Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[O:36][C:35]([C:37](Cl)=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:37]([C:35]3[O:36][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=3)=[O:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc([N+](=O)[O-])o3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 5-nitro-2-furoyl chloride: ESMS m/e: 519.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[CH:19][CH:20]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[ClH:33]>CCOCC.O.O1CCCC1>[ClH:33].[CH2:7]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2c(cccc2-c2ccccc2)CCN1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3cccc(-c4ccccc4)c3C2)cc1

Procedure:
3.6 Parts of lithium aluminum hydride is added to a solution of 10 parts of 2-benzyl-3,4-dihydro-8-phenyl-1(2H)-isoquinolone in 225 parts by volume dry tetrahydrofuran and the resulting mixture is stirred at reflux temperature for about 5 hours. Then the mixture is cooled in an ice bath and treated successively with 7.5 parts by volume of water in 15 parts by volume of tetrahydrofuran, 7.5 parts by volume of 25% sodium hydroxide, and 7.5 parts by volume of water. The salts which form are filtered off and the filtrate is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield clear oil. The oil is taken up in ether and treated with isopropanolic hydrogen chloride to give, as a white solid, 2-benzyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, melting at about 187°-189° C. after recrystallization from a mixture of ethanol and ether. This compound has the following formula ##STR16##
Reaction SMILES: C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=1.[CH2:35]([O:37][C:38](=[O:48])/[C:39](/Br)=[CH:40]/[CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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].C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:48])/[C:39](/[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[CH:40]/[CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH3:36]
Reactant: CC(C)Sc1ccc(Br)cc1
Reactant: CCOC(=O)/C(Br)=C/C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(SC(C)C)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Add potassium acetate (2.5 g, 26 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.42 g, 9.52 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (629 mg, 0.86 mmol) to a solution of 1-bromo-4-isopropylsulfanyl-benzene (2.0 g, 8.65 mmol) in 30 mL DMF and stir 2 hour at 80° C. Then add (Z)-2-bromo-3-cyclohexyl-acrylic acid ethyl ester is (4.5 g, 17.3 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (629 mg, 0.86 mmol) and sodium carbonate solution (2 M, 21.0 mL, 42.0 mmol) and stir at 80° C. over night. Add 100 mL ethyl acetate and filter. Wash with water and brine, filter through a hydrophobic filter paper and concentrate. Further purification via silica gel column chromatography, eluting with a gradient from 100:0 to 98:2 hexane:ethyl acetate affords the title compound as yellow oil (1.25 g). MS (m/e): 333 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]#N)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C1C=CC(C2(C=[O:30])CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:14]=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Product: O=CC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
1-(3,4-Dichlorophenyl)cyclopentanecarbaldehyde (482) was synthesized from 1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (481) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:22]=[S:23]1(=[O:31])[CH2:27][CH:26]([C:28]([NH2:30])=[O:29])[NH:25][CH2:24]1.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH:26]([C:28]([NH2:30])=[O:29])[CH2:27][S:23](=[O:31])(=[O:22])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CS(=O)(=O)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CC[n+]1ccccc1Br
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CS(=O)(=O)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 20.8 %

Procedure:
A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 200 mg, 704 μmol), 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 169 mg, 844 μmol), 2-bromo-1-ethylpyridinium tetrafluoroborate (212 mg, 774 μmol) and DIEA (273 mg, 361 μL, 2.11 mmol) in THF (20 mL) was stirred for 24 h at ambient temperature. The solvent was removed under reduced pressure, ice/sat. aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (75 mL). The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL). The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the title compound (63 mg, 21%) as colorless oil, MS (EI): m/e=431.3 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([NH2:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(Cl)Cl.C(N(CC)CC)C>[C:25]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:11]([C:4]1[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-methyl-4-trifluoromethylpyrrol-3-carboxylic acid (1.9 g) and oxalyl chloride (0.9 ml) in methylene chloride (20 ml) is stirred at room temperature in the presence of a catalytic amount of DMF. The solvent is evaporated under reduced pressure to give a crystalline solid. This solid is dissolved in methylene chloride (1 ml) and added to a solution of 2-biphenylamine (1.7 g) and triethylamine ( 4.2 ml) in methylene chloride (20 ml) at 0° C. The reaction mixture is stirred at room temperature for 2 hours. Evaporation of the solvent under reduced pressure, addition of water and filtering gives the N-(2-biphenylyl)-1-methyl-4-trifluoromethylpyrrol-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[CH-]1C=CC=C1.[Fe+2].[Pd].CN(C=O)C>[NH2:12][C:4]1[CH:3]=[C:2]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Into a 50 mL round bottom flask was placed 3-bromo-5-(trifluoromethyl)benzenamine (1 g, 4.16 mmol) and DMF (10 mL). To this was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.67 g, 5.4 mmol), palladium dichlorodiphenylphosphinoferrocene (183 mg, 0.24 mmol), potassium carbonate (2.29 g, 16.6 mmol). Allowed to heat at 80° C. with stirring for 20 h. Work up: Reaction cooled to RT, solvents removed under reduced pressure. Purified via silica column using 0 to 8% MeOH gradient in DCM. Best fractions pooled, solvents removed under reduced pressure. Affords a clear oil. LC-MS (+) shows mass 343 (N+H) as expected for C17H2lF3N2O2, mw 342.36.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](/[CH:13]=[CH:14]/[CH2:15][O:16][CH3:17])[C:11]=1[CH3:12])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](/[CH:13]=[CH:14]/[CH2:15][O:16][CH3:17])[C:11]=1[CH3:12])[CH:5]=[O:6]
Reactant: COC/C=C/c1cc(C(=O)OC)cc(Br)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: COC/C=C/c1cc(C=O)cc(Br)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane (0.1 M) solution of methyl 3-bromo-5-[(1E)-3-methoxy-1-propen-1-yl]-4-methylbenzoate (1 eq., Amine 88, Step 1) was added DIBAL-H (1.5 M solution in toluene, 2.2 eq.). The resulting solution was stirred at RT for 1.5 h and then carefully quenched with 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude alcohol thus obtained was taken up again in dichloromethane (0.1M) and then added Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.). After stirring at RT for 40 min, the reaction mixture was diluted with ether and washed sequentially with sat. aq. NaHSO3, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil that solidified upon standing.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([C:36]3[CH2:40][CH2:39][O:38][N:37]=3)[CH2:23][C:24]([O:26]CC3C=CC(OC)=CC=3)=[O:25])=[CH:18][CH:17]=2)=CC=1>C(Cl)Cl>[O:38]1[CH2:39][CH2:40][C:36]([CH:22]([C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)[CH2:23][C:24]([OH:26])=[O:25])=[N:37]1
Reactant: COc1ccc(COC(=O)CC(C2=NOCC2)c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(C1=NOCC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.1 %

Procedure:
TFA (1 mL) was added to 42.1 (100 mg) in DCM (1 mL). The mixture was stirred at room temperature for 40 hours. TFA and DCM were removed under vacuum, and the residue was treated with EtOH (50 mL). The insoluble solid was removed by filtration. The filtrate was concentrated to give 42.2 (50 mg), which was used in the next step without further purification. MS ESI (pos.) m/e: 236 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][CH:13]=2)[CH:10]=1)=[O:4].O.[OH-].[Li+]>O.CO>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[C:11]1[N:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]2=[CH:13][N:12]=1
Reactant: COC(=O)c1ccc2cnc(-c3c(-c4ccccc4)noc3C)n2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)O)cn12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 83.5 %

Procedure:
To a suspension of 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester ( 0.25 g, 0.75 mmol) in water (6 mL) and methanol (3 mL) was added lithium hydroxide monohydrate (0.21 g, 5 mmol) in one portion. The reaction mixture was stirred for 4.5 h at room temperature. After evaporation (removal of methanol), the remaining mixture was extracted with diethyl ether. Then the aqueous layer was acidified to pH˜5 with aqueous HCl (2N). The light yellow precipitate was collected by filtration and washed with water to afford the title compound (0.2 g, 83%) as light yellow solid. MS: m/e: 320.1 [M+H]+.
Reaction SMILES: [C-]#N.[Na+].C(O)(=O)C.[C:8](#[N:10])C.[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]=[O:25])[N:17]=[C:16]1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:12]#[C:13][CH3:14]>C(OCC)(=O)C>[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]([C:8]#[N:10])[OH:25])[N:17]=[C:16]1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:12]#[C:13][CH3:14]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OC
Reactant: CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C#N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of sodium cyanide and 0.010 ml of acetic acid were added to a 15 ml acetonitrile solution of t-butyl 4-[1-(2-butynyl)-5-methoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 100 ml of ethyl acetate was added to the solution, and the mixture was washed twice with 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.274 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: Cl[C:2]1[C:3]([CH:13]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.O1CCOCC1>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.C(Cl)Cl>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([CH:13]([N:15]1[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]1=[O:25])[CH3:14])[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[N:11]2
Reactant: CC(c1nc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1nc2ccc(F)cc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 94.1 %

Procedure:
A solution of 2-(1-(3-chloro-6-fluoroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (50.14 g, 140.9 mmol), 2-tri-n-butylstannylpyridine (80% pure) (76.95 ml, 211.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (16.29 g, 14.09 mmol) in 1,4-dioxane (1175 ml, 140.9 mmol) was stirred at 110° C. for 29 h. After 29 h, the mixture was cooled to rt and concentrated under reduced pressure to give a green syrupy solid. To the residue was added DCM (200 mL). The mixture was heated under reflux for 20 min and then cooled to 0° C. with stirring. The solid was collected by filtration and washed with EtOAc-hexane (1:5, 500 mL) to give the desired product (52.82 g, 94.07% yield). The dark brown solid was dissolved in CH2Cl2:MeOH (9:1, 400 mL, warm), filtered through a plug of silica gel (150 g, 8.5 cm diameter×5.5 cm height) to remove residual palladium and washed with CH2Cl2:MeOH (9:1, 600 mL). The filtrate was concentrated under reduced pressure to give a brown solid (49.94 g, 88.9% yield). The brown solid was suspended in EtOAc-hexane (1:9, 400 mL) and the mixture was heated under reflux for 40 min. The mixture was cooled to rt, filtered, washed with EtOAc-hexane (1:9, 600 mL), and dried to give the desired product 2-(1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (47.76 g, 85.06% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47-8.53 (m, 1H), 8.20 (dd, J=9.4, 5.9 Hz, 1H), 7.94 (dd, J=9.4, 2.7 Hz, 1H), 7.85 (td, J=8.9, 2.9 Hz, 1H), 7.64-7.80 (m, 6H), 7.30-7.37 (m, 1H), 6.42 (q, J=6.9 Hz, 1H), 1.76 (d, J=7.0 Hz, 3H). Mass Spectrum (ESI) m/e=399.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1>O1CCCC1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:11]1([CH2:14][OH:15])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2F)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
A flask was charged with 1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)piperidine-4-carboxylic acid (1.51 g, 4.6 mmol) and tetrahydrofuran (10 mL). The reaction was placed under nitrogen. To the flask was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 9.2 mL, 9.2 mmol). The reaction was allowed to stir at rt for 48 hr. The reaction was cooled to 0° C. and quenched with methanol (50 mL). The solution was then concentrated in vacuo. The residue was purified via column chromatography (25% ethyl acetate/75% hexanes→60% ethyl acetate/hexanes) to yield 1.0 g (70%) of the desired alcohol. 1H-NMR (CDCl3, 400 MHz) δ ppm 7.26 (m, 2H), 7.11 (m, 1H), 7.01 (m, 1H), 3.72 (m, 4H), 3.09 (m, 2H), 2.27 (m, 2H), 1.79 (m, 2H), 1.42 (s, 9H). Mass Spec.: 332.18 (MNa)+. LC: tr=3.301 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:11][CH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20](B(O)O)[C:15]=2[O:14][C:13]1([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.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.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:20]2[C:15]3[O:14][C:13]([CH3:24])([CH3:25])[CH:12]([OH:11])[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2c(B(O)O)cccc2C1O
Reactant: N#Cc1nc(Br)cnc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(-c3cnc(N)c(C#N)n3)cccc2C1O

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine, 2.5 grams (0.012 mole) of 2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(O) in 150 mL of toluene, yielding 2-amino-3-cyano-5-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pyrazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][C@H:26]([CH3:28])[N:25]([CH3:29])[C@H:24]([CH3:30])[CH2:23]2)=[CH:18][CH:17]=1.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[O:31]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/3=[CH:14]\[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][C@H:26]([CH3:28])[N:25]([CH3:29])[C@H:24]([CH3:30])[CH2:23]3)=[CH:18][CH:17]=2)=[CH:32]1
Reactant: OB(O)c1ccoc1
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C[C@H](C)N1C
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-c5ccoc5)cc43)cc2)C[C@H](C)N1C
Reaction time: 2 h
Yield: 0 %

Procedure:
An amount of 0.15 g (0.32 mmol) of (4Z)-6-bromo-4-[({4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl}amino)-methylene]-isoquinoline-1,3(2H,4H)-dione in 2 mL of DMF is added 0.076 g (0.64 mmol) of 3-furanboronic acid, 0.02 g (0.017 mmol) of tris(dibenzyldeneaacetone)-dipalladium(0), 0.02 g (0.064 mmol) of 2-(di-t-butyl-phosphino)-biphenyl, and 0.072 g (0.64 mmol) of sodium carbonate. The reaction mixture is stirred at 100 oC under N2 for 2 h. Mass spectroscopy suggested the completion of reaction. Solids were removed by filtration, and solvent is subsequently evaporated under high-pressure vacuum to brown solid. The residue is purified using silica gel chromatography (using 5% MeOH/CHCl3 as eluent), 0.064 mg (43.8% yield) of yellow solid is obtained: mp 204-205 oC; MS (ESI) m/z 457.2 (M+H)+1
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pt]=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: c1ccc(CC2CCCNC2)cc1

Procedure:
Catalytic reduction of 3-benzylpyridine in glacial acetic acid over a platinum oxide catalyst and isolation of the product using the procedure described above in Preparation 1 affords 3-benzylpiperidine.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:4]=1[CH3:13])=[O:2].[CH3:14]N(C=O)C.[H-].[Na+].CI>O>[CH:1]([C:3]1[N:7]([CH3:14])[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:4]=1[CH3:13])=[O:2]
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cc(C)c(C=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate (0.97 g) and DMF (10 ml) was added sodium hydride (0.23 g) under ice-cooling, followed by stirring at room temperature for 0.5 hour. To a reaction mixture was added methyl iodide under ice-cooling, followed by stirring at room temperature for 15 hours. To the reaction mixture was added water under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration and washed with water to obtain ethyl 5-formyl-1,4-dimethyl-1H-pyrrole-2-carboxylate (1.0 g).