Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([OH:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([O:31][CH2:32][CH2:33]Br)(=[O:30])[CH3:29]>CN(C)C=O>[C:28]([O:31][CH2:32][CH2:33][O:14][C:4]1[C:3]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:2]([NH2:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc(-c2c(O)nn(Cc3ccccc3)c2N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(Cc2ccccc2)c(N)c1-c1ccc(C)cc1
Reaction time: 8 h

Procedure:
To a stirring suspension of 5-amino-1-benzyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 42) (2.4 g) and cesium carbonate (8.4 g) in dimethylformamide (30 ml) under nitrogen at room temperature was added 2-bromoethyl acetate (1.44 g) and the reaction mixture stirred overnight. The reaction was quenched with 2M hydrochloric acid (100 ml) and extracted into ethyl acetate (2×100 ml). The two combined organic extracts were further washed with water (2×100 ml), then dried (MgSO4) and the solvent removed under reduced pressure to give the crude material. This was purified using the Biotage™ Flash 40 system (90 g Silica) with a gradient elution of hexane 75% to 30%) and ethyl acetate (25% to 70%) to yield the title product as a brown oil.(1.75 g, ca. 60%)
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10](=[O:22])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Sn](CCCC)(CCCC)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)CCC>C(OCCOCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:9]=2)=[O:22])=[CH:14][C:15]=1[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(C#N)c(Br)c2)cc1C
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCOCCOCC
Product: COc1ccc(C(=O)C(=O)c2ccc(C#N)c(-c3cccnc3)c2)cc1C
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 2-bromo-4-[(4-methoxy-3-methylphenyl)(oxo)acetyl]benzonitrile (200 mg, 0.56 mmol) and 3-(tributylstannyl)pyridine (268 mg, 0.73 mmol) in 1,2-diethoxyethane is treated with dichlorobis(tri-o-tolylphosphine)palladium(II) (39.6 mg, 0.05 mmol), heated at 145° C., stirred for 30 min. and filtered to remove the catalyst. The filtrate is evaporated to dryness. The resultant residue is purified by flash chromatography (SiO2, 2/1 hexanes/EtOAc as eluent) and crystallization from ethyl ether/hexanes to afford the title compound as a yellow solid, 181 mg (91% yield), identified by HNMR and mass spectral analyses. MS m/e 357 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 3H), 3.93 (s, 3H), 7.18 (d, J=8.69 Hz, 1H), 7.61 (m, 1H), 7.82 (d, J=8.54, 1H), 7.84 (dd, J=8.54, 1.99 Hz 1 H), 8.07 (dd, J=7.76, 1.67 Hz, 1H), 8.12 (m, J=1.38 Hz, 2H), 8.25 (d, J=8.08 Hz, 1H), 8.74 (m, 1H), 8.85 (d, 1.68 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=4)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[OH-:34].[Na+].OO>C1COCC1.O>[OH:34][CH:22]1[CH:21]([C:18]2[CH:17]=[CH:16][C:15]([N:13]3[CH:14]=[C:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)[N:11]=[N:12]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)CC1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
To a stirred solution of borane-methyl sulfide complex (587 μl of a 2.0 M solution in THF; 1.18 mmol; 1.3 eq.) in THF (6.0 mL) maintained at 0° C. under nitrogen atmosphere, was added dropwise a solution of tert-butyl 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (400 mg; 0.90 mmol; 1.0 eq.) in THF (6.0 mL). The reaction mixture was stirred at RT for 12 h. Further borane-methyl sulfide complex (135 μl of a 2.00 M solution in THF; 0.27 mmol; 0.3 eq.) was added and the reaction mixture was stirred at RT for 1 more hour. The reaction mixture was then cooled down to 0° C. before the dropwise addition of NaOH (3.6 mL) followed by hydrogen peroxide (615 μl). It was then allowed to warm to RT and stir O/N. The reaction mixture was then diluted with water and extracted with DCM (four times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtOAc:heptanes, gradient from 90:10 to 40:60) to give the title compound as a white foam (90 mg, 22%). HPLC (max plot) 96.4%; Rt % 4.16 min. UPLC/MS: (MS+) 461.4, (MS−) 459.5.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[CH3:8][O:9][CH2:10][CH2:11]Cl.C(N(CC)CC)C>>[CH3:8][O:9][CH2:10][CH2:11][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1ncc[nH]1
Reactant: COCCCl
Solvent: CCN(CC)CC
Product: CCc1nccn1CCOC
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-ethylimidazole (19.2 g, 200 mmol) was made reacted with chloroethyl methyl ether (22.7 g, 240 mmol) at 140 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The product was a transparent liquid which has a boiling point of 160-163 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.95 (d, 1H), 6.75(d, 1H), 4.08-4.05(t, 2H), 3.62-3.60 (t, 2H), 3.27(s, 3H), 2.68-2.62 (m, 2H), and 1.25-1.22 (t, 3H), and 1-(2-methoxyethyl)-2-ethyl imidazole was synthesized.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[CH:11]=[N:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]2)[N:8]=1.Cl[C:29]1[N:34]=[C:33](I)[N:32]=[CH:31][CH:30]=1>>[Cl:1][C:30]1[CH:31]=[N:32][C:33]([N:15]2[CH2:16][CH2:17][CH:12]([N:9]3[N:8]=[C:7]([CH2:6][O:5][C:4]4[CH:19]=[CH:20][C:21]([N:23]5[CH:27]=[N:26][N:25]=[N:24]5)=[CH:22][C:3]=4[F:2])[CH:11]=[N:10]3)[CH2:13][CH:14]2[CH3:18])=[N:34][CH:29]=1
Reactant: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1
Reactant: Clc1ccnc(I)n1
Reactant: Cl
Product: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1c1ncc(Cl)cn1

Procedure:
The title compound was synthesized from 4-(4-((2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)methyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine hydrochloride and 6-chloro-2-iodopyrimidine in a manner similar to that described in Example 9. The title compound was isolated as a mixture of four stereoisomers.
Reaction SMILES: [O:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>O1CCCC1>[O:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:4][CH:3]=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccno1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccno1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.9 %

Procedure:
To a solution of isoxazole-5-amine (740 mg, 8.80 mmol) and pyridine (2.14 ml, 26.4 mmol) in tetrahydrofuran (10 ml) was added 2,2,2-trichloroethyl chloroformate (1.82 ml, 13.2 mmol) with ice-cooling and the mixture was stirred for 40 minutes with ice-cooling. To the mixture was further added 2,2,2-trichloroethyl chloroformate (1.82 ml, 13.2 mmol) with ice-cooling and the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (1.23 g, 53.9%) as a solid.
Reaction SMILES: [C:1]([C:4]1[O:15][C:7]2=[C:8]([O:13][CH3:14])[N:9]=[CH:10][C:11]([Br:12])=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17]C(OC)OC.O.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:12][C:11]1[CH:10]=[N:9][C:8]([O:13][CH3:14])=[C:7]2[O:15][C:4]([C:1]([O:17][CH3:16])([O:3][CH3:24])[CH3:2])=[CH:5][C:6]=12
Reactant: COc1ncc(Br)c2cc(C(C)=O)oc12
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ncc(Br)c2cc(C(C)(OC)OC)oc12
Yield: 61 %

Procedure:
A solution of 2-acetyl-4-bromo-7-methoxyfuro[2,3-c]pyridine (1.4 g), trimethylorthoformate (1.1 g) and p-toluenesulfonic acid monohydrate (1.2 g) in dry methanol (50 ml) was heated at reflux for 3 h. The mixture was cooled and the methanol removed in vacuo. The residue was taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 33% ethyl acetate in hexane gave the title compound (contaminated with 15% 2-acetyl-4-bromo-7-methoxyfuro[2,3-c]pyridine) as a white solid (1.0 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[CH:7][C:6]=1[F:13].[C:14](=[O:17])(O)[O-:15].[Na+].C(O)(=O)C>O.S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:14]([OH:15])=[O:17])=[CH:7][C:6]=1[F:13]
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OCCBr)c(F)c1
Yield: 65 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and concentrated sulfuric acid (18 mL) was heated at 110° C. for 12 hours. The solution was then cooled to room temperature and neutralized with solid sodium bicarbonate. Acidification with glacial acetic acid gave a white solid precipitate, which was collected by filtration and dissolved in dichloromethane. The resultant solution was dried over sodium sulfate. The dichloromethane solution was then filtered and evaporated to give the product as a beige-colored solid (2.65 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 7.29 (dd, J=8.8 Hz, 8.4 Hz, 1H), 4.48 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](=[O:44])[C:41](O)=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:41](=[O:42])[C:40]([C:36]2[O:35][CH:39]=[CH:38][CH:37]=2)=[O:44])[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 45 h
Yield: 12.8 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (155 mg, 0.32 mmol), 2-(furan-2-yl)-2-oxoacetic acid (278 mg, 1.98 mmol), DIPEA (0.5 ml, 3 mmol), and HATU (251 mg, 0.66 mmol) were mixed in DMF (30 ml), the resulting reaction mixture was stirred at room temperature for 45 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, and the water phase was extracted with DCM (50 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford the desired product (20 mg, 20.4%) as a light yellow solid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23](=[O:24])[NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[CH:27][CH:28]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 31 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.070 g, 0.25 mmol) was dissolved in toluene (3 ml). 4-Methoxyphenyl chloroformate (0.042 mL, 0.28 mmol) and triethyl amine (0.053 mL, 0.38 mmol) were added and the reaction mixture was stirred at 60° C. for 10 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic phases were dried on sodium sulfate, filtered and the filtrate was evaporated. The crude product was purified by column chromatography (silica gel, heptane/ethyl acetate 4:1=>2:1) to yield the title compound as a colorless solid (33 mg, 31%); MS: m/e=326.6 (M+H+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.C(N(CC)CC)C.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)=[O:13])[CH2:8]2
Reactant: c1nc[nH]n1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1-n1cncn1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol), triethylamine (0.22 mL; 1.56 mmol) and 1,2,4-triazole (0.21 g; 3.0 mmol) under microwave irradiation for 4 hr according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-[1,2,4]triazol-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (11 mg, 11%) as an off-white powder. ES-HRMS m/e calcd for C17H22N6O (M+H+) 327.1928, found 327.1924.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:20])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([CH2:16][C:17]([OH:19])=[O:18])[CH:7]=[CH:6][C:5]1=2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:3][C:4]1([CH3:20])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH2:16][C:17]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:18])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)OCc3ccccc3)ccc21

Procedure:
730 mg (0.024 mol) of sodium hydride (80 and 100 ml of DMF were introduced into a three-necked flank under a nitrogen stream. A solution of 5 g (0.02 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid in 40 ml of DMF was added dropwise and the mixture was stirred until the gaseous emission ceased. 2.9 ml (0.024 mol) of benzyl bromide were then added and the mixture was stirred at room temperature for 4 hours. The reaction medium was poured into water, and extracted with ethyl acetate. The organic phase was decanted off, dried over magnesium sulfate and evaporated. 6.7 g (100%) of the expected ester were recovered in the form of a slightly yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:16]([N-:19]C(C)C)(C)[CH3:17].[Li+].BrCC#N.Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:17][C:16]#[N:19])[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g, obtained in example 121, step 1) in THF (8 mL) was added dropwise over a period of 10 minutes at −5° C. (ice/methanol bath) to a solution of lithiumdiisopropylamide (2M in THF/heptane/ethyl benzene, 4.67 mL) in THF (12 mL) and the mixture was stirred for 1 hour at 0° C. The reaction mixture was re-cooled to −5° C. and a solution of bromoacetonitrile (0.65 mL, [CAS Reg. No. 590-17-0]) in THF (4 mL) was added dropwise over a period of 10 minutes. The mixture was allowed to warm to RT and stirring was continued for 16 hours. The reaction was poured into ice/water and was acidified with 1M aqueous HCl solution (50 mL). The aqueous layer was extracted two times with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a brown liquid (528 mg, 45%). MS (m/e): 254.2 [MH+].
Reaction SMILES: Cl.[CH:2]12[NH:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=O)[CH2:3]2.[F:12]C1C=CC(NN)=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C=C1>C(Cl)Cl>[F:12][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]2[CH:2]3[NH:10][CH:6]([CH2:5][C:4]1=2)[CH2:7][CH2:8][CH2:9]3
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CC2CCCC(C1)N2
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Solvent: ClCCl
Product: Fn1c2c(c3ccccc31)C1CCCC(C2)N1
Yield: 74 %

Procedure:
This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and 4-fluorophenylhydrazine by the Fischer indole synthesis as described in Example 1, Method A. The product was obtained as yellow crystals (74% yield), mp 200°-201° C. (from methylene chloride).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[O:25][C:26]([CH3:29])([CH3:28])[CH2:27]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)O1
Temperature: 75 °C
Yield: 95.1 %

Procedure:
Ethyl (2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate (54) (0.1095 g, 0.260 mmole) was dissolved in ethanol (5 mL). Potassium hydroxide (0.260 mL of a 3 M aqueous solution, 0.780 mmole) was added and the mixture was heated to 75° C. for 2.5 h. The solution was cooled to RT and concentrated. Water (25 mL) was added and the mixture was extracted with ether (10 mL). The organics were thrown out and the aqueous layer was treated with 1 N aqueous HCl to pH=3. The resulting mixture was extracted with methylene chloride (3×10 mL). The organics were dried (Na2SO4) and concentrated to provide 0.097 g (95%) of compound 55 as a pale yellow solid. 1H NMR (DMSO-d6): δ 12.33 (s, 1H), 9.34 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.44 (d, J=15.9 Hz, 1H), 2.14 (s, 2H), 2.11(s, 2H), 1.11 (s, 6H), 1.10 (s, 6H). LRMS (ESI): m/z 391 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:11][N:10]=1)(C)(C)C.Cl.CCO>CCOC(C)=O.O1CCOCC1>[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[O:35])=[CH:11][N:10]=1
Reactant: COc1ccc(CNC(=O)Cc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CNC(=O)Cc2cnc(CN)c3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {6,7-dimethoxy-4-[(4-methoxy-benzylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester (64 mg, 0.13 mmol) in 1.5 mL of EtOAc was added 3 mL of a 4 M solution of HCl in dioxane. After stirring at room temperature for 1 h, 1 mL of EtOH was added to facilitate solution. The reaction was stirred for 48 hours and the precipitated HCl salt was collected by filtration (58 mg, >100%). H1-NMR (DMSO): 9.00 (m, 1H), 8.79 (br s, 3H), 8.35 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.80 (d, 2H, J=8.3 Hz), 4.75 (br s, 2H), 4.18 (d, J=5.4 Hz, 2H), 4.02 (s, 3H), 4.00 (s, 2H), 3.82 and 3.68 (s, 3H); MS: APCI (M+H) calc'd for C22H25N3O4+H 396.5; found 396.2.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:4])[CH3:3].C1COCC1.[CH3:36][C:37]([CH3:41])([CH3:40])[CH:38]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:36][C:37]([CH3:41])([CH3:40])[CH2:38][NH:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:3])[CH3:4]
Reactant: CC(C)(N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CNC(C)(C)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of N-[(S)-6-(1-amino-1-methylethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (30 mg), THF (1 ml), methanol (0.5 ml), trimethylacetaldehyde (10 mg) and acetic acid (9 mg) was added polymer-bound sodium cyanoborohydride (0.15 mmol), and the suspension was agitated at room temperature for 12 hours. The polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 478.68 (C30H42N2O3); MS (ESI): 479 (M+H+).