Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N+](C1C=CC=CC=1)([O-])=O.[CH3:18][O:19][C:20]1[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=1[O:22][C:23]1[CH:28]=[C:27]([O:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[C:25]([NH2:36])[C:24]=1[NH2:37]>>[CH3:18][O:19][C:20]1[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=1[O:22][C:23]1[C:24]2[N:37]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:36][C:25]=2[CH:26]=[C:27]([O:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:28]=1
Reactant: O=Cc1ccccn1
Reactant: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1N
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc2[nH]c(-c3ccccn3)nc12
Reaction time: 1 h

Procedure:
0.026 ml of pyridin-2-carboxaldehyde was added to a nitrobenzene (0.5 ml) solution of 59 mg of 3-(2-methoxyphenoxy)-5-(pyridin-3-yloxy)-benzene-1,2-diamine at 120° C., and the reaction liquid was stirred for 1 hour at the same temperature. The reaction mixture was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 to ethyl acetate to chloroform/methanol=20/1). The solvent of the resulting fraction was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]([NH:12][C@@H:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:14]([O:16]C)=O)=[O:11])[CH3:6].[Na]>C(O)C>[OH:16][C:14]1[C@H:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:12][C:10](=[O:11])[C:9]=1[C:8]([O:7][CH2:5][CH3:6])=[O:22]
Reactant: CCOC(=O)CC(=O)N[C@@H](CC(C)C)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(O)[C@H](CC(C)C)NC1=O
Temperature: 25 °C

Procedure:
A solution of 123.1 g (0.38 mol, 2.5% less than theory) of "21 weight percent sodium ethoxide in ethanol" (Aldrich Chemical Co.) is added all at once to a solution of 101 g (0.39 mol) of (S)-2-[(3-ethoxy-1,3-dioxopropyl)amino]-4-methylpentanoic acid, methyl ester in 200 ml of absolute ethanol. There is no heat of reaction. After about two minutes a solid separates (sodium salt of product) and the mixture becomes thick. The mixture is heated at reflux for 30 minutes (complete solution) and then cooled to room temperature (solid reappears). The solid is collected by filtration and washed with diethyl ether. The resulting cake is dissolved by adding to 1 L of ice water with stirring, 400 ml of 1 N hydrochloric acid solution is added and the separated solid is filtered, washed with water and dried one hour under suction to afford (S)-2,5-dihydro-4-hydroxy-5-(2-methylpropyl)-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester as a moist solid which is used in the next steps without further purification. TLC (acetic acid, methanol, chloroform, silica gel, iodine) Rf =0.6.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][C:4]1[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[C:7]([C:9]([O:11]CC)=[O:10])[N:8]=1.[OH-].[Na+]>C1COCC1.O>[F:23][C:2]([F:1])([F:22])[CH2:3][C:4]1[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(CC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.41 mmol, 850 mg) was dissolved in THF (30 ml) and H2O (20 ml). NaOH (4.82 mmol, 200 mg) was added and the mixture was stirred at RT for 48 h. The reaction mixture was concentrated and acidified to pH 2 using 1 N HCl. The mixture was extracted with DCM and the organic layer was concentrated. Yield 310 mg. LC-MS: [M+1]=325.01.
Reaction SMILES: [Cl:1]Cl.[C:3]([NH2:13])(=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O>[Cl:1][NH:13][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(N)=O
Reactant: ClCl
Solvent: O
Product: CCCCCCCCC(=O)NCl
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 97.4 %

Procedure:
Gaseous chlorine is introduced at a speed of 95 g/h into a suspension of 194 g of 98.15% pure pelargonamide (1.21 mol) in 1400 ml of water. The introduction of chlorine is discontinued after 60 min and the suspension is still left under stirring for 20-30 min at 20° C. The solid is filtered off, is washed with water until all HCl has disappeared (300 cc. of water) and the chlorinated derivative is dried. 226 g of N-chloropelargonamide (yield 97.4%) having an active chlorine titer of 17.6% (theory 18.5%) are thus obtained.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21]
Reactant: C[C@]12C=CC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)C=C[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A tetrahydrofuran solution of 1,5-androstadiene-3,17-dione is added to a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran under nitrogen. After stirring overnight at room temperature, an aqueous solution of potassium sodium tartrate is added with stirring to form a readily filterable white solid. The reaction mixture is filtered and the filtrate dried over magnesium sulfate. The solvent is removed and the residue recrystallized from acetone to yield 1,5-androstadiene-3β,17β-diol.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH:7]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[Br:22])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OCc1cccc(COC(C)=O)c1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(Br)c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.7 %

Procedure:
To a suspension of m-xylylene glycol diacetate (28.4 g) and sodium acetate (55.2 g) dispersed in glacial acetic acid (130 ml) was added dropwise bromine (102.5 g) over 30 min at 15-20° C., and the mixture was stirred at 20-30° C. for 13 hr. The reaction mixture was poured into 10% aqueous sodium sulfite solution (700 ml) in an ice bath. The mixture was stirred and extracted twice with ethyl acetate (250 ml). The ethyl acetate layer was washed 3 times with 10% aqueous sodium hydrogencarbonate solution (300 ml) and the solvent was evaporated to give an about 93:7 mixture (37.6 g, 97.6%) of 2,4-bis(acetoxymethyl)bromobenzene and 2,6-bis(acetoxymethyl)bromobenzene as a yellow oil. 2,4-bis(Acetoxymethyl)bromobenzene was isolated by preparative HPLC and used in the measurement.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1>[CH2:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][OH:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C(O)c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirred solution of LAH (72.8 g, 1.92 mol) in THF (2.5 L) at 0° C. was slowly added 2,3-dihydro-1H-indene-5-carboxylic acid (100.0 g, 0.62 mol). The reaction mixture was stirred at 0° C. for 1 h. Then the reaction was quenched with H2O (72 ml) and NaOH (68 ml, 20%). The mixture was filtered and the organic layer was dried over Na2SO4, evaporated in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give the desired product (82.0 g, 90%). 1H NMR (CDCl3, 300 MHz); δ 2.03-2.13 (m, 2H), 2.91 (t, J=7.5 Hz, 4H), 4.64 (s, 2H), 7.13 (d, J=7.5, 1H), 7.18-7.24 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][C@@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@@H:12]([CH3:21])[CH2:11]2)=[CH2:9])=[N:6][CH:7]=1.[F:22][CH:23]([F:47])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[C:33]([CH3:46])[CH:32]=2)[N:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C)C=O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:47][CH:23]([F:22])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35]([C:2]3[CH:3]=[N:4][C:5]([C:8]([CH:10]4[CH2:15][CH2:14][C@@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@@H:12]([CH3:21])[CH2:11]4)=[CH2:9])=[N:6][CH:7]=3)[CH:34]=[C:33]([CH3:46])[CH:32]=2)[N:25]=1
Reactant: C=C(c1ncc(Cl)cn1)C1CC[C@@H](C(=O)OCC)[C@@H](C)C1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C=C(c1ncc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1)C1CC[C@@H](C(=O)OCC)[C@@H](C)C1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl rel-(1R,2S)-4-[1-(5-chloropyrimidin-2-yl)ethenyl]-2-methylcyclohexanecarboxylate (480 mg, 1.6 mmol), 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (570 mg, 1.6 mmol), tris(dibenzylideneacetone)-dipalladium(0) (140 mg, 0.16 mmol), XPhos (140 mg, 0.32 mmol) and potassium phosphate tribasic trihydrate (1.25 g, 4.8 mmol) in N,N-dimethylformamide (2 mL) was stirred at 90° C. under a nitrogen atmosphere for 12 hours. After cooling to 20° C., the mixture was diluted with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate. MS ESI calc'd for C28H32F2N5O2[M+G]+ 508. found 508. 1H NMR: (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.64 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.21 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 6.58 (t, J=54.4 Hz, 1H), 6.36 (s, 1H), 5.52-5.49 (m, 1H), 4.16-4.10 (m, 2H), 2.44 (s, 3H), 1.94-1.59 (m, 7H), 1.25-1.24 (m, 5H), 1.03 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1.[Br:21]N1C(=O)CCC1=O.C(OO)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:21][CH2:20][C:1]1[CH:2]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2nc(-c3cccc(C)c3)oc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OO)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Yield: 30 %

Procedure:
Methyl 2-m-tolylbenzo[d]oxazole-7-carboxylate (500 mg, 1.87 mmol), 1-bromopyrrolidine-2,5-dione (367 mg, 2.06 mmol) and benzoperoxoic acid (25.81 mg, 0.187 mmol) were added to toluene (30 mL) and the mixture was stirred at reflux overnight. The resulting mixture was evaporated, extracted with ethyl acetate (100 mL×4) and concentrated to obtain methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate as a solid (194 mg, yield 30%). LC-MS (ESI) m/z 347 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[C:9]([F:12])([F:11])[F:10].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ncnc(O)c1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1ncnc(Cl)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The mixture of 6-amino-5-(trifluoromethyl)pyrimidin-4-ol (N-4) (300 mg, 1.66 mmol) in POCl3 (8 mL) in a pressure vessel is stirred at 100° C. for 1 h. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is taken up in water (20 mL), basified with saturated NaHCO3 aqueous solution to pH=9 and then extracted with DCM (30 mL×3). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the desired product, 6-chloro-5-(trifluoromethyl)pyrimidin-4-amine (N-5) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(Cl)cccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Cl

Procedure:
The dichloride was prepared according to Procedure E using 2,4,8-trichloro-3-methylquinoline (0.475 g, 1.927 mmol), 2-(tributylstannyl)pyridine (0.780 mL, 2.120 mmol), palladium tetrakistriphenylphosphine (0.223 g, 0.193 mmol) in toluene (3.85 mL) to give 4,8-dichloro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=289.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH2:10]([N:17]1[CH2:22][C:21](OC)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CCOCC.C1COCC1>[CH2:10]([N:17]1[CH2:22][C:21]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC1=CC(=O)CN(Cc2ccccc2)C1
Reactant: Clc1cccc([Mg]Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C=C(c2cccc(Cl)c2)CN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of m-chlorophenyl magnesium bromide (85 mM) in ether (50 ml) was treated dropwise with a solution of 1-benzyl-1,6-dihydro-5-methoxy-3-[2H]pyridone (16.3 g, 75 mM) in THF (75 ml) and stirred 1 hour. The reaction mixture was poured onto cold 2 N hydrochloric acid (150 ml) and stirred 30 min. Removal of the resulting precipitate by filtration, followed by air-drying and recrystallisation from ethanol gave the title compound as the hydrochloride hydrate (14.7 g) m.p. 143°-5°.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[CH:16][C:17]3[C:18]([N:23]=2)=[N:19][CH:20]=[CH:21][N:22]=3)=[N:6]1>CO.[Pt](=O)=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[CH:16][C:17]3[NH:22][CH2:21][CH2:20][NH:19][C:18]=3[N:23]=2)=[N:6]1
Reactant: Fc1ccccc1Cn1nc(-c2ccc3nccnc3n2)c2cccnc21
Agent: O=[Pt]=O
Solvent: CO
Product: Fc1ccccc1Cn1nc(-c2ccc3c(n2)NCCN3)c2cccnc21

Procedure:
80 mg (0.22 mmol) of the compound from example 68 were initially charged in methanol (4 ml), then 12 mg (0.045 mmol) of platinum(IV) oxide were added and the reaction mixture was hydrogenated at standard pressure overnight. The reaction mixture was filtered through Celite and the filtercake was washed with methanol. The filtrate was concentrated to give 79 mg (92% purity, 90% of theory) of the title compound, which were converted without further purification.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].[CH2:29]([OH:31])[CH3:30]>S(=O)(=O)(O)O>[CH2:29]([O:31][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH3:30]
Reactant: CCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2α,3α-Epoxy-5α-pregnan-20-one (180 mg) was dissolved in 20 mL of absolute ethanol and cooled to °C. and added to a cold 1.0 mL ethanol solution containing 3-drops of concentrated sulfuric acid. This reaction mixture was stirred for 30 minutes at this temperature and an additional 30 minutes at room temperature, poured into 20% sodium bicarbonate solution and washed several times with chloroform. The combined organic phase was dried over potassium carbonate and concentrated and purified by preparative TLC silica plate in hexane/ethyl acetate (1:1), to give (80 mg, 40% yield) the title compound as fine white crystals.
Reaction SMILES: [CH:1]1([C:7]2[N:8](S(C)(=O)=O)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>C1COCC1>[CH:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)n1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2[nH]c(C3CCCCC3)cc2c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution containing 2-cyclohexyl-1-(methylsulfonyl)-5-nitro-1H-indole (5.8 g; 18 mmol) in THF (50 ml), tetrabutylammonium fluoride (1M solution in THF; 18 ml; 18 mmol) was added dropwise. The reaction mixture was refluxed for 18 hours, then cooled to room temperature. Water (50 ml) and EtOAc (50 ml) were added, the biphasic solution was transferred into a separating funnel, the organic layer separated and dried over Na2SO4, and the solvent was removed by evaporation under reduced pressure. The residue was purified by flash chromatography on silica gel (n-hexane/EtOAc, n-hexane 100→80%) to give 2-cyclohexyl-5-nitro-1H-indole (3.2 g), which was used without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH2:44][OH:45]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([N:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH:44]=[O:45])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 22.1 g of N-benzyloxycarbonyl-proline. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 450 ml of THF. To this solution was added 8.2 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant white solid substance were added 40.5 g of WSCD.HCl and 150 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 6.3 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 350 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 200 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 200 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 3.4 g (10.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:19])[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1
Reactant: Cc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
Reactant: c1cncc(B2OCCCO2)c1
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: ClCCl
Product: Cc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1

Procedure:
A mixture of 5-(3-chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole (75 mg, 0.275 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 40% ethyl acetate in hexane to 100% ethyl acetate afforded 5.4 mg (7.4%) of 5-[3-methyl-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazble. 1H-NMR (CDCl3), δ (ppm): 9.32 (s, 1H), 8.87 (d, 1H), 8.70 (d, 1H), 8.30 (m, 2H), 8.25 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.47 (m, 2H), 2.77 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.O1CCC[CH2:35]1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:35])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Dissolve 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (860 mg, 2.08 mmoles) in diethyl ether (100 mL) under N2. Cool the solution to 0° C. in an ice bath, and add sodium hydride (1.1 equiv; 2.29 mmoles; 91.52 mg), followed by injecting methyl iodide (2.00 equiv; 4.16 mmoles; 259.12 μL). Stir the mixture for 1 hour at 0° C., and then warm to room temperature. Inject tetrahydrofuran (40 mL) into the above mixture, and then stir at room temperature overnight. Concentrate the mixture under reduced pressure, and then dissolve the residue in EtOAc. Wash with saturated aqueous sodium chloride. Purify the residue via silica gel chromatography, eluting with EtOAc:hexane (7:3) to offer 270 mg (30% yield) of a title compound.