Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:9][CH2:8][C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)C2CCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g, 224 mmol) was dissolved in methylene chloride (1650 mL) followed by addition of 1-(2-methoxyphenyl)piperazine hydrochloride (56.3 g, 246 mmol). Acetic acid (41 mL) may optionally be added to turn the slurry into a solution. To the stirred solution, sodium triacetoxyborohydride (60.3 g, 284 mmol)was slowly added. A slight exotherm resulted and a slurry was produced. The reaction mixture was stirred for an additional 3 hours at room temperature. The reaction was then quenched by addition of 2.0 N sodium hydroxide (1050 mL) producing a pH of about 10 for the quenched reaction mixture. The mixture was then extracted with methylene chloride (2 times, 1L and 300 mL). The organic extracts were combined, washed successively with 1.0 N HCl (600 mL), 1.0 N sodium hydroxide (600 mL), brine (600 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the final title compound as a thick oil;
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@H:8]2[C@@H:13]([CH3:14])[N:12]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](=[O:20])[C@@H:10]([NH:21]C(=O)OC(C)(C)C)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:21][C@H:10]1[CH2:9][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C@@H:13]([CH3:14])[N:12]([CH2:15][C:16]([F:17])([F:18])[F:19])[C:11]1=[O:20]
Reactant: C[C@@H]1[C@H](c2cccc(Cl)c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl [(3S,5S,6R)-5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (2.75 g, 6.53 mmol) and 20 wt. % palladium hydroxide on carbon (˜50 wt. % wet, 700 mg, 0.50 mmol) in methanol (100 mL) was stirred under a hydrogen balloon at ambient temperature for 16 h. The catalyst was removed by filtration through Celite® and washed thoroughly with methanol and ethyl acetate. Following concentration of the filtrate, a solution of the residue in ethyl acetate (100 mL) pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to ambient temperature as stirring was continued for 2 h. The mixture was then concentrated to dryness in vacuo to afford the title compound as a hydrochloride salt. HRMS: m/z=287.1361, calculated m/z=287.1366 for C14H18F3N2O. 1H NMR (500 MHz, CD3OD) δ 7.39 (t, 2H, J=7.3 Hz), 7.31 (t, 1H, J=7.3 Hz), 7.27 (d, 2H, J=7.3 Hz), 4.81-4.73 (m, 1H), 4.24 (dd, 1H, J=12.0, 6.8 Hz), 3.94 (p, 1H, J=6.0 Hz), 3.76-3.67 (m, 2H), 2.56 (q, 1H, J=12.7 Hz), 2.42 (m, 1H), 1.00 (d, 3H, J=6.3 Hz).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19](=[O:36])[C@H:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](O)[CH:30]=1)[NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH3:17]>N1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:36])[C@H:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:30]=1)[NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[CH3:17]
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)NC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Trifluoromethanesulfonic anhydride (1.51 ml) was added dropwise to an ice-cold solution of N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (915 mg, 3.00 mmol) in pyridine (9 ml) in 5 minutes under argon atmosphere. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 16 hrs. The reaction mixture was poured into ice-water (500 ml) and extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, water and brine in turn and then dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7) to give N-trifluoroacetyl-3-trifluoromethanesulfonyloxy-L-phenylalanine ethyl ester (1.25 g, 95%) as pale yellow crystals.
Reaction SMILES: C([Li])CCC.[Br-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][C:9]=1[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]([C:54]([F:57])([F:56])[F:55])([CH3:53])[CH:51]=O)=[CH:46][CH:45]=1.[CH3:58][CH2:59][CH2:60][CH2:61][CH2:62]C>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]=[CH:51][C:50]([C:47]2[CH:48]=[CH:49][C:44]([O:43][C:42]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:45][CH:46]=2)([C:54]([F:57])([F:56])[F:55])[CH3:53])=[CH:10][C:9]=1[O:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Reactant: CCCCCC
Reactant: COc1ccc(C(C)(C=O)C(F)(F)F)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C=CCc1ccc(F)c(Oc2ccccc2)c1)(c1ccc(Oc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A solution of butyllithium in hexane (1.6 molar; 30 ml) was added, dropwise, under a nitrogen atmosphere to [2-(4-fluoro-3-phenoxyphenyl)ethyl]triphenylphosphonium bromide (26.76 g; 48 mmol) in absolute tetrahydrofuran (200 ml). After stirring for two hours, 2-(4-methoxyphenyl)-2-trifluoromethylpropionaldehyde (10.13 g; 43.63 mmol) dissolve in absolute tetrahydrofuran (80 ml) was added, dropwise. The mixture was heated at reflux for 3 hours and then added to ice-water, extracted with ethyl acetate, the extract dried over sodium sulphate and evaporated. After chromatography on silica gel using hexane/ethyl acetate as eluent, there was obtained 1-(4-fluoro-3-phenoxyphenyl)-4-(4-phenoxyphenyl)-4-trifluoromethyl-2-pentene (15.2 g=80.5% of theory).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][NH2:31]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:31][CH2:30][C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:21]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NCc1cccs1
Product: O=C(NCc1cccs1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and thiophene-2-methylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.25 (1H, br), 11.10 (1H, br), 10.2 (1H, br), 8.28 (1H, br s), 7.38 (1H, br s), 7.34-7.22 (6H, m), 7.04 (1H, s), 6.97 (1H, d, J=4.3 Hz), 4.68 (2H, br), 4.04 (2H, br s); HRMS calcd for C21H17N3O3S+H+: 392.1069. Found: 392.1070.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9](=[O:25])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Cl-]>CCN(CC)CC.CO.CS(C)=O>[C:9]([C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9](=[O:25])[O:10]2)=[CH:15][CH:14]=1)([O:10][CH3:11])=[O:25]
Reactant: O=c1cc(-c2ccccc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1

Procedure:
A solution of 4-phenyl-7-trifluoromethanesulfonyloxycoumarin (1.75 g) and tetrakis (triphenylphosphine)palladium (0) (600 mg) in Et3N (1.3 mL), MeOH (15 mL) and DMSO (25 mL) was stirred under an atmosphere of carbon monoxide for 1 hr. at 70° C. The mixture was then poured onto sat. NH4Cl solution, extracted with EtOAc, dried and evaporated. Chromatography on silica gel (30% EtOAc/hexane) yielded the title compound as a solid, m.p. 133°-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Br:13]N1C(=O)CCC1=O.O>C(#N)C.[Fe](Cl)(Cl)Cl>[Br:13][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:10])[F:11])[C:2]([NH2:1])=[C:7]([F:8])[CH:6]=1
Reactant: Nc1c(F)cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Solvent: O
Product: Nc1c(F)cc(Br)cc1C(F)(F)F
Yield: 96.9 %

Procedure:
To a solution of 2-amino-3-fluorobenzotrifluoride (0.7 ml, 5.6 mmol) in acetonitrile (2 ml) was added N-bromosuccinimide (994 mg, 5.6 mmol), followed by iron (III) chloride (90.1 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 90 min, before addition of water (20 ml). The mixture was extracted with tert-butyl methyl ether (2×15 ml) and the combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (1.4 g), which was used directly.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[OH:6][CH2:5][CH2:4][C@H:3]([NH:2][C:36]([C:21]1([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:25][CH2:26]1)=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: N[C@@H](CCO)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccccc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 48.9 %

Procedure:
(S)-3-Amino-3-phenylpropan-1-ol hydrochloride (260 mg, 1.38 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 21) (500 mg, 1.38 mmol) and DIPEA (0.967 mL, 5.53 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (579 mg, 1.52 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(3-hydroxy-1-phenylpropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (334 mg, 48.8%) as a white solid. The product (334 mg, 0.67 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.961 mL, 27.67 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The resulting gum was triturated with EtOAc to give a solid which was collected by filtration and dried under vacuum to give (S)-4-amino-N-(3-hydroxy-1-phenylpropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (93 mg, 17.0%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[C:5](OC)=[O:6].C(S)CS.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COC(=O)c1ccc(C#N)c(Cl)c1C
Agent: SCCS
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CO)ccc(C#N)c1Cl
Temperature: 70 °C
Yield: 66.5 %

Procedure:
To a pressure reaction flask containing compound 7A (1.5 g, 7.2 mmol) in THF (30 mL) were added 1,2-ethanedithiol (2.4 g, 28.6 mmol) and NaBH4 (812 mg, 21.5 mmol). It was sealed, and heated at 70° C. for 2 hr, and cooled to RT. The reaction mixture was concentrated, dissolved in EtOAc, washed with water, dried over Na2SO4, and concentrated. Recrystallization in EtOAc/hexanes give the title compound (870 mg). (ES) m/z 182 [M+H]+; 204 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][CH2:27]2.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2
Reactant: COc1cc2c(Oc3ccc4c(c3)CCCN4C(=O)OC(C)(C)C)ncnc2cc1OCCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4c(c3)CCCN4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To 6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)quinazoline (110 mg, 0.2 mmol) in solution in dichloromethane (3 ml) was added TFA (0.3 ml) and the mixture stirred for 1 hour at ambient temperature. The solvents were evaporated and the remaining oil was diluted with dichloromethane and the pH adjusted to 9 with a saturated solution of sodium hydrogen carbonate. The organic phase was washed with, brine, dried (MgSO4), filtered and the solvent evaporated to give 6-methoxy-7-(3-morpholinopropoxy)4-(1,2,3,4-tetrahydroquinolin-6-yloxy)quinazoline (84 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH2:3][C:4]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([CH2:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl:16]N1C(=O)CCC1=O.C1C=CN=CC=1.[FH:30]>C(Cl)Cl>[CH3:15][O:14][C:12](=[O:13])[C:4]1[CH2:3][CH:2]([Cl:1])[C:11]([Cl:16])([F:30])[CH2:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C1=C(C(=O)OC)CC(Cl)=CC1
Reactant: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C(=O)OC)CC(F)(Cl)C(Cl)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethyl 4-chloro-3,6-dihydrophthalate (1.1 g) and N-chlorosuccinimide (0.6 g) in methylene chloride (4.1 g) was added to pyridinium poly(hydrogen fluoride) (3.1 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully poured into methylene chloride containing solid sodium carbonate. The methylene chloride layer was filtered and dried with magnesium sulfate and the solvent removed under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[CH2:16]([N:18]1[C:30]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=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>[CH2:16]([N:18]1[C:30]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17]
Reactant: COc1cccc(-c2ccccc2Br)c1
Reactant: CCn1c2ccccc2c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
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: O
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2ccc(-c3ccccc3-c3cccc(OC)c3)cc21
Reaction time: 5 h
Yield: 68.9 %

Procedure:
3.93 g (15.00 mmol) of 2-bromo-3′-methoxybiphenyl, 5.3 g (16.50 mmol) of 9-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)carbazole, and 0.35 g (0.30 mmol) of Pd(PPh3)4 were dissolved in 50 ml of toluene, and 4.77 g (45.00 mmol) of Na2CO3 was put into 25 ml of distilled water and then refluxed and agitated for 5 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=7:3 (v/v) to obtain 3.90 g of 9-ethyl-2-(3′-methoxybiphenyl-2-yl)carbazole (yield 69%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12])C=C.Cl.CN(C)[C:16]1[CH:21]=CC=C[CH:17]=1>>[CH2:21]([C:10]1[C:9]([F:11])=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[OH:4])[CH:16]=[CH2:17]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(F)ccc1F
Agent: Cl
Product: C=CCc1c(F)ccc(F)c1O
Temperature: 170 °C
Reaction time: 5 h

Procedure:
13 g 2,5-difluorophenol allyl ether was dissolved in 90 ml N,N-dimethylaniline and stirred at 170° C. for 5 hours in a nitrogen stream. The reaction solution was poured into 10% aqueous hydrogen chloride solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated The resulting residue was subjected to silica gel chromatography (developing solvent: 7% ethyl acetate/n-hexane) to give 7.8 g of 2-allyl-3,6-difluorophenol as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C(C1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1C)(=O)C>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:2]([CH3:1])[CH:7]=2)=[O:10])=[CH:24][C:23]=1[O:31][CH3:32]
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Agent: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccccc4)c(C)c3)c2cc1OCCN(C)C

Procedure:
The title compound was prepared from 2-methylbiphenyl-4-carboxylic acid (D23) and 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D13) using a similar procedure to Example 4 (80%). This was converted to its oxalate salt to afford a white solid. mp 152°-154° C.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([CH:28]3[CH2:31][C:30](=[CH:32][O:33]C)[CH2:29]3)[N:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=23)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(C(O)=O)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>O>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([CH:28]3[CH2:31][CH:30]([CH:32]=[O:33])[CH2:29]3)=[N:19][C:18]=2[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:13]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COC=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Nc1nccn2c(C3CC(C=O)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a methylene chloride solution (6.0 mL) of 1-(3-Benzyloxy-phenyl)-3-(3-methoxymethylene-cyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine (287.0 mg, 0.696 mmol), CF3CO2H (0.11 mL, 1.392 mmol) was added, followed by H2O (0.5 mL). The reaction mixture was allowed to react for 1 h at rt. After which an ethanolic solution (5.0 mL) of K2CO3 (192.3 mg, 1.392 mmol) was added to the reaction and allowed to stir at rt for an additional 2 h. The reaction mixture extracted between water and EtOAc. The organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo to yield the desired product as a brown solid; 1H NMR (CDCl3, 400 MHz) (mixture of cis and trans isomers) δ 2.45-2.84 (m, 4H), 3.25-3.32 (m, 1H), 3.74-3.79 (m, 1H), 5.22 (s, 2H), 6.84-6.85 (m, 1H), 7.00-7.17 (m, 5H), 7.27-7.39 (m, 6H), 9.69 (s, 1H), 9.88 (s, 1H); MS (ES) 399.07 (M+1), 400.0 (M+2), 401.0 (M+3).
Reaction SMILES: [C:1](O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].C(=O)(O)[O-].[Na+].ClCCl.[I:46]C>O.C(OCC)C>[I-:46].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH+:19]2[CH3:1])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CI
Reactant: O=C(O)C(=O)O
Reactant: COC(=O)CC[C@]1(Cc2ccc(OC)c(OC)c2)NCCc2cc(OC)c(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COC(=O)CC[C@@]1(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2CC[NH+]1C
Product: [I-]
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
(1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methoxycarbonylethylisoquinoline oxalate (7.0 g, 0.0135 moles) was dissolved in water (50 ml) and aqueous sodium bicarbonate solution was added to produce a pH in the range of 9-10. Dichloromethane (100 ml) was added and the mixture was stirred for 15 minutes at that temperature. The upper organic layer was separated and the aqueous layer was extracted three times with dichloromethane (3×100 ml). The combined organic layer was dried over magnesium sulfate and washed with 10% sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford a residual oil. Iodomethane (30 ml, 0.482 moles) was added to the oily residue and the mixture was stirred to obtain a solution and kept at ambient temperature overnight. The reaction mixture was added to diethyl ether (100 ml) to afford a suspension. The suspension was stirred at ambient temperature for 30 minutes to afford a solid, which was collected by filtration, washed with diethyl ether (2×15 ml) and dried to afford a mixture of 70% of the cis and 30% of the trans isomers of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-methoxycarbonylethyl-isoquinolinium iodide (5.9 g; 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:7][CH3:8])[CH3:2].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][N:10]([C:20]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(CNC1CCCC1)C(=O)OCC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCC(CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A solution of 1.14 g (0.005 mole) of (rac)-2-cyclopentylaminomethyl-pentanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-2-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-pentanoic acid ethyl ester (IV-16).