Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1>Cl.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccc(CCCC2CCNCC2)c(F)c1
Temperature: 25 °C
Yield: 108.3 %

Procedure:
A solution of 4-(3-(2,4-difluorophenyl)propyl)-1-t-butoxycarbonylpiperidine (90 mg, 0.27 mmol, from EXAMPLE 113, Step E) in 2 mL of 1% HCl in MeOH was heated to 50° C. for 2 h. After cooling to rt, the material was concentrated to provide 70 mg (93%) of the title compound: HPLC (YMC ODS-A 4.6×50 mm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN+0.1% TFA over 2.0 min, hold 1 min, 5.0 mL/min, 220 nm): Retention Time: 1.18 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CC(=O)CC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C)C=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[CH:9][S:8][C:7]=2[C:2]=1[Cl:1])[CH3:25]
Reactant: Oc1ccc2c(-c3ccccc3F)csc2c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)csc2c1Cl
Yield: 78.2 %

Procedure:
A mixture of 8.3 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)benzo[b]thiophene, 6.0 g of ethyl bromoacetate, 60 ml of 2-butanone, 5 ml of dimethylformamide and 4 g of potassium carbonate is heated under reflux until the standing material completely dissovles. Methylene chloride is added to the cooled reaction mixture and the resultant precipitate is collected. Evaporation of the filtrate gives 8.5 g of ethyl{[7-chloro-3-(2-fluorophenyl)benzo[b]thien-6-yl]oxy}acetate.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH2:10][NH:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)[O:6][CH2:5][CH2:4][O:3]1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:12]([NH:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[C:7]([C:2]3([CH3:1])[O:3][CH2:4][CH2:5][O:6]3)[CH:8]=2)=[O:23])=[CH:30][CH:29]=1
Reactant: CC1(c2cccc(CNC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)OCCO1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cccc(CNC(=O)Nc3ccc(Cl)cc3)c2)OCCO1
Temperature: 25 °C
Yield: 62 %

Procedure:
4-Nitrophenyl-N-benzylcarbamate 21 (267 mg, 0.767 mmol) was added to a solution of 4-chloroaniline (97 mg, 0.767 mmol) and triethylamine in dichloromethane (5 mL). The mixture was stirred at room temperature until starting materials were consumed. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with aq. NaOH, water and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated The residue was purified by column chromatography eluting with methanol/chloroform to give 22 (165 mg, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 3H), 3.71 (t, J=6.8 Hz, 2H), 3.99 (t, J=6.8 Hz, 2H), 4.36 (d, J=5.6 Hz, 2H), 6.78 (s, 1H), 7.16-7.18 (m, 4H), 7.23-7.26 (m, 1H), 7.35 (d, J=5.6 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[N:6]=[CH:5]2.[NH2:17][CH:18]([CH3:29])[CH:19]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.C1(C)C=CC=CC=1.[Cu]I>[CH3:28][O:27][C:24]1[N:23]=[CH:22][C:21]([CH:19]([O:20][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[CH:5]3)[CH:18]([NH2:17])[CH3:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(O)C(C)N)cn1
Reactant: Ic1ccc2c(cnn2-c2cccnc2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)cn1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-Iodo-1-(3-pyridinyl)indazole (750 mg, 2.3 mmole), 2-Amino-1-[6-methoxypyridin-3-yl]propan-1-ol (410 mg, 2.2 mmol), copper(I)iodide (42 mg, 0.22 mmol) and caesium carbonate (1.45 g, 4.5 mmole) were suspended in butyronitrile (2.4 mL) and toluene (4.8 mL). The reaction vessel was capped and the mixture was stirred at 130° C. for 20 hours. Then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 254 mg (3 0%) as a racemic mixture of two diastereomeres.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[C:11]([O-])(=[O:13])C.[NH4+]>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]=[O:13])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Product: COC(=O)c1sccc1NC=O
Temperature: 22.5 °C
Yield: 86.3 %

Procedure:
To a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (25 g, 159 mmol) in 125 mL of formic acid was added ammonium acetate (15.9 g, 207 mmol). The reaction mixture was heated to reflux for 3 hours after which time the solution was cooled to room temperature (20-25° C.). The solid that formed was filtered, washed with water, and dried in vacuo to afford 25.4 g (86%) of 3-formylamino-thiophene-2-carboxylic acid methyl ester. 1H NMR (400 MHz, DMSO) d 10.2 (s, 1H), 8.35 (s, 3H), 7.92 (d, 1H), 7.91 (d, 1H), 3.76 (s, 3H). LC-MS: 186 (MH+); HPLC RT: 2.81 minutes.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C:5]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:8]2)[CH2:4]1)[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:3]1[CH2:7][CH2:6][C:5]2([CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCC2(CCN(CCc3ccc([N+](=O)[O-])cc3)C2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCC2(CCN(CCc3ccc(N)cc3)C2)C1
Reaction time: 16 h

Procedure:
2-Ethyl-7-[2-(4-nitro-phenyl)-ethyl]-2,7-diaza-spiro[4.4]nonane from above was dissolved in ethanol (60 ml) and 20% Pd(OH)2 (30 mg) was added and the reaction was stirred 16 h under an atmosphere of hydrogen gas by means of a balloon reservoir. The reaction was filtered thru Celite and the filtrate evaporated to afford 4-[2-(7-Ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenylamine and a crude oil (1.45 g) which was used as is in the next step.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[CH3:12][C:13]1[CH:17]=[CH:16][O:15][C:14]=1[C:18]([NH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25](ON2C(=O)CCC2=O)=[O:26])=[CH:23][CH:22]=1)=[O:19].CN(C=O)C.C(N(CC)CC)C>C(OCC)C>[CH3:12][C:13]1[CH:17]=[CH:16][O:15][C:14]=1[C:18]([NH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:26])=[CH:23][CH:22]=1)=[O:19]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: Cc1ccoc1C(=O)Nc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
(R)-aminocarnitine (20 mg, 0.12 mmol) and 2,5-dioxopyrrolidin-1-yl 4-(3-methylfuran-2-carboxamido)benzoate (82 mg, 0.24 mmol) were dissolved into DMF (1 mL). Triethylamine (50 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 48 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The powder was purified by silica gel chromatography (elution 10% MeOH/CH2Cl2 to 80% MeOH/CH2Cl2) to give the title compound as a white solid (20 mg, 43%). 1H NMR (400 MHz, D2O) δ 7.62 (d, 1H, J=1.4 Hz), 7.32-7.30 (m, 1H), 7.27-7.16 (m, 3H), 6.55 (d, 1H, J=1.8 Hz), 4.90-4.80 (m, 1H), 3.63-3.42 (m, 2H), 3.13 (s, 9H), 2.48-2.45 (m, 2H), 2.10 (s, 3H); MS ESI 388.2 [M+H]+, calcd for [C20H25N3O5+H]+ 388.18.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[H-].[Na+].[I:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[CH:22]([CH2:30][CH2:31]OS(C)(=O)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:15][CH:14]=1>CN(C)C=O>[I:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH:22]([CH2:30][CH2:31][N:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:9])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:17][CH:18]=1
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCn2ccc(=O)n(C)c2=O)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
3-Methyl-2,4(1H,3H)-pyrimidinedione (0.28 g, 2.2 mmol) was added in one portion to a stirred suspension of sodium hydride (60% suspension in mineral oil; 80 mg, 2.0 mmol) in dimethylformamide (3 mL) at room temperature under nitrogen. The resulting suspension was stirred for 5 min then a solution of 1,1-dimethylethyl 5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide (3 mL) was added in one portion. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The layers were separated and the organic phase evaporated to dryness. The residue was chromatographed on silica gel (10% methanol:dichloromethane) to give the title compound (0.33 g, 27%) as a yellow oil which was a mixture of diastereomers. LC/MS: 3.87 min; z/e 649, calcd (M+1) 649. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.25 (2H), 7.10 (1H), 6.90-6.75 (4H), 5.70 (1H), 4.40 (2H), 3.85-3.60 (6H), 3.75-2.45 (3H), 2.00-1.70 (4H), 1.40 (9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[CH3:13]
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)OC
Yield: 70.6 %

Procedure:
A mixture of (S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (80 mg, 0.34 mmol), 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (82 mg, 0.37 mmol), cesium carbonate (120 mg, 0.37 mmol) and a trace of potassium iodide were suspended in acetone (8 ml). The suspension was heated under reflux for 5 h, the solvent evaporated under reduced pressure and the residue dissolved in 2 N HCl/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 100 mg (0.24 mmol, 70%) of the title compound as yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:30])[N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[BrH:31].C(O)(=O)C>C(O)C>[BrH:31].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:30])[N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2cc(O)ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1

Procedure:
A mixture of 7-methoxy-3-[4-[4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.2 g), 47% hydrobromic acid (2.6 ml) and acetic acid (6 ml) was refluxed for 28 hours. After cooling, the reaction mixture was diluted with ethanol and the precipitated crystals were collected. Recrystallization from ethanol afforded 7-hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione hydrobromide (0.1 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[C:11]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:4]([O:3][CH2:2][CH3:1])=[O:5])[O:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCCC12OCCO2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at −78° C. Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][CH2:13]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:13][CH:12]=[CH:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc3ccccc3c1)CC2
Yield: 20 %

Procedure:
Prepared from 3-(2-naphthyl)allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 3 days at 20° C. Yield: 20% of theory, Melting point: 164°-165° C. (chloroform).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[N:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[N:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(-c2ccc3c4ccc(Br)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c4ccc(-c5ccccc5-c5ccccc5)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 57.6 %

Procedure:
A mixture of 3 g (5.9 mmol) of 2-bromo-7-(5-methoxybiphenyl-2-yl)-9-phenyl-9H-carbazole, 1.5 g (7.7 mmol) of biphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (2 g, 3.4 mmol, 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[C:21]([CH3:27])([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)[C:21]([CH3:27])([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: Fc1cc(Br)c2occc2c1
Product: CC1(C)CN(Cc2ccccc2)CCC1(O)c1cc(F)cc2ccoc12
Yield: 546.6 %

Procedure:
Beginning with 0.28 gm (1.32 mMol) 5-fluoro-7-bromobenzofuran and 0.19 gm (0.088 mMol) 1-benzyl-3,3-dimethyl-4-oxo-piperidine, 0.17 gm (53%) of the desired compound were prepared essentially as described in EXAMPLE 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([NH:38][C:39]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:46])=[O:37]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:12]([OH:19])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:35][C:36]([NH:38][C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:46])=[O:37])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Cc1cccc(C)c1NC(=O)CBr
Reactant: Nc1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(C)c1NC(=O)CNc1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of (5-amino-1H-indazol-1-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.1 g, 0.27 mmol) in N,N-dimethylformaide (1 ml) was slowly added potassium carbonate (0.037 g, 0.27 mmol) at 0° C. and followed by stirring for 30 min. The addition of 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.065 g, 0.27 mmol) to the solution was followed by stirring at room temperature for hours and concentrated by evaporation in a vacuum condition. The crude product was purified by chromatography on silica gel to give the title compound (Yield 50%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (28 mg, 34%), MS (ISP) m/z=441.5 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ccnc3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[N:14][C:13]([N+:16]([O-:18])=[O:17])=[N:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[C:19]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:16]([C:13]1[N:14]=[CH:15][N:11]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:19])=[CH:10][C:7]=2[C:8]#[N:9])[N:12]=1)([O-:18])=[O:17]
Reactant: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cnc([N+](=O)[O-])n2)c(C#N)c1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a stirred solution of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27 ([M−H]−); IR (thin film) 2240, 1514, 1312 cm−1.
Reaction SMILES: C(OC1C=CC([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=CC=1)C1C=CC=CC=1>CO>[CH3:20][C:18]1([CH3:21])[C:17](=[O:22])[C:16]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:15][O:19]1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(c2ccncc2)C1=O
Solvent: CO
Product: CC1(C)OC=C(c2ccncc2)C1=O
Reaction time: 1 h
Yield: 147983.3 %

Procedure:
To a stirred solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one (620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH)2 (120 mg, 0.85 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 544-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one (280 mg, 60%) as a solid.