Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[CH3:23][N:16]([CH2:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccncc1
Agent: Cl
Solvent: CO
Product: CN(CC1CCNCC1)c1ccncc1
Reaction time: 7 h
Yield: 100 %

Procedure:
Hydrogen chloride gas is passed through a methanol (500 mL) solution of 1-t-butoxycarbonyl-4-{[(methyl)(pyridin-4-yl)amino]methyl}piperidine maintaining <20° C., for 5 minutes. The mixture is kept at this temperature for 7 hours, then at 4° C. for 16 hours before it is concentrated in vacuo providing 4-{[(methyl)(pyridin-4-yl)amino]methyl}piperidine hydrochloride (4.85 g, >100%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(Nc2ccccc2)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCc1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(CCCC)cc4)cc3)cc2)cc1
Yield: 58.7 %

Procedure:
21.1 g (0.094 mol) of N-phenyl-p-normalbutylaniline, 15.4 g (0.038 mol) of 4,4'-diiodobiphenyl, 15.7 g (0.11 mol) of anhydrous potassium carbonate, and 1.1 g (0.017 mol) of copper powder were mixed. The mixture was then allowed to undergo reaction at a temperature of 170° to 220° C. for 27 hours. The reaction product was then extracted with 140 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain an oily material. The crude product thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/5 mixture of toluene and n-hexane) to obtain 13.4 g (yield: 58.6%) of N,N'-bis(p-normalbutylphenyl)-N,N'-diphenylbenzidine. The melting point of the product was from 135.0° C. to 135.5° C.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18](O)=[O:19])=[C:13]([F:22])[CH:12]=1.CN.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18]([NH:4][CH3:1])=[O:19])=[C:13]([F:22])[CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(O)c1ccc(Br)cc1F
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (0.2 mL, 0.001 mol) was added to a mixture of (4-bromo-2-fluorophenyl)(hydroxy)acetic acid (0.1 g, 0.4 mmol), methylamine (2M in THF, 0.24 mL, 0.48 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.21 g, 0.00048 mol) in methylene chloride (2 mL). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated. The residue was purified by chromatography on silica gel with 10% methanol in dichloromethane to afford the desired product. LCMS: (M+H)=261.9/263.9.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>CS(C)=O.[Cl-].[Na+].O>[C:19]1([CH:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(Br)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(C=O)cc1)c1ccccc1
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (528 mg, 4.32 mmol) in dimethylsulfoxide (8 mL) was added potassium t-butoxide (558 mg, 4.97 mmol) and the mixture was stirred for 20 mins. 1-Bromoethylbenzene was added dropwise and the reaction was stirred for 1 hour at room temperature It was then poured into brine (8 mL) and extracted with ethyl acetate (3×10 mL). The organics were combined; dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 15:85) to afford 930 mg (95%) of 4-(1-phenylethoxy)benzaldehyde as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:25][CH2:24]3)[C:15]=2[C:16]=1[CH3:17])=O)C.[F-].[K+]>C1COCC1.O.C(OCC)(=O)C>[CH3:17][C:16]1[C:15]2[C:18]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:25][CH2:24]3)=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][C:12]=1[CH2:10][OH:9]
Reactant: CCOC(=O)c1oc2cccc(OC3CCN(Cc4cccnc4)CC3)c2c1C
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)oc2cccc(OC3CCN(Cc4cccnc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a cooled (0° C.) suspension of LiAlH4 (17 mg) in THF (1 ml) was added a solution of 3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (44 mg), the compound in Example 108, in THF (0.5 ml) and the resulting suspension was stirred at 0° C. for one hour. To the suspension was dropwise added a solution of KF (122 mg) in H2O (100 μl) at 0° C. over five minutes. The suspension was stirred at room temperature for 30 minutes and diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH=10:1 as a developing solvent) to give [3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-benzofuran-2-yl]-methanol (33 mg) as a colorless oil. FAB-MS: m/z 353 (MH+); 1H-NMR (CDCl3): δ 2.00 (4H, m), 2.38 (3H, s), 2.42 (2H, m), 2.68 (2H, m), 3.55 (2H, s), 4.51 (1H, m), 4.71 (2H, s), 6.59 (1H, d, J=8 Hz), 7.00 (1H, d, J=8 Hz), 7.13 (1H, t, J=8 Hz), 7.26 (1H, dd, J1=8 Hz, J2=5 Hz), 7.68 (1H, dt, J1=8 Hz, J2=2 Hz), 8.51 (1H, dd, J1=5 Hz, J2=2 Hz), 8.54 (1H, d, J=2 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[C:27]1=[O:44])([CH3:25])[CH3:24]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:44])[N:26]([CH:23]([CH3:25])[CH3:24])[CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC(C)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C(C)C)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=466.0.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7].N1C=CC=CC=1.C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:34][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NNC(=O)CC(CCO)c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
tert-Butyl N′-[5-hydroxy-3-(3-trifluoromethylphenyl)pentanoyl]hydrazinecarboxylate (2.0 g) was dissolved in methylene chloride (53 mL). Pyridine (1.29 mL), carbon tetrabromide (2.64 g) and triphenylphosphine (2.1 g) were added at room temperature, followed by stirring for 30 minutes. The reaction solution was partitioned with water and ethyl acetate. Then, the organic layer was washed with saturated ammonium chloride aqueous solution and a saturated sodium bicarbonate aqueous solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (1.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.C(=O)=O.Cl.[CH3:23][O:24][NH:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:23][O:24][N:25]([CH3:26])[C:7](=[O:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[C:3]([O:2][CH3:1])=[O:12]
Reactant: CNOC
Reactant: COC(=O)C(C)(C)CCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methoxy-4,4-dimethyl-5-oxopentanoic acid from Step B (7.00 g, 40.2 mmol), in DCM, was added DMF (0.1 mL), followed by the slow addition of oxalyl chloride (5.00 g, 39.4 mmol) over 33 minutes, during which time the reaction flask was maintained under a constant stream of dry nitrogen. Stirring was continued under a light stream of dry nitrogen for an additional hour, during which time the rate of carbon dioxide evolution diminished. This freshly formed acid chloride was then transferred via cannula into a 500 mL round bottom flask, cooled to 0° C., which already contained N-methoxymethanamine hydrochloride (5.76 g, 59.1 mmol) and triethylamine (15.9 g, 158 mmol). Fifteen minutes after complete addition of the acid chloride, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 h at ambient temperature, diethyl ether (100 mL) was added to precipitate some of the triethylamine hydrochloride, which was filtered and washed with more diethyl ether. The combined organics were then washed with 1M HCl (100 mL×2), 1M NaOH (100 mL), water (100 mL), half-saturated brine (100 mL) and saturated brine (100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound which was used without further purification. MS: m/z=218 (M+1).
Reaction SMILES: [C:1]12(C(O)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mn]([O-])(=O)(=O)=[O:15].[K+]>[OH-].[Na+]>[C:1]12([OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: OC12CC3CC(CC(C3)C1)C2

Procedure:
Adamantane-1-carboxylic acid and potassium permanganate were reacted by oxidation using sodium hydroxide as a catalyst to obtain adamantan-1-ol, 4-carboxylic acid.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[CH3:21][NH:22][C:23]([NH:25][CH3:26])=[O:24]>C(O)CO.O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:22]([CH3:21])[C:23](=[O:24])[N:25]([CH3:26])[C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)NC
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: OCCO
Product: COc1ccc(-c2c(-c3ccc(OC)cc3)n(C)c(=O)n2C)cc1
Temperature: 180 °C
Yield: 68.5 %

Procedure:
A mixture of 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone (1 g, 3.6 mmol) and 1,3-dimethylurea (1.29 g, 14.7 mmol) in ethylene glycol (10 mL) was refluxed at 180° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc in hexanes to afford 4,5-bis(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.8 g, 67%) as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:20])([F:19])[C:9]1[C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]=1[C:8]([F:20])([F:7])[F:19]
Reactant: COC(=O)c1cnccc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnccc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred suspension of LAH (0.64 g, 17.0 mmol) in THF (30 mL) at -78° C. was added dropwise methyl 4-trifluoromethylnicotinate (1.74 g, 8.48 mmol) in THF (20 mL). The mixture was stirred for 1 h then carefully quenched with aqueous NaHCO3 (80 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-hydroxymethyl-4-trifluoromethylpyridine as an oil (TLC: Rf = 0.35 (1:1 hexane:EtOAc)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Yield: 43 %

Procedure:
2-chloro-4-pyridinecarboxylic acid (2.5 g) in dry THF (100 ml) was added to a stirred solution of lithium aluminum hydride (20.6 ml, solution 1M in THF), kept at 23° and under a nitrogen atmosphere. The mixture was poured onto ice and extracted with EA (3×100 ml) and the organic extracts washed with brine, dried and concentrated in vacuo to give the title compound as a yellow solid (0.98 g).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[Li][CH3:21]>C1COCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]12[CH2:4][CH:3]3[CH2:11][CH:7]([CH2:8][CH:9]([C:2]3([OH:1])[CH3:21])[CH2:10]1)[CH2:6]2)([CH3:16])([CH3:18])[CH3:17]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)C(C)(O)C(C3)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
At −78° C., to a solution of 7B (400 mg, 1.51 mmol) in 5 mL of THF was added MeLi (1.6 M in ether, 2.36 mL, 3.78 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes before it was quenched by 5 mL of NH4Cl aq (Sat'd) solution. The mixture was extracted by DCM (5 mL×3) and the combined DCM layers were dried over Na2SO4. Solvent was remove under vacuum and the residue was purified by silica gel chromatography [0 to 5% of MeOH in DCM:Hexane 1:1(v/v)] to give the title compounds (9A) as a mixture of equatorial and axial isomers (310 mg, 7.3%)). LC-MS (ESR): m/z=282 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH:17]=2)[CH:5]=1)([O-:3])=[O:2].[CH:26](=O)[CH2:27][CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.O>[CH2:26]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH:17]=2)[CH2:11][CH2:12]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC=O
Reactant: CC1(C)C=C(c2cc([N+](=O)[O-])ccc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc([N+](=O)[O-])cc2C2=CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (10 mg, 0.029 mmol) produced in Example (88c) in tetrahydrofuran (1 mL) were added butyraldehyde (3.2 mg, 0.044 mmol), sodium triacetoxyborohydride (12 mg, 0.058 mmol) and acetic acid (2 mg, 0.029 mmol) in that order, followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-butyl-4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Br:13])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[Br:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]([N:1]=[CH:16][N:17]([CH3:19])[CH3:18])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cc(Br)c([N+](=O)[O-])cc1N
Product: CN(C)C=Nc1cc([N+](=O)[O-])c(Br)cc1C#N
Reaction time: 0.33 h
Yield: 86 %

Procedure:
2-Amino-5-bromo-4-nitrobenzonitrile (815 mg, 3.37 mmol) is admixed with N,N-dimethylformamide dimethyl acetal (1.65 mL, 12.5 mmol). After 20 minutes in an ultrasonic bath, excess N,N-dimethylformamide dimethyl acetal is removed on a rotary evaporator to leave, after chromatographic purification of the residue (silica gel, n-hexane/ethyl acetate: 0→60% ethyl acetate) the product in 86% yield (863 mg).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@:4]2([CH2:10][CH2:9][C@H:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:7]2)[NH:3]1.[C:21](Cl)(=O)[C:22](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[O:19]=[C:18]1[CH2:22][CH2:21][C:15]2[CH:16]=[C:11]([C@H:8]3[CH2:9][CH2:10][C@@:4]4([NH:3][C:2](=[O:1])[O:6][CH2:5]4)[CH2:7]3)[CH:12]=[CH:13][C:14]=2[CH2:17]1
Reactant: O=C(O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a mixture of 2-(4-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetic acid (I-5B, 800 mg, 2.91 mmol) in DCM (20 mL) was added oxalyl chloride (1 ml, 11.42 mmol) and a few drops of DMF. After one hour, the reaction mixture was concentrated in vacuo. The residue was re-dissolved in DCM (20 mL) in a glass pressure vessel. Granular aluminum chloride (1550 mg, 11.62 mmol) was added and the reaction mixture was cooled to −78° C. Ethylene was bubbled through the solution for 5 minutes and then the reaction vessel was sealed. The reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours. The mixture was poured onto ice, diluted with dichloromethane and washed with 1M HCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (80 g) using a MeOH/DCM gradient (0-10% MeOH over 13CV). The product containing fractions were collected and dried in vacuo to afford 770 mg of (5R,7S)-7-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one. HPLC retention time=0.74 min (Condition G); LC/MS M+1=286: 1H NMR (400 MHz, chloroform-d) δ 7.20-7.00 (m, 3H), 5.49 (br. s., 1H), 4.45-4.25 (m, 2H), 3.59 (s, 2H), 3.08 (t, J=6.8 Hz, 3H), 2.58 (t, J=6.7 Hz, 2H), 2.38 (dd, J=13.2, 7.3 Hz, 1H), 2.27-2.11 (m, 2H), 2.05-1.92 (m, 2H), 1.92-1.74 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:23]([O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[CH2:24][CH3:25]
Reactant: CCCOCCCl
Reactant: Oc1ccc2occc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc2occc2c1
Temperature: 95 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
To a solution of 5-hydroxybenzofuran (1.90 g) in DMF (30 ml) were added potassium carbonate (5.09 g) and sodium iodide (5.52 g) and then was added 2-chloroethylpropylether (3.47 g), and the mixture was stirred, under nitrogen atmosphere, at 95° C. for 3 days and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer washed with 1N sodium hydroxide solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give yellow oil of 5-propoxyethoxybenzofuran (1.22 g).
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[C:27]([C:41]([F:44])([F:43])[F:42])[CH:26]=1.[Cl:45][C:46]1[N:54]=[C:53]2[C:49]([N:50]=[CH:51][N:52]2[CH3:55])=[C:48](Cl)[N:47]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.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.CCOC(C)=O.O>[Cl:45][C:46]1[N:54]=[C:53]2[C:49]([N:50]=[CH:51][N:52]2[CH3:55])=[C:48]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[C:27]([C:41]([F:44])([F:43])[F:42])[CH:26]=2)[N:47]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: COc1ccc(COc2ccc(Br)cc2C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(-c3nc(Cl)nc4c3ncn4C)cc2C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
Bis(pinacolato)diboron (4.12 g), potassium acetate (4.35 g), and dichlorobis(triphenylphosphine)palladium (II) (1.04 g) were added to a solution of 4-bromo-1-[(4-methoxybenzyl)oxy]-2-(trifluoromethyl)benzene (5.87 g) in dioxane (90 mL) at room temperature in an argon atmosphere, and the mixture was stirred at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, 2,6-dichloro-9-methyl-9H-purine (3 g), Na2CO3 (4.7 g), tetrakis(triphenylphosphine)palladium (0) (854 mg), and water (15 mL) were added thereto. The reaction mixture was stirred at 100° C. for 4 hours. After the reaction mixture was cooled to room temperature, EtOAc was added thereto, followed by stirring, and the insoluble material was separated by filtration using Celite. Extraction was performed on the filtrate using EtOAc, and the extract was washed with water. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=4:1 to 1:1), whereby 2-chloro-6-{4-[(4-methoxybenzyl)oxy]-3-(trifluoromethyl)phenyl}-9-methyl-9H-purine (1.1 g) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].C1COCC1.O>CO.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnccc1OCc1ccccc1
Yield: 81.8 %

Procedure:
To a solution of 4-(benzyloxy)-3-nitropyridine (42.0 g, 0.18 mol), Fe (30.6 g, 0.55 mol) and NH4Cl (48.8 g, 0.91 mol) in MeOH:THF:H2O=(2:2:1, 750 mL) was stirred at reflux for 3 h. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (DCM:MeOH=10:1) to give to give the pure 4-(benzyloxy)pyridin-3-amine (29.5 g, yield: 80.7%). 1H-NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 7.88 (s, 1H), 7.20˜7.65 (m, 5H), 6.89 (s, 1H), 5.18 (s, 2H). MS (M+H)+: 201.