Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:51][OH:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:51][OH:52])[CH2:32][O:31]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Temperature: -10 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 4m (1.11 g, 1.46 mmol) was dissolved in 20 mL dichloromethane and cooled to −10° C., followed by addition of trifluoroacetic acid (0.23 mL, 3 mmol). The reaction mixture was warmed and stirred for 2 hours and partitioned after 20 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with dichloromethane (20 mL×2). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 4n (830 mg, colourless grease), yield: 78.3%. MS m/z (ESI): 742.3 [M+18].
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15]OC(OC)N(C)C>C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])([O:3][CH3:15])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: C=C(C)C1CCC(C)=C1CCC(=O)O
Solvent: c1ccccc1
Product: C=C(C)C1CCC(C)=C1CCC(=O)OC
Yield: 91 %

Procedure:
A mixture of 2 g of 2-(2-carboxyethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene, 150 ml of absolute benzene and 4 ml of dimethoxy-dimethylamino-methane was heated for 5 hours to reflux. The solution was concentrated and the residue, obtained as a red oil, chromatographed on 50 g of silicagel with hexane/ether (19:1). There were obtained 1.95 g (91%) of 2-(2-carbomethoxyethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.01 about 70°C; nD20 = 1.4761; IRfilm : μmax = 3100, 1742, 1645, 1440, 1375, 1330, 1255, 1195, 1170, 1085, 1025, 990, 895 and 840 cm-1. The compound has a floral, woody, ester-like fragrance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:21]=2[O:20][CH2:19]1.C(O)(C)C>C1COCC1.O>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=3)[OH:28])=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: CCOc1cc(Br)ccc1OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOc1cc(C(O)c2ccc3c(c2)OCO3)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.65 g, 7.1 mmol) and dry THF (15 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (2.9 mL, 7.1 mmol) and stirred for 20 min. Then a mixture of benzo[1,3]dioxole-5-carbaldehyde (0.98 g, 6.5 mmol) in dry THF (20 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.0 mL, 39 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give benzo[1,3]dioxol-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (1.1 g, 56% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH2CH3), 2.11 (d, J=3 Hz, 1H, OH), 3.86 (s, 3H, OCH3), 4.07 (q, J=7 Hz, 2H, CH2CH3), 5.71 (d, J=3 Hz, 1H, CH), 5.93 (s, 2H, CH2), 6.74-6.91 (m, 6H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][C:3]=1[CH3:16].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)cnc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 2-(6-chloro-5-methylpyridin-3-yl)acetate 86-6 (7.8 g, 32 mmol) and TFA (32 mL) in DCM (32 mL) was stirred at room temperature for 3 hours. The solution was adjusted to pH around 12 by sodium carbonate and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by 1N HCl aqueous solution and stirred for 15 minutes. The suspension was extracted with dichloromethane (100 mL×3). The combined organic phases were washed with water and brine, dried over Na2SO4 and then dried to give 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 86-7 as pale yellow solid. MS m/z 186.1 (M+1); 1H NMR 400 MHz (CD3Cl) δ 8.17 (d, 1H, J=2.0 Hz), 7.55 (d, 1H, J=2.0 Hz), 3.63 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:26]=[C:25]([N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=[C:36]2[CH:44]([F:46])[F:45])[N:24]=1.C(O)(=O)C>C1COCC1.O>[F:46][CH:44]([F:45])[C:36]1[N:35]([C:25]2[N:26]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:28]=[C:23]([NH:1][C:2]3[CH:3]=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:24]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cnc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cnc3ccccc3c2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 0.323 g (2.24 mmol) of 3-aminoquinoline in THF (5 mL) at 0° C. was added 1.6 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.280 g (0.77 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (4 mL) was added and the resulting mixture was stirred for 1 hr at RT. The resulting mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1), and then CH2Cl2-EtOAc (1:3) gave a pink powder. Recrystallization from ethanol gave 0.167 g (46% yield) of N-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-quinolinamine: mp 270-273° C.; 1H NMR (CDCl3) δ 9.08 (br s, 1H), 8.48-8.43 (m, 2H), 8.12 (d, J=8.4 Hz, 1H), 7.93-7.90 (m, 1H), 7.80 (dd, J=8.0, 1.1 Hz, 1H), 7.69 (dt, J=6.9, 1.4 Hz, 1H), 7.61-7.41 (m, 4 H), 7.30 (d, J=5.3 Hz, 1H), 3.97-3.95 (m, 4H), 3.83 (s, 4H); Anal. Calcd. for C24H20F2N8O: C, 60.75; H, 4.3; N, 23.6. Found: C, 60.7; H, 4.2; N, 23.5%.
Reaction SMILES: [Br:1][C:2]([F:6])=[C:3]([F:5])[F:4].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[OH-].[K+]>CC(C)=O>[Br:1][CH:2]([F:6])[C:3]([F:5])([F:4])[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: FC(F)=C(F)Br
Reactant: COC(=O)c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OC(F)(F)C(F)Br)c1
Yield: 68 %

Procedure:
72.3 parts by weight of bromotrifluoroethene are passed, over 10 hours, into a mixture of 45.6 parts by weight of methyl 3-hydroxybenzoate and 9.5 parts by weight of potassium hydroxide powder in 50 parts by weight of acetone under reflux at 45°-52° C. After having been concentrated on a rotary evaporator under reduced pressure, the reaction mixture is taken up in methylene chloride and this solution is extracted with sodium bicarbonate solution, dried and concentrated. Methyl 3-(2'-bromo-1',1',2'-trifluoroethoxy)-benzoate of nD 25 =1.4850 is obtained in a yield of 68% of theory, and can be hydrolyzed, in a yield of 98% of theory, to 3-(2'-bromo-1',1',2'-trifluoroethoxy)-benzoic acid, of melting point 88°-90° C..
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[BH4-].[Na+]>CO>[OH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 12.9 %

Procedure:
A mixture of 4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (140 mg, 0.42 mmol) and 27% methylamine alcohol solution (194 mg, 1.69 mmol) in methanol (15 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (48 mg, 1.26 mmol) was added. After the addition, the mixture was stirred at room temperature for 4 hr. TLC (petroleum ether/ethyl acetate=2:1) show the reaction was complete. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (20 mg, yield: 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD)δ: 4.33-4.35 (d, J=8.0 Hz, 1H), 4.53 (s, 2H), 4.74-4.76 (d, J=8.0 Hz, 1H), 7.08-7.10 (d, J=8.0 Hz, 2H), 7.18-7.24 (m, 6H), 7.27-7.29 (d, J=6.8 Hz, 2H), 7.54-7.56 (d, J=7.6 Hz, 1H), 7.62-7.66 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 370 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[CH:3]=[CH:4]/[C:5]#[N:6].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl>[C:5](/[CH:4]=[CH:3]/[C@H:2]([NH:1][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:15]([F:14])([F:27])[F:28])(=[O:25])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:6]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: N#C/C=C/[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N#C/C=C/[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of compound 31f (2.5 g, 14.5 mmol) in DCM (100 mL) was added 2-(trifluoromethoxy)benzene-1-sulfonyl chloride (4.2 g, 16.0 mmol) and TEA (4.4 g, 3.5 mmol). The mixture was stirred at rt for 12 h, then DCM (50 mL) and 2N HCl (20 mL) were added to the mixture. The organic layer was separated and washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=5:1) to give compound 31g (4.2 g, 74% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([CH3:17])=[CH:10][C:9]2[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-dimethylamino-4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M87) (0.32 g, 0.65 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (140 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([O:29]C)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([OH:29])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Br)ccc12)C(=O)OC
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Br)ccc12)C(=O)O
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-bromo-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.2 g, 1.8 mmol), LiOH.H2O (1.5 g, 36 mmol), H2O (3 mL) and methanol (10 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated. The water phase was acidified to “pH” 2-3 by addition of concentrated HCl solution and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was washed with methanol to give the title compound (660 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[OH:13].[Cl:14][CH2:15][CH:16]=O.OS(O)(=O)=O>CCO>[Cl:14][CH2:15][CH:16]1[O:13][C:4]2[CH:5]=[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: CS(=O)(=O)c1ccc(CO)c(O)c1
Reactant: O=CCCl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CCl)OC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(hydroxymethyl)-5-(methylsulfonyl)phenol (0.2 g, 1.0 mmol) was dissolved in EtOH (4.5 ml) and chloroacetaldehyde (0.15 ml, 1.2 mmol) was added. The mixture was cooled to 0° C. and concentrated H2SO4 (2.5 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 10 min and then in room temperature for 2-3 h. Chloroacetaldehyde (50 μl) and concentrated H2SO4 (0.5 ml) was added and the reaction mixture was stirred for another 1-2 h before the reaction was quenched with water. The aqueous phase was extracted with EtOAc and the combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (isooctane/EtOAc 2:1) gave the title compound (0.58 g, with some inpurities). MS m/z (rel. intensity, 70 eV) 264 (M+, 5), 262 (M+, 13), 213 (31), 184 (bp), 77 (61), 51 (47).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][C@H:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:7]=1.[BH4-].[Na+]>CO>[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:8]([O:14][C@H:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:7]=1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C=O
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CC[C@H](C)Oc1cc(C)ccc1CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
A mixture of cyclopropanamine (40.0 mg, 0.700 mmol), (S)-4-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (130 mg, 0.636 mmol) in MeOH (5 mL) was stirred at rt for 0.5 h. Sodium borohydride (12.04 mg, 0.318 mmol) was then added and the reaction was stirred at rt for 2 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to isolate (S)—N-(4-methyl-2-(pent-4-en-2-yloxy)benzyl)cyclopropanamine (20 mg, 0.082 mmol, 12.81% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=7.8 Hz, 1H), 6.77-6.67 (m, 2H), 5.90 (ddt, J=17.2, 10.2, 7.1 Hz, 1H), 5.20-5.07 (m, 2H), 4.51 (sxt, J=6.0 Hz, 1H), 3.86-3.69 (m, 2H), 2.60-2.39 (m, 2H), 2.34 (s, 3H), 2.12-2.02 (m, 1H), 1.36 (d, J=6.1 Hz, 3H), 0.48-0.32 (m, 4H).
Reaction SMILES: C1COCC1.[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH:9][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=1)=[O:25]
Reactant: Nc1ccc(Br)cc1I
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1I
Temperature: 65 °C
Yield: 92.3 %

Procedure:
To a 100 mL of anhydrous THF in a 250 mL round bottom flask containing a stirring bar, 2-iodo-4-bromoaniline (2.00 g, 6.70 mmol) was added along with 3-trifluoromethylphenylisocyanate (1.51 g, 7.00 mmol) and 52 mg of pyridine. The resulting solution was heated at 65° C. overnight. THF was removed by rotary evaporation and the product was recrystallized from ethyl acetate to give 3.0 g (92%) of 1-(2-iodo-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=[C:2]2[CH:7]=1)[CH3:9]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCc1ccnc(N)c1
Solvent: CCO
Product: CCOC(=O)c1cn2ccc(CC)cc2n1
Yield: 18.6 %

Procedure:
A mixture of 2-amino-4-ethylpyridine (3.8 g), ethyl 3-bromo-2-oxopropionate (6.84 g) and ethanol (30 ml) was refluxed for 6 hours. After the reaction mixture was concentrated, water (30 ml) and ehtyl acetate (30 ml) were added to the residue. The mixture was made basic with an aqueous solution of potassium carbonate, and the separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to a column chromatography on silica gel (150 g) and eluted with 15% solution of ethyl acetate in chloroform. The fractions containing the object compound were combined and concentrated to give ethyl 7-ethylimidazo[1,2-a]pyridine-2-carboxylate (1.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(B(O)O)C2C=CC3C(=CC=CC=3)C=2C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Agent: OB(O)c1cccc2c1ccc1ccccc12
Product: Brc1ccc(-c2cccc3c2ccc2ccccc23)cc1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that phenanthrene-1-boronic acid was used instead of phenanthrene-2-boronic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:19]2[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(Br)nc(-c2ccc(OC)nc2)c1N
Temperature: 80 °C
Yield: 50.3 %

Procedure:
A mixture of methyl 3-amino-2,6-dibromoisonicotinate (300 mg, 0.97 mmol), 6-methoxypyridin-3-ylboronic acid (163 mg, 1.07 mmol), tetrakis(triphenylphosphine)-palladium(0) (56 mg, 0.048 mmol) and cesium fluoride (323 mg, 2.13 mmol) in a vial was flushed with nitrogen. Dimethoxyethane (4.8 mL) was added and the reaction was heated at 80° C. overnight. It was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, washed with brine, and dried with sodium sulfate. The solvent removed and the major product was isolated by silica gel radial chromatography (step gradient with hexane containing 5 to 20% ethyl acetate). This gave methyl 3-amino-6-bromo-6′-methoxy-2,3′-bipyridine-4-carboxylate (165 mg, 50% yield) as a yellow solid. MS (ESI) m/z 338 and 340 (M+H). 1H NMR (CDCl3) δ ppm 8.45 (1H, d, J=2.14 Hz), 7.82 (1H, dd, J=8.55, 2.44 Hz), 7.80 (1H, s), 6.85 (1H, d, J=8.55 Hz), 5.91 (2H, br. s.), 3.97 (3H, s), 3.92 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([C:40](O)=[O:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:40]([C:36]3[CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH:39]=[CH:38][CH:37]=3)=[O:41])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C=CC=C(C(=O)Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
30 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 2 mL of methylene chloride, to which 25 mg of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid, 21 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 13 mg of N,N-dimethylaminopyridine were added, and stirred overnight at room temperature. The reaction mixture was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol) to obtain 38 mg (78%) of the title compound as a light pink crystalline powder.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:41][C:42]([N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]1([CH3:53])[CH3:52])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]2([CH3:53])[CH3:52])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 5.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.0 mg) was obtained.