Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:32]=[CH:31][CH:30]=[CH:29][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26](C)=[CH2:27])=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.C1C[O:36]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.O.[Ru](Cl)Cl>[C:26]([C:23]1[N:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[C:12]4[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=24)[N:10]=[CH:9][N:8]([C@H:7]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[OH:1])[C:17]3=[O:18])=[CH:25][CH:24]=1)(=[O:36])[CH3:27]
Reactant: C1CCOC1
Reactant: C=C(C)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: Cl[Ru]Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-isopropenylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one (0.042 g, 0.098 mmol) in a mixture of 1 mL of acetone, 1 mL of THF, and 1 mL of water was added ruthenium(II) chloride hydrate (5.5 mg, 0.025 mmol) and sodium periodate (0.084 g, 0.39 mmol). After 1.5 h, the mixture was diluted with water and extracted 3× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 460.1763 for [M+H]+ [Calc'd for C25H24N3O4, [M+H]+=430.1761]: 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J=8.1 Hz, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.65-7.56 (m, 2H), 7.47-7.45 (m, 1H), 4.84-4.78 (m, 1H), 4.33 (s, 2H), 4.26-4.09 (m, 2H), 4.07-4.05 (m, 1H), 3.70 (br s, 1H), 3.57 (t, J=11.0 Hz, 1H), 3.34 (t, J=10.0 Hz, 1H), 2.64 (s, 3H), 2.25-2.20 (m, 1H), 2.01-1.97 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([F:19])=[C:14]([CH3:20])[CH:13]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[I-].[F:22][C:23]([F:28])([F:27])[CH2:24][CH2:25][Zn+]>C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2N(C)C)CCCCC1.C1COCC1>[F:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH2:25][CH2:24][C:23]([F:28])([F:27])[F:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:13][C:14]=1[CH3:20]
Reactant: Cc1cc(-c2ncnc3cc(Cl)ccc23)cc(C)c1F
Reactant: FC(F)(F)CC[Zn+]
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CN(C)c1cccc(N(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [I-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ncnc3cc(CCC(F)(F)F)ccc23)cc(C)c1F
Yield: 98.8 %

Procedure:
7-chloro-4-(4-fluoro-3,5-dimethylphenyl)quinazoline (2.75 g, 9.59 mmol), 2′-(dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine (CPhos) (0.34 g, 0.77 mmol), and diacetoxypalladium (0.090 g, 0.38 mmol) and 100 mL anhydrous THF were placed in an oven dried three neck round bottom flask. The system was evacuated and purged with nitrogen three times. (3,3,3-trifluoropropyl)zinc(II) iodide (86 ml, 19.2 mmol) was added via syringe. Upon completion of the reaction, it was quenched with ammonium chloride solution then transferred to a separatory funnel with ethyl acetate. The aqueous was partitioned off, then the organics were washed once with brine, dried with sodium sulfate, filtered and concentrated down. The crude solid was purified with silica gel using DCM to 90/10 DCM/ethyl acetate solvent system to get 3.3 g of a brownish-red solid. The 3.3 g solid was purified using C18 cartridges using 80/20 to 85/15 acetonitrile/water solvent system. The combined fractions were concentrated down then dried in the vacuum oven overnight to get 2.36 g of a white solid for a 71% yield.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:16]=1[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])C(CO)=[C:25]([O:35][CH3:36])[CH:24]=1)[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C.O.C(#N)C>[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:16]=1[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:10]([CH2:9][N:8]([CH3:6])[C@@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:13][CH:14]=3)[CH2:18][CH2:19][CH2:20]2)=[C:25]([O:35][CH3:36])[CH:24]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(CO)c(C(F)(F)F)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1cccc(CC)c1-c1cc(OC)c(CN(C)[C@H]2CCCc3ccccc32)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.42 g, 3.7 mmol) and triethylamine (0.37 g, 3.7 mmol) are added to a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-trifluoromethyl-pyridin-3-yl]-methanol (1.0 g, 3.0 mmol) in DCM (1 mL) and the mixture is stirred at room temperature for 1 hour. The volatile material is removed in vacuo. K2CO3 (1.3 g, 9.3 mmol), (S)-methyl-(1,2,3,4-naphthalen-1-yl)-amine (1.5 g, 9.3 mmol), and acetonitrile (20 mL) are added to the residue. The mixture is stirred at room temperature for 16 hours. The reaction is diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 mL). The combined organic layers are dried and solvent removed. The crude product is purified by PTLC (hexanes/ethyl acetate 6:1) to give (S)-[6-(2,6-diethyl-phenyl)-4-methoxy-2-trifluoromethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR: (CDCl3) 7.68 (d, 1H), 7.29 (m, 1H), 7.12 (m, 5H), 6.95 (S, 1H), 4.04 (m, 3H), 3.91 (s, 3H), 2.76 (m, 2H), 2.35 (m, 4H), 2.06 (m, 5H), 1.80 (m, 2H), 1.07 (t, 6H). [α]D=+10.7 (16.7 mg/l mL benzene).
Reaction SMILES: [ClH:1].Cl.C1(NC2C=C(N3CCNCC3)C=CN=2)CCCC1.C1(N[C:27]2[CH:32]=[C:31]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:30]=[CH:29][N:28]=2)CCCC1>C(O)=O.Cl>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:1])[CH:32]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(NC3CCCC3)c2)CC1
Agent: c1cc(N2CCNCC2)cc(NC2CCCC2)n1
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)c2)CC1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.5 mmol) in toluene (100 mL) was added piperazine-1-carboxylic acid tert-butyl ester (3.2 g, 17.2 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask was evacuated and flushed with N2(g) twice. A mixture of Xantphos (600 mg, 1.0 mmol) and Pd2(dba)3 (318 mg, 0.35 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to rt, diluted with H2O (75 mL), and extracted with EtOAc (3×). The combined organic layers were dried and concentrated to give a clear golden oil. The oil was purified on FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to give the title product as a beige solid (5.1 g, 100%). MS (ESI): mass calcd. for C14H20ClN3O2, 297.1; m/z found, 298.2 [M+H]+. 1H NMR (DMSO-d6): 7.95 (d, J=5.9, 1H), 6.88-6.78 (m, 2H), 3.46-3.32 (m, 8H), 1.42 (s, 9H). tert-Butyl 4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1-carboxylate. To a stirring solution of 4-(2-chloro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.55 mmol) in toluene (2 mL) in a vial was added cyclopentylamine (136 μL, 1.38 mmol) and sodium tert-butoxide (161 mg, 1.68 mmol). A mixture of racemic BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (18 mg, 0.027 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to rt and purified directly by FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to provide the title compound as a white solid (34 mg, 17%). MS (ESI): mass calcd. for C16H30N4O2, 346.2; m/z found, 347.3 [M+H]+. 1H NMR (DMSO-d6): 7.65 (d, J=6.0, 1H), 6.10 (d, J=6.0, 1H), 5.92 (d, J=7.1, 1H), 5.78 (s, 1H) 4.08-4.02 (m, 1H), 3.41 (t, J=5.4, 4H), 3.16 (t, J=5.4, 4H), 1.89-1.82 (m, 2H), 1.67-1.61 (m, 2H), 1.59-1.48 (m, 2H), 1.42 (s, 9H), 1.43-1.35 (m, 2H). N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine dihydrochloride. To a stirring solution of tert-butyl 4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1-carboxylate (34 mg, 0.1 mmol) in 96% formic acid (4 mL) was added 6 N aq HCl (2 drops). The mixture was stirred for 2 h and concentrated to give the desired product as a white solid (26 mg, 93%). MS (ESI): mass calcd. for C14H22N4, 246.2; m/z found, 247.2 [M+H]+. 1H NMR (DMSO-d6): 9.32 (s, 2H), 7.89 (d, J=7.1, 1H), 7.69 (d, J=7.5, 1H), 6.58 (d, J=7.6, 1H), 6.04 (s, 1H), 4.03-3.96 (m, 1H), 3.73 (t, J=4.9, 4H), 3.20 (t, J=5.0, 4H), 2.03-1.95 (m, 2H), 1.73-1.68 (m, 2H), 1.64-1.52 (m, 2H), 1.50-1.42 (M, 2H). The compounds in Example 17 through Example 20 were prepared using methods analogous to those described for Example 16.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[CH:19]12[CH2:24][CH:23]1[C:22](=[O:25])[O:21][C:20]2=O>O1CCOCC1>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:20](=[O:21])[CH:19]3[CH:23]([CH2:24]3)[C:22]2=[O:25])[CH:7]=1)=[O:18]
Reactant: O=C1OC(=O)C2CC12
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(N2C(=O)C3CC3C2=O)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (1.41 g, 5 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (2.24 g, 20 mmol) in 1,4-dioxane (25 mL) was heated at 90° C. for 4 hours. The reaction was cooled to room temperature and the precipitated white solid was collected by filtration to give 2,6-dichloro-N-(2-(−2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)benzamide (1.28 g, yield: 68%). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.67-7.59 (m, 3H), 7.55 (dd, J=9.2, 6.8 Hz, 1H), 2.74 (dd, J=8.0, 3.6 Hz, 2H), 1.69 (ddt, J=20.6, 8.1, 4.2 Hz, 2H). LCMS (ESI) m/z: 376.0 [M+H+].
Reaction SMILES: [C:1]([O:3][CH2:4][CH3:5])#[CH:2].B.O1CCCC1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)[CH3:2]
Reactant: C#COCC
Reactant: CSc1nccc(Cl)n1
Agent: [Pd+2]
Agent: B
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCO/C=C/c1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
50 g of ethyl ethynyl ether (50% v/v hexane solution) was dissolved in 200 mL of tetrahydrofuran, 119 mL of borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution) was added dropwise over 30 minutes under an ice-cold condition, then the reaction mixture was heated to room temperature, and further stirred for 4 hours. Thereto, 100 mL of tetrahydrofuran solution containing 19.1 g of 4-chloro-2-methylthiopyrimidine, 1.87 g of palladium acetate, 2.18 g of triphenylphosphine, and 159 mL of a 3N aqueous solution of sodium hydroxide were added, and was further stirred overnight at room temperature. Under reduced pressure, the tetrahydrofuran was distilled off, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to obtain 9.7 g of 4-[(E)-2-ethoxyvinyl]-2-(methylthio)pyrimidine [25-2] as a brown oily product.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:9])(=[O:3])[CH3:2]>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCC=O
Solvent: C1CCOC1
Product: CC(=O)OCCCCO

Procedure:
Alternatively, at least a portion of the 4-acetoxybutyraldehyde reaction product may be preferably converted to produce tetrahydrofuran (THF). Preferably, the 4-acetoxybutyraldehyde is hydrogenated to produce 4-acetoxybutanol, which then is dehydroacetoxylated to produce THF. The hydrogenation to produce 4-acetoxybutanol is preferably conducted according to the conditions described above. The 4-acetoxybutanol can then undergo a dehydroacetoxylation reaction to produce THF and acetic acid. The dehydroacetoxylation step is preferably performed at temperatures in the range of from 20 to 300° C. in the presence of a dehydroacetoxylation catalyst, such as silica, silica-alumina, and/or tungsten oxide. A final hydrolysis step may be performed to convert any 3-acetoxy-2-methylpropanol, formed by the hydrogenation of 3-acetoxy-2-methylpropionaldehyde, to 2-methyl-1,3-propanediol (MPD)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH3:21][Si:22]([O:25][C:26](=[O:33])[CH2:27][O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[CH3:23]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:33][CH:26]([O:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:27][O:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of trimethylsilyl-2-(trimethylsiloxy)acetate (24.4 mL, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath. The THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 min and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a mixture of geometrical isomers (4:1).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.CCCCCC.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][CH:52]1[CH2:57][CH2:56][CH2:55]CO1>O1CCCC1.CCOCC>[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][CH2:52][CH:57]=[CH:56][CH:55]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CCCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCC=CC=CCOC1CCCCO1
Temperature: 0 °C

Procedure:
Tridecyltriphenyl phosphonium bromide (0.3 mole) was dissolved in 900 ml of tetrahydrofuran and cooled to 0° C. in an ice-salt bath while stirring under argon. A 2.2N solution of n-butyllithium in hexane (0.36 mole) was added dropwise over a period of 30 minutes. The mixture was stirred for an additional 20 minutes and then cooled to -70° C. in a dry ice-acetone bath. The 4-hydroxybut-2(E)-ene-1-al tetrahydropyranyl ether (0.3 mole) in 225 ml of tetrahydrofuran was added dropwise over a period of 35 minutes and the mixture stirred for an additional hour at -70° C. The mixture was then poured into 6.25 liters of ether and stirred for 20 minutes. The resulting mixture was filtered through glass fiber filter paper. The filtrate was evaporated and the residue triturated with hexane, filtered and evaporated to give a ~3:1 mixture of trans:cis isomers of the desired compound.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][N:13]2[C:31]([O:32][CH3:33])=[O:34])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(C)(C)C)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
To a suspension of methyl 2-(4-tert-butylphenyl)piperidine-4-carboxylate hydrochloride (9.66 g, 30.98 mmol) in dichloromethane (100 mL) was added DIPEA (12 mL, 68.89 mmol). The reaction mixture was cooled in an ice-bath and methyl carbonochloridate (2.8 mL, 35.56 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 18 h at room temperature and washed with 3.8 N HCl. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Dimethyl 2-(4-tert-butylphenyl)piperidine-1,4-dicarboxylate (10.6 g, quant.) was isolated as a dark brown oil. MS m/z 334 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5]2.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1B(O)O.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5]2
Reactant: Cc1c(OCC#N)ccc2cc(Br)ccc12
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1c(OCC#N)ccc2cc(-c3cc4ccccc4o3)ccc12

Procedure:
Following the procedure described in Step 1 of Example 1, 2-[(6-bromo-1-methyl-2-naphthyl)oxy]acetonitrile (4.93 g, 17.9 mmol) was coupled to 2-benzofuranboronic acid (3.58 g, 22.1 mmol) using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.452 g, 0.553 mmol) and potassium carbonate (3.75 g, 27.1 mmol) in dioxane (130 mL) and water (13 mL). Purification by flash chromatography using 3-9% ethyl acetate in hexane as an eluant yielded 2-{[6-(1-benzofuran-2-yl)-1-methyl-2-naphthyl]oxy}acetonitrile a light yellow solid (3.03 g), mp 143-145° C., 1HNMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 7.95-8.15 (m, 3H), 7.7 (t, 2H, J=7.3 Hz), 7.5-7.6 (m, 2H), 7.2-7.4 (m, 2H), 5.35 (s, 2H), and 2.55 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH:24]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CCOC(=O)c1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 65 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-(ethoxycarbonyl)phenylboronic acid. Yield: 65%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.4 (t, 3H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 4.4 (t, 2H), 7.48 (d, 2H), 7.54 (d, 1H), 7.64 (d, 2H), 7.8 (d, 1H), 8.04 (d, 1H), 8.3 (t, 1H). MS (M+H, 368).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])=[C:10]([F:25])[CH:9]=[C:8]([Cl:26])[C:6]=2[CH:7]=1.[CH3:27][O-:28].[Na+].O>O1CCCC1>[Cl:26][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][O:28][CH3:27])[O:4][C:5]=2[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[C:10]([F:25])[CH:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CBr)oc23)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
1.5 g (3.3 mmol) of 3-(2-bromomethyl-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of tetrahydrofuran, and 0.7 g (3.6 mmol) of sodium methoxide (28% methanol solution) was dropwise added thereto under cooling with ice. After stirring at room temperature for 5 minutes, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.75 g (yield: 56.0%) of the desired product as a yellowish brown glassy substance. Refractive index: 1.5389 (20° C.).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>CN(C=O)C.O>[CH:1]1[CH:10]=[C:9]([O:11][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OC1c3ccc(OCCN4CCCCC4)cc3OCC21
Yield: 69.1 %

Procedure:
Compound 6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by 1-(2-chloroethyl)piperidine hydrochloride (366 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 1-(2-(6a,11a-dihydro-6H-benzofuro[3,2-c]chromen-3-yloxy)ethyl)piperidine (102 mg, 70%) as white solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[NH:17][C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)=[CH:26][CH:25]=1
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccc(F)cc3)ccc2c1O
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)Nc3ccc(F)cc3)ccc2c1O

Procedure:
3-({7-[3-(4-Fluoro-phenyl)-ureido]-4-hydroxy-isoquinoline-3-carbonyl}-amino)-propionic acid was prepared from 7-[3-(4-Fluoro-phenyl)-ureido]-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using β-alanine. MS ESI(−) m/e: 411.1046 (M−1), MS ESI(+) m/e: 413.0810 (M+1).