Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>O>[O:37]=[C:28]1[C:29]2[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C(c1cccc(O)c1)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 0.09 g. (0.0024 mole) of 60% sodium hydride in 10 ml. of dry N,N-dimethylformamide is added dropwise over 5 minutes a solution of 0.5 g. (0.0024 mole) of 1-(3-hydroxybenzoyl)piperidine, prepared according to the method of G. Tilly, Chem. Ther. 2 (1), 57-65 (1967); C. A. 67 32432S, in 10 ml. of dry N,N-dimethylformamide. The mixture is stirred at room temperature for 5 minutes and then 0.64 g. (0.0024 mole) of N-(3-bromopropyl)phthalimide is added. The mixture is stirred at room temperature for 1 hour and is diluted with water to the cloudy point. The precipitate which forms is collected and is air dried to give 0.5 g. of product. A small amount is recrystallized from ethanol to give the analytical sample, m.p. 120°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 54.3 %

Procedure:
To a solution of 4-fluoroaniline (1 g, 9 mmol) in DCM (20 mL) at room temperature was added isobutyraldehyde (985 μL, 10.8 mmol) followed by portionwise sodium triacetoxyborohydride (2.86 g, 13.5 mmol) and the reaction was stirred at room temperature for 64 hours. The reaction was concentrated and then dissolved in DCM and MeOH, dry loaded onto silica then purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give (4-fluoro-phenyl)-isobutyl-amine (817 mg, 54%). LCMS (m/z, Method A) ES+ 168 [M+1]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15]O)=[NH:14])=[CH:11][N:10]=1>CN(C=O)C>[Cl:8][C:9]1[N:10]=[CH:11][C:12]([C:13]2[N:15]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][N:14]=2)=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)O1
Reactant: N=C(NO)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc(-c2ccc(Cl)nc2)no1
Temperature: 120 °C
Yield: 70.9 %

Procedure:
Succinic anhydride (0.39 g, 3.89 mmol) and 6-chloro-N-hydroxy-nicotinamidine (0.67 g, 3.89 mmol) were dissolved in 2 mL of DMF and heated at 120° C. for 2 h. The cooled solution was filtered and the precipitate was washed with water, and dried to give the product as 0.70 g (71%) of colorless solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1.C[CH2:19][OH:20]>[Ni]>[Cl:1][C:2]1[C:7]([NH:8][CH:19]=[O:20])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: CCO
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Ni]
Product: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
The title compound of Example 24 (6.77 g, 24.26 mmol) was placed in a Parr bottle containing 220 ml absolute EtOH and 10.0 g (wet) Raney nickel catalyst that had been previously shaken under hydrogen (40 psi) for 10 minutes. The mixture was shaken under hydrogen (40 psi) for an hour, filtered over celite, and the filtrate was concentrated to a yellow-white solid that was dried under vacuum overnight. This solid was stirred in 1,2-dichloroethane (250 ml) at 0° C. Acetic anhydride (30 ml) was added, followed by formic acid (30 ml), dropwise under nitrogen. The resulting mixture was stirred at room temperature for 2 hours, concentrated to half the original vlume; and azeotroped with toluene to remove residual formic/acetic acid. The crude solid was triturated with methanol to give the title compound (4.92 g, 73%) as an off-white solid; m.p. 206°-209° C. (dec); 1H-NMR (DMSO-d6) δ 1.08 (d, J=6.8 Hz, 6.0 (CH3)2CH), 2.74 (m, J=6.8 Hz, 1.0 (CH3)2CH), 8.18 (d, J=10.3 Hz) and 10.26 (br s) [total 1.0, NHCHO from two conformers], 11.17 br s, 1.0).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8]1.ClC1[N:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:24]=1[C:25]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:26]>>[Cl:45][C:42]1[CH:43]=[N:44][C:12]([N:9]2[CH2:10][CH2:11][CH:7]([CH2:6][O:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[C:24]([CH:41]=1)[C:25]([NH:27][C:28]1([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(COc4cccc(F)c4)C3)CC2)cc1
Yield: 42.9 %

Procedure:
The title compound (D200) (38 mg) was prepared according to the experimental procedure described in Description 160 starting from tert-butyl 3-((3-fluorophenoxy)methyl)pyrrolidine-1-carboxylate (D40) (100 mg, 0.338 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (61.8 mg, 0.169 mmol).
Reaction SMILES: N(OS(=O)(=O)O)=[O:2].[CH2:8]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[C:17]=1[C:18](N)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.ClCCl>[CH2:8]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[C:17]=1[C:18]([OH:2])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(N)=O
Reactant: O=NOS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of 1.81 g (12.81 mmol) nitrosylsulfuric acid in 1.5 ml water at 0° C. under nitrogen, was added dropwise a suspension of 463 mg (1.423 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzamide in 2.9 ml dichloromethane. The reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was poured over ice and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude solid was purified with flash column chromatography on silica (20 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>100% in 15 minutes) to provide 431 mg (y: 64.9% yield) of the title compound as a white solid. MS (m/e): 325.1 (M−H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:6][C:7]([C:9]1([NH:14][C:15](=[O:21])[C@@H:16]([SH:20])[CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:2].[CH:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[NH:6][C:7]([C:9]1([NH:14][C:15](=[O:21])[C@@H:16]([S:20][C:36]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:37])[CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](S)C(C)C)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(=O)C2CCCC2)C(C)C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[[1-[(2-(S)-mercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine ethyl ester (0.32 g, 0.73 mmole), cyclopentanecarboxylic acid (0.083 g, 0.73 mmole), dicyclohexylcarbodiimide (0.15 g, 0.73 mmole), 1-hydroxy-7-azabenzotriazole (0.10 g, 0.73 mmole), and triethylamine (0.10 ml, 0.73 mmole) in methylene chloride (30 ml) is stirred overnight at room temperature. The resulting mixture is filtered, washed with sodium bicarbonate solution, then with brine, dried over magnesium sulfate and evaporated to dryness. The residue is purified by flash chromatography on silica gel eluting with hexane ethyl acetate. The pure fractions are concentrated and the residue is crystallized from diethyl ether to yield N-[[1-[(2-(S)-cyclopentylcarbonylmercapto-3-methyl- 1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine ethyl ester, m.p. 130°-131° C., the compound of formula Ill wherein R4 is 4-hydroxyphenyl, R2 is ethyl, R3 is cyclopentylcarbonyl, and R4 is isopropyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[O:9][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(I)cc1Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1ccc(I)cc1Cl)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 2-chloro-4-iodophenol (351.2 g, 1.38 moles) in toluene (1750 ml) under nitrogen, was added triethylamine (168 g, 1.66 moles), dimethylaminopyridine (8.5 g, 0.069 moles) and chlorotriisopropylsilane (320 g, 1.66 moles), then stirred for 16 hours. After this time the reaction was quenched by the addition of aqueous hydrochloric acid (2M, 1000 ml) and the organic phase washed with water (1000 ml). The solution was dried by azeotropic distillation of toluene, to give the title compound as a clear oil (497 g, 87%).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].I[C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1>N1CCCCC1.[Cu]I>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(OCCN2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 7.0 mL (49.5 mmol) ethynyl-trimethyl-silane is slowly added to a mixture of 14.3 g (45 mmol) 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine, 1.04 g (0.9 mmol) tetrakis-triphenylphosphane-palladium and 171 mg (0.4 mmol) CuI in 140 mL piperidine (exothermic reaction) and stirred for 30 minutes. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:25]([NH:27][NH2:28])=[O:26])[CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:28][NH:27][C:25]([CH:21]1[CH2:24][CH2:23][CH2:22]1)=[O:26])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: Brc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cccc(Br)c1
Reaction time: 8 h
Yield: 190.7 %

Procedure:
A mixture of 2-methoxyphenylboronic acid (4.3 g, 28.3 mmol), 3,5-dibromobenzene (20 g, 85.5 mmol, 3 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (100 mg) in ethyleneglycol dimethylether (25 mL) and a solution of sodium bicarbonate (8.2 g, 0.098 mol) in water (140 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic phase was washed with water (2×300 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica (150 g) with heptane (6 L) to afford pure 21 (14.2 g, 58%).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](O)[CH3:34].O>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:5])[C:34]1[CH:33]=[CH:15][C:14]([C:2]2[C:7](=[O:8])[N:6]3[CH:9]=[CH:10][S:11][C:5]3=[N:4][C:3]=2/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:13][CH:12]=1
Reactant: CCO
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(N(C)C)cc2)c1OCC(C)C

Procedure:
The title compound was prepared from Intermediate 7 (100 mg, 0.207 mmol), 4-N,N-dimethylaminophenylboronic acid (47 mg, 0.290 mmol), Pd[(C6H5)3P]4 (10 mg, 0.009 mmol) and sodium carbonate (131 mg, 1.244 mmol) in a mixture of toluene, ethanol and water according to the procedure outlined in Example 1 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 75 mg of the product; 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.9 Hz, 6H), 1.85-1.89 (m, 1H), 2.95 (s, 6H), 3.62 (d, J=6.3 Hz, 2H), 3.77 (s, 3H), 6.77 (d, J=9.0 Hz, 2H), 6.82-6.92 (m, 1H), 6.98-7.04 (m, 3H), 7.15 (d, J=9.0 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 476.46 (M+H)+.
Reaction SMILES: C([Sn]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(CCCC)CCCC)CCC.Br[C:21]1[O:22][CH:23]=[CH:24][C:25]=1[Br:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:26][C:25]1[CH:24]=[CH:23][O:22][C:21]=1[C:18]1[CH:19]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccoc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccoc1-c1ccncc1
Temperature: 100 °C
Yield: 24.7 %

Procedure:
A solution of tributylstannylpyridine (8.0 g, 21.7 mmol) and 2,3-dibromofuran (5.9 g, 26.1 mmol) in dry toluene (200 ml) was treated with bis(triphenylphosphine)palladium (II) chloride (1.5 g, 2.2 mmol) and heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.2 g, 25%); 1H NMR (CDCl3) 8.66 (2H, d, J 11 Hz), 7.84 (2H, d, J 11 Hz), 7.50 (1H, d, J 3 Hz), 6.60 (1H, d, J 3 Hz).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C@H:12]1[C:20]2[C:15](=[C:16]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([C:36]#[N:37])[CH:27]=4)[O:23][N:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)[S:8]([CH3:11])(=[O:10])=[O:9])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:36]([C:28]1[CH:27]=[C:26]([C:24]2[O:23][N:22]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH2:14][CH2:13][C@H:12]4[N:7]([CH2:6][CH2:5][OH:4])[S:8]([CH3:11])(=[O:9])=[O:10])[N:25]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH:33]([CH3:35])[CH3:34])#[N:37]
Reactant: CC(=O)OCCN([C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N(CCO)S(C)(=O)=O)no2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)methylsulfonamido)ethyl acetate (12 mg, 0.22 mmol) in a 1:1 mixture of MeOH/H2O was added K2CO3 (9.48 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated to dryness. The crude reaction mixture purified by preparative HPLC to afford (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-N-(2-hydroxyethyl)methanesulfonamide 112. LCMS-ESI (m/z) calculated for C24H26N4O5S: 482.2. found 505.1 [M+Na]+, tR=3.55 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[CH2:11][CH2:10][C@:9]3([OH:26])[C@H:12]4[C@H:22]([CH2:23][CH2:24][C@:7]23[CH3:8])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([OH:25])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)=[CH:2]1.CN(C)C=O.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>O>[Si:37]([O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@:9]3([OH:26])[CH2:10][CH2:11][C@@H:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH2:16]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Yield: 113.7 %

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH:28]=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
The product from Step B was dissolved in methanol (20 mL) with naphthalene-1-carboxaldehyde (0.67 mL, 4.7 mmol), sodium cyanoborohydride (0.350 g, 5.6 mmol) at pH 6 (adjusted with acetic acid) and the reaction stirred overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was chromatographed on silica gel with ethyl acetate in hexane, and the title compound isolated as an oil. NMR (CDCl3, 300 MHz) d 8.34 (1H, d, J=7 Hz), 7.85 (1H, dm, J=7 Hz), 7.79 (1H, m), 7.51 (2H, m), 7.39 (2H, m), 4.34 (1H, d, J=12 Hz), 3.98 (1H, br s), 3.91 (1H, dd, J=12, 6 Hz), 3.75 (3H, s), 3.60 (1H, br s), 3.44 (1H, d, J=12 Hz), 3.27 (1H, t, J=3 Hz), 3.19 (1H, d, J=12 Hz), 3.09 (1H, td, J=10, 3 Hz), 2.42 (1H, br s), 1.44 (9H, s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(O)c2)c1
Yield: 95.6 %

Procedure:
1.35 g of Methyl (3′-benzyloxy-4′-methoxybiphenyl-3-yl)acetate was dissolved in a mixed solvent of 10 ml of ethyl acetate and 30 ml of ethanol, then 500 mg of 10% palladium-carbon was added thereto, and the mixture was stirred overnight in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 970 mg of the title compound in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)nn1C(C)(C)C

Procedure:
92 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2,3-dimethylphenyl)piperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).