoal (50% wet, 2.0 g, 33% w/w) and the resulting mixture was refluxed for 30 min then cooled to room temperature. The catalyst was filtered off through a pad of celite and washed with DMF. The combined organic phases were concentrated in vacuo and the residue triturated with Et2O/iso-hexane to give methyl 3,4-diamino-5-nitrobenzoate (D204) (2.1 g, 80%) as a red solid which was used in the next step without further purification. [M+H]+=212.2, RT=2.46 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].OS(O)(=O)=O.II.[I:19](O)(=O)(=O)=O>O.C(O)(=O)C>[I:19][C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(I)cc(C)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 88.2 %

Procedure:
To a mixture of 2,6-dimethylnitrobenzene (151 g, 1.0 mol), acetic acid (1200 ml), and conc. H2SO4 (60 ml) was added iodine (102 g, 0.4 mol) and periodic acid dehydrate (205 g, 0.9 mol). The resulting solution was heated at 90° C. for 4 days. After cooling to room temperature, the reaction mixture was diluted with water (2000 ml). The yellow crystals were filtered and washed with water to give 220 g of pure product (79%). 1H-NMR δ (DMSO-d6, 300 MHz): 7.95 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 2.27 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1Cl
Yield: 143.6 %

Procedure:
An acetonitrile solution (20 ml) of 3-trifluoromethyl-1H-pyrazole (0.5 g), dicerium ammonium nitrate (1.0 g) and N-chlorosuccinimide (0.7 g) was refluxed for 3 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying an organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-chloro-3-trifluoromethyl-1H-pyrazole (0.9 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[Br:1][C:2]1[C:10]2[C:9]([N:24]3[CH2:25][CH2:26][CH:21]([CH2:20][O:19][CH2:18][CH2:17][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:22][CH2:23]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: C1CCN(CCOCC2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Brc1csc2ncnc(N3CCC(COCCN4CCCC4)CC3)c12
Temperature: 110 °C
Yield: 93.4 %

Procedure:
5-Bromo-4-chlorothieno[2,3-d]pyrimidine (828 mg 3.33 mmol) in dry acetonitrile (13 mL) was treated with 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (1.057 g, 5.0 mmol,) and potassium carbonate (687 mg, 5.0 mmol) and heated at 110° C. for 30 min in a microwave. The reaction was then poured into ethyl acetate (50 mL) and water (30 mL) and the ethyl acetate layer separated, dried over sodium sulphate and concentrated in vacuum to give 5-bromo-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (1.322 g, 3.11 mmol, 93%). LCMS RT=2.91 min. M+1=427.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].II.[Br:20]Br.S([O-])(O)=O.[Na+]>ClCCl.[Fe].O>[Br:20][C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: BrBr
Agent: [Fe]
Agent: II
Agent: O=S([O-])O
Solvent: O
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Temperature: -10 °C
Reaction time: 6 h

Procedure:
In 30 ml of dichloromethane was dissolved 11.1. g of trans-4-pentylcyclohexylbenzene, and 0.1 g of iron powder and 0.05 g of iodine were added thereto. To the mixture was added dropwise 7.7 g of bromine dissolved in 20 ml of dichloromethane at 0° C. or lower. The mixture was stirred at -10° C. for 6 hours and then allowed to warm to room temperature. Water and then an aqueous solution of sodium hydrogensulfite were added to the reaction mixture, and the product was extracted with hexane. The extract was washed successively with a sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation, and the resulting crude crystals were recrystallized from ethanol to give 4.8 g of 1-bromo-4-(trans-4-pentylcyclohexyl)benzene. (
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][C:4]([C:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:23])=[CH:3][CH:2]=2)[CH2:10][CH2:11]1)[CH3:16]
Reactant: CC[C@H]1CC[C@H](CCc2ccccc2)CC1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](CCc2ccc(C(=O)CCC(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of 1-phenyl-2-(trans-4-ethylcyclohexyl)ethane (200.0 g, 0.93 mol), pulverized succinic acid anhydride (111.6 g, 1.11 mol) and CS2 (500 ml) was cooled with ice down to 0° to 5° C. Pulverized anhydrous aluminum chloride (248.0 g, 1.86 mol) was gradually added to the mixture. After removing the ice bath, the mixture was agitated for one hour and successively agitated for 2 hours on a water bath at 60° C. The resulting material was allowed to stand overnight. The reaction material was poured into a mixture of ice (500 g) and 6N-HCl (300 ml). The mixture was agitated sufficiently and CS2 and water were distilled off on a water bath, to obtain a residue. Toluene was added to the residue and then heated under reflux. After separating water by means of a DeanStoke type water separator, the resulting liquid was filtered off while hot and recrystallized to obtain the following 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)benzoyl)propanic acid (214 g, m.p.: 141.2°-142.6° C.). ##STR8##
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[O:30][CH3:31])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:28][C@:18]12[CH2:19][C:20](=[O:51])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]/[C:17]/2=[N:29]\[O:30][CH3:31]
Reactant: CO/N=C1\C[C@H]2[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCCC[C@]12O
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: CO/N=C1\C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Yield: 80 %

Procedure:
The title compound II-ar was prepared in 80% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone/CH2Cl2 60/20/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 5.46 (1H, s), 3.75 (3H, s), 3.20-2.93 (1H, dd), 2.86-2.75 (1H, d), 2.30-1.10 (17H, m), 0.96 (3H, s), 0.77 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:16]([C:18]1[C:30]([O:31][CH3:32])=[CH:29][C:21]([O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[C:20]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[CH:19]=1)=O.C[O-].[Li+]>CN(C=O)C.CO.O>[CH3:14][S:11]([N:10]([CH3:15])[C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:16]/[C:18]2[C:30]([O:31][CH3:32])=[CH:29][C:21]([O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[C:20]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[CH:19]=2)=[CH:9][CH:8]=1)(=[O:12])=[O:13]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide (Ex-101A, 298 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide (182 mg, 4.8 mmol) and stirred for 6 hours at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2×50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCl. The aqueous solution was then extracted with isopropyl acetate (2×50 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1Br.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[S:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cccc(S)c1
Reactant: O=Cc1cc(Br)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Sc2sc(C=O)cc2Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5-dibromothiophene-2-carbaldehyde (1.0 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (665 mg) and 3-methoxybenzenethiol (571 mg) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:1) to give the title compound as a pale-yellow crude oil (yield 1.30 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1>Cl>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(Cc1ccncc1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCOC(=O)C(CC(=O)O)(Cc1ccncc1)C(=O)OCC

Procedure:
8.75 g of ethyl 4-(4-pyridyl)-3,3-bisethoxycarbonylbutyrate are stirred at 50°-60° C. in 500 ml of 6N HCl for 2 h. The mixture is then concentrated in vacuo and allowed to react again at 50°-60° C. with 500 ml of 6N HCl for 2 h. It is then concentrated to dryness in vacuo and redistilled twice using a little toluene. The residue is taken up in a little water and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].C(O)(C(F)(F)F)=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([NH2:10])=[O:12])=[N:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(C#N)ccc1Br
Agent: O=S(=O)(O)O
Product: Cc1nc(C(N)=O)ccc1Br
Temperature: 40 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution of 5-bromo-6-methylpicolinonitrile (1.8 g, 9.14 mmol) in a mixture of TFA and sulfuric acid (30 mL, 4:1, V/V) was stirred at 40° C. for 16 h. The reaction mixture was poured into ice water. The resulting solid was filtered off and washed with water and dried to give the desired product as a white solid (1.0 g, 4.65 mmol, 54% yield). MS (ESI) m/z 217.1 [M+2]+.