Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl.CO>[Br:1][CH2:18][C:17]([C:13]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CBr)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of bromine (4.3 ml) in chloroform (20 ml) was added dropwise over 30 minutes at 10°-15° C. to a stirred solution of 1-[1-(2-naphthyl)cyclobutyl]-ethanone (20 g) in a mixture of methanol (20 ml) and chloroform (30 ml). The mixture was then stirred at ambient temperature for 1.5 hours, poured onto ice-water (300 ml) and the product extracted into dichloromethane (3×150 ml). The extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then water, dried over calcium chloride and the solvent removed in vacuo to give 2-bromo-1-[1-(2-naphthyl)cyclobutyl]-ethanone as an oil (24.0 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9]CC)=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH:13][NH2:14])=[O:9]
Reactant: NN
Reactant: CCOC(=O)c1nc[nH]c1C
Solvent: O
Solvent: CCO
Product: Cc1[nH]cnc1C(=O)NN
Yield: 86.6 %

Procedure:
To a hot solution of 154 g of 5-methyl-1H-imidazole-4-carboxylic acid, ethyl ester in 2 liters of absolute ethanol was added dropwise, but rapidly, 100 g of hydrazine hydrate. The solution was stirred at reflux temperature for 3 hours, then 150 ml of hydrazine hydrate was added and the solution was refluxed for 3 days. The mixture was partially evaporated, the solid collected, washed twice with absolute ethanol, then ether and dried, giving 121.3 g of 5-methyl-1H-imidazole-4-carboxylic acid hydrazide.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34](C(Cl)=O)[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:45][NH2:46]>>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:45][NH:46][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([N:15]4[C:14](=[O:39])[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=5)[C:16]4=[O:20])[CH:26]=[CH:25][CH:24]=3)[O:28][C:29]=2[CH:35]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Product: COc1ccc(CNc2ccc3nc(-c4cccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)oc3c2)cc1OC

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and 3,4-dimethoxybenzylamine (23 mg, 0.14 mmol) the title compound was obtained (17 mg, 33%). 1H NMR (DMSO) δ 9.14(t, 1H), 8.44(dd, 1H), 8.36(m, 2H), 8.29(m, 2H), 8.11(d, 1H), 7.99(dd, 1H), 7.91(d, 1H), 7.85–7.76(m, 2H), 6.97(d, 1H), 6.92–6.85(m, 2H), 4.45(d, 2H), 3.73(s, 3H), 3.71(s, 3H). MS 576.2 m/z (M−H)−.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C)C=O>[C:20]1(=[O:30])[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[O:7][C:8]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: CCOC(=O)c1ccc2cc(CCCCBr)oc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(CCCCN3C(=O)c4ccccc4C3=O)oc2c1

Procedure:
A solution of ethyl 2-(4-bromobutyl)benzofuran-6-carboxylate (3.25 g., 0.01 mole) and potassium phthalimide (2.04 g., 0.011 mole) in dimethylformamide (25 ml.) is stirred at 25°-27° C. for 18 hours. The solution is poured into water. The precipitated ethyl 2-(4-phthalimidobutyl)benzofuran-6-carboxylate is collected by filtration.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=O)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13][C:12]=2[N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:41]>C(#N)C>[CH2:1]([C:8]1[N:9]=[C:10]([Cl:41])[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13][C:12]=2[N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: O=C(OCc1ccccc1)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Temperature: 80 °C
Yield: 85.8 %

Procedure:
To a suspension of the product from step A (4 g, 10 mmol) in acetonitrile (100 ml) was added N,N-dimethylaniline (1.4 ml, 11.3 mmol), followed by careful addition of POCl3 (9.6 ml, 100 mmol). The resulting brown solution was heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo, azeotroped with PhMe (×2) and DCM. The residue was partitioned between 2 N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 3.5 g (84%) of title compound as brown oil, which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:4][C:3]=1[OH:20].[N:21]#[C:22]Br.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[NH2:21][C:22]1[O:20][C:3]2[CH:4]=[C:5]([CH2:8][CH2:9][C:10]3[N:11]=[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]4[CH:19]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: Cc1ccn2cc(CCc3ccc(N)c(O)c3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccn2cc(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (1.5 g) and cyanogen bromide (0.7 g) in ethanol (25 ml) was stirred for 2 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with potassium carbonate and the mixture was extracted with a solution of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by alumina column chromatography eluting with a solution of chloroform and methanol (19:1, V/V). The fractions containing object compound were concentrated to give 2-amino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.44 g).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[C:28]([CH3:41])=[N:29][N:30]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=5)[C:31]=4[CH3:32])=[CH:25][N:24]([S:42]([C:45]4[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=4)(=[O:44])=[O:43])[C:21]3=[N:22][CH:23]=2)=[CH:14][C:13]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:30]1[C:31]([CH3:32])=[C:27]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:14]=4)[CH:19]=3)[N:24]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:44])=[O:43])[CH:25]=2)[C:28]([CH3:41])=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCOCc5ccccc5)c(NS(C)(=O)=O)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Temperature: 25 °C

Procedure:
A stirred solution of N-(2-(2-(benzyloxy)ethoxy)-5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (120 mg, 0.151 mmol), toluene/TFA (5/5 ml) was heated to 70° C. for overnight. TLC showed reaction completion. Reaction mass was cooled to RT and solvents evaporated under reduced pressure. This afforded 152 mg of the crude titled compound. MS: m/z=704.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCc1ccc(O)cc1
Reactant: CCOc1ccc(-c2ccnc(Cl)n2)cc1
Product: CCOc1ccc(-c2ccnc(NCCc3ccc(O)cc3)n2)cc1

Procedure:
Intermediate 47 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 336. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.2 (d, 1H), 8.0 (d, 2H) 7.0 (m, 4H) 6.6 (d, 3H), δ 4.0 (q, 2H), 3.4 (t, 2H), δ 2.7 (t, 2H), 1.3 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[Br:1])=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cccc2oc(-c3sccc3Br)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4sccc4Br)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
A mixture of 2-(3-bromothiophen-2-yl)benzoxazole-4-carboxylic acid (188 mg, 0.58 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (159 mg, 0.70 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (222 mg, 1.16 mmol) and 1-hydroxybenzotriazole (157 mg, 1.16 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.40 mL, 2.9 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide (199 mg, 75%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=6.5 Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.58 (d, J=5.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.24 (d, J=5.5 Hz, 1H), 4.68-4.59 (m, 1H), 3.22-3.13 (m, 2H), 2.70-2.55 (m, 5H), 2.13-1.98 (m, 3H), 1.63-1.49 (m, 3H), 1.26-1.12 (m, 2H); MS (ESI+) m/z 460 (M+H); HPLC>99% (AUC), tR=13.09 min.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: NCCc1cccnc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCCc4cccnc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-pyridin-3-yl-ethyl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and 2-pyridin-3-yl-ethylamine (0.95 mL, 8.1 mmol) in a manner analogous to Example 406. Product isolated as a light yellow powder (98.5 mg, 31%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.71 (d, J=6.4 Hz, 1H), 8.51 (m, 1H), 8.39 (d, J=7.8 Hz, 2H), 8.03 (d, J=7.4 Hz, 2H), 7.86 (d, J=7.4 Hz, 1H), 7.70 (t, J=15.1, 7.6 Hz, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 7.04 (t, J=13.9, 7.3 Hz, 1H), 6.86 (m, 1H), 3.62 (m, 2H), 3.28 (s, 3H), 3.06 (m, 2H). MS=394 (MH)+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:27])[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[CH3:27][C:11]1([NH2:10])[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2nccc(C(F)(F)F)n2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(c2nccc(C(F)(F)F)n2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamic acid benzyl ester (0.060 g, 0.17 mmol) in acetonitrile (1.0 mL) at room temperature was added iodotrimethysilane (0.04 mL, 0.25 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 3% methanol in dichloromethane to provide the titled compound. MS (CI) m/z 261(M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.61(d, 1H), 6.92 (d, 1H), 4.83 (m, 2H), 4.50 (m, 2H), 3.51 (m, 2H), 1.90-1.74 (m, 4H), 1.51 (s, 3H).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(SCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)thio)methyl)phenyl)propanoate (136 mg) in ethanol (2.5 mL) was added 2N aqueous sodium hydroxide solution (634 μL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (56 mg) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:20][C:21]([OH:23])=[O:22].[H][H]>[C].[Pd].CO>[CH3:13][O:12][C:8]1[C:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6]2[C:11]([CH:2]=[C:3]([NH:20][C:21]([OH:23])=[O:22])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCCCCOc1c(OC)ccc2c(Cl)c(NC(=O)O)cnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCOc1c(OC)ccc2cc(NC(=O)O)cnc12
Yield: 78.6 %

Procedure:
4-Chloro-7-methoxy-8-pentyloxyquinoline-3-carbamic acid (101 mg, 0.312 mmol) and methanol (10 ml) were mixed, and 10% palladium-carbon catalyst (30 mg) was added to this solution. The mixture was stirred at room temperature for 5 hours in a stream of hydrogen. The palladium-carbon catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=10/1-6/4) to give 7-methoxy-8-pentyloxyquinoline-3-carbamic acid (74.6 mg, 83%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13]OC(OC)N(C)C>CN(C)C=O>[CH3:13][N:7]1[C:8]2[C:3](=[C:2]([CH3:1])[N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:12]
Reactant: Cc1nccc2[nH]c(=O)ccc12
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1nccc2c1ccc(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture containing 4.5 g of 5-methyl-1,6-naphthyridin-2(1H)-one, 15 ml of dimethylformamide and 4 ml of dimethylformamide dimethyl acetal was stirred at room temperature overnight, then heated on a steam bath for 7 hours and then evaporated to dryness on a rotary evaporator. The solid residue was recrystallized from isopropyl alcohol and dried at 90°-95° C. to yield 3.5 g of 1,5-dimethyl-1,6-naphthyridin-2(1H)-one, m.p. 203°-205° C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[OH:14][CH:15]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[Si:10]([O:14][CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC(O)CC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)CC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C

Procedure:
Imidazole and tert-butylchlorodimethylsilane are added to a solution of diethyl 3-hydroxyglutarate in methylene chloride, and the reaction is performed to give diethyl 3-[(tert-butydimethylsilyl)oxy]pentanedioate.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH:28]([O:27][CH3:26])[CH3:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: COC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (13.9 mg, 46.1%), MS (ISP) m/z=431.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 3-methoxybutanoic acid
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C(O)CCC>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][NH:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)CC1
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A mixture of 69 (0.2 g, 0.57 mmol), 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 1.13 mmol) and DIEA (0.20 mL, 1.14 mmol) in 1-butanol (5 mL) was heated to 120° C. for 1.5 h. After concentration, the residue was purified by silica gel chromatography using 2-5% MeOH/DCM, to give 4-[2-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-ylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester 71 (0.20 g). Compound 71 was subjected to 20 mL of 20% TFA/DCM at rt for 2 h, then the reaction was concentrated almost to dryness under reduced pressure, and purified by silica gel column chromatography using 0.1% MeOH/DCM containing 1 mL ammonium hydroxide, to give 72 (0.15 g). MS: 400.2(M+1). 1HNMR (DMSO-d6) ppm 8.36 (s, 1H), 7.61-7.33 (m, 10H), 5.49 (t, 1H, J=4.48 Hz), 3.45 (dd, 2H, J1=5.10 Hz, J2=5.84 Hz), 2.33 (t, 2H, J=5.80 Hz), 2.13 (br, 4H), 1.95 (br, 1H) (note: some peaks overlapped with water peak in DMSO-d6). 1HNMR (CCl3-d) ppm 8.43 (s, 1H), 7.60-7.50 (m, 6H), 7.50-7.26 (m, 4H), 5.39 (t, 1H), 3.54 (dd, 2H, J1=5.05 Hz, J2=6.20 Hz), 2.73 (t, 4H, J=4.71 Hz), 2.44 (t 2H, J=5.91 Hz), 2.28 (br, 4H), 1,87 (br, 1H).
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[NH2:19]>O1CCOCC1>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:6]2[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: CC(C)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C(C)C)n2)c1
Temperature: 120 °C
Yield: 98.1 %

Procedure:
Acetic acid (0.192 mL, 3.35 mmol) was added to commercially available 2-chloro-4-(propan-2-yl)pyrimidine (0.5 g, 3.19 mmol) and 3-bromo-5-methylaniline (0.900 g, 3.19 mmol) suspended in dioxane (6.39 mL). Reaction was heated to 120° C. (bath temp) overnight. Then, the reaction was cooled to room temperature and purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give N-(3-bromo-5-methylphenyl)-4-(propan-2-yl)-pyrimidin-2-amine (959.8 mg, 3.13 mmol, 98%) as a white solid.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])([CH3:4])[CH3:3].[Na].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.Cl>C(O)C.C(O)(=O)C>[O:18]=[C:19]1[NH:10][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:2]([CH3:4])[CH3:3])=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)Oc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2OC(C)C)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-Isopropoxybenzamidine hydrochloride (10.0 g., 0.0465 mole) was added to a stirred, cooled (ice-water) solution of sodium 2.14 g., 0.093 g-atom) in ethanol (100 ml.). To this cooled, stirred solution was added dropwise a solution of diethyl ethoxymethylenemalonate (10.1 g., 0.0465 mole) in ethanol (30 ml.) over a 10 minute period. The mixture was refluxed for 2 hours and stored at 22° for 18 hours. The mixture was then poured onto ice-water containing acetic acid (10 ml.) and concentrated HCl (10 ml.) to precipitate the desired product. The precipitate was washed and dried to give 15.5 g. of the title product, m.p. 123° 124°. Recrystallizations from ethyl acetate and then cyclohexane gave colorless crystals of the ester, m.p. 128°-130°.
Reaction SMILES: FC(F)(F)C1C=CC(C(O)=O)=CC=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][C:28]3=[O:31])=[CH:24][CH:23]=2)=[N:19][CH:20]=1>>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:29]3[C:30]=2[CH2:26][CH2:27][C:28]3=[O:31])=[N:19][CH:20]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)C(=O)CC3)nc1
Agent: O=C(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[(5-amino-2-pyridinyl)oxy]-1-indanone obtained in Reference Example 18 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.