Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1.O>CN(C=O)C>[ClH:15].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:12][CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][N:2]([CH3:1])[CH2:11]2)=[CH:18][CH:17]=1
Reactant: CN1Cc2ccccc2C(O)C1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2C(Oc2ccc(Cl)cc2)C1
Product: Cl
Temperature: 75 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.3 g, 0.020 mole) in dry DMF is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (1.6 g, 0.033 mole), previously washed with hexane, in 40 ml dry DMF, at 65° C. After the evolution of gas ceases, a solution of p-chlorofluorobenzene (3.6 g, 0.028 mole) in 15 ml dry DMF is added slowly, and the resulting mixture is allowed to stir at 75° C. for 16 hours. After cooling to room temperature the solution is poured into water (110 ml), extracted with chloroform, the chloroform phase is washed twice with water, dried (saturated NaCl, anhydrous MgSO4) and removed via reduced pressure to yield an oil which is purified by dry column chromatography, over silica gel using ethyl acetate as the eluent. The desired product is crystallized from ether as the hydrochloride salt, yielding 1.9 g (31%) of a solid of 4-(p-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, d@92° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:17][CH2:18][P:19]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:11]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O>[CH2:1]([O:8][CH2:9][C@H:10]([O:17][CH2:18][P:19]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:11][I:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)OP(=O)(CO[C@H](COCc1ccccc1)COS(C)(=O)=O)OC(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)OP(=O)(CO[C@H](CI)COCc1ccccc1)OC(C)C
Yield: 88.7 %

Procedure:
A mixture of (R)-3-O-benzyl-2-O-[(diisopropylphosphono)methyl]-1-O-(methanesulfonyl)glycerol (10.0 g, 22.8 mmol) and sodium iodide (5.15 g, 34.4 mmol) in 70 mL of acetone was heated at reflux for 14 hours. The mixture was concentrated to about 30 mL volume, and insoluble material was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=1:0 to 5:1) to give 9.51 g (89%) of the title compound as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[S:23][C:22]([C:24](OCC)=[O:25])=[CH:21][CH:20]=1>CCCCCC.C1COCC1>[Cl:18][C:19]1[S:23][C:22]([C:24](=[O:25])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
At 0° C., 64.5 ml of a 1M solution of lithium bis(trimethylsilyl)amide in hexane are added dropwise to a solution of 3.00 g (32.3 mmol) of 4-methylpyridine and 6.77 g (35.5 mmol) of ethyl 5-chlorothiophene-2-carboxylate in 58 ml THF, and the reaction mixture is stirred at 5° C. for 3 h. The resulting precipitate was filtered off, acidified with 6M HCl, filtered again and dried. This gives 2.9 g (35%) of the desired product; 1H-NMR (DMSO-d6): δ=8.53 (d, 2H), 8.09 (d, 1H), 7.40 (d, 1H), 7.34 (d, 2H), 4.39 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(OC([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)/[C:26](=[CH:34]/[C:35]2[CH:40]=[C:39]([Br:41])[CH:38]=[CH:37][C:36]=2[O:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)/[C:25]1=[O:56])=O)(C)(C)C>C1(C)C=CC=CC=1>[Br:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH:43]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]2)=[C:35]([CH:34]2[CH2:12][C:10](=[O:11])[NH:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:26]32[C:27]2[C:32](=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[NH:24][C:25]3=[O:56])[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1

Procedure:
In a manner similar to the method described in Example 37d, 1-(3-chloro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in example 35d (43 mmol) in was reacted with E/Z-3-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in example 37c (10.8 g, 17 mmol) in toluene at 140° C. for 5 h to give the title compound as a yellow solid (Yield: 1.5 g).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C(C1C=CN=CC=1)#N.[CH2:27]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1C=CC=CC=1.B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[C:39]1([C:35]2[N:34]=[CH:27][C:38]([C:12]3[NH:8][C:9]([C:13]4[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=4)=[N:10][CH:11]=3)=[CH:37][N:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(Cn2ccnc2-c2ccccc2)cc1
Reactant: c1ccc(Cn2ccnc2-c2ccncc2)cc1
Agent: N#Cc1ccncc1
Agent: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: CO
Product: c1ccc(-c2ncc(-c3cnc(-c4ccncc4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, except that 4-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to Example 8, Step A, except that commercially available 4-cyanopyridine was used instead of 3-fluorobenzonitrile) was used in place of the 1-benzyl-2-phenyl-1H-imidazole in Step C; Rf 0.26 with 95:5 v/v dichloromethane-methanol; melting point 300° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.40 (s, 2H), 8.73 (d, 2H), 8.50-8.45 (m, 2H), 8.25 (bs, 1H), 8.00 (d, 2H), 7.62-7.55 (m, 4H); MS (ESI+) m/z 300.0 (M+1); H-PGDS FPBA IC50: 0.125 μM; H-PGDS inhibitor EIA IC50: 0.075 μM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[CH2:18][C@@H:17]([NH:21]C(=O)OCC2C=CC=CC=2)[CH2:16]1.[H][H]>CO.[Pd]>[NH2:21][C@H:17]1[CH2:16][N:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])=[CH:7][C:2]=2[F:1])[C:19](=[O:20])[CH2:18]1
Reactant: O=C(N[C@@H]1CC(=O)N(c2ccc(N3CCOCC3=O)cc2F)C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CC(=O)N(c2ccc(N3CCOCC3=O)cc2F)C1

Procedure:
260 mg (0.6 mmol) benzyl (R)-{1-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamate are dissolved in 10 ml of methanol, combined with 180 mg palladium on charcoal and hydrogenated for 3.75 hours in a Parr apparatus at 3 bar hydrogen pressure at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](O)=[O:15])[S:13][C:6]=12.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([Cl:27])=[O:15])[S:13][C:6]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: ClCCl
Product: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of 39 (2.0 g, 5.98 mmol) in anhydrous CH2Cl2 (30 ml) under an atmosphere of nitrogen, was added oxalyl chloride (2.6 ml, 29.8 mmol). After stirring for 2 hours the solvent was evaporated, anhydrous toluene (10 mL) was added and the resultant mixture was evaporated (procedure of addition of toluene followed by evaporation was performed twice) to afford title compound 40 (2.2 g, 94% yield) as a white solid. The product was used without further purification and characterization and was assumed to be the mono-HCl salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH2:2]1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH2:2]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCCOC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCCOC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A mixture of (S)-1-[1-(tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethylamine from Example 18 (295 mg, 1.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (400 mg, 1.68 mmol) and DIPEA (0.38 mL, 2.16 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 16 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. Purification by Isolute® SCX-2 was repeated a second time and then the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 128 as a white solid (310 mg, 71%). LCMS: RT 2.42 and 2.46 min [M+H]+ 364.0. 1H NMR (DMSO, 400 MHz): δ 8.38-7.88 (3H, m), 7.80 (1H, t, J=8.38 Hz), 7.65-7.54 (1H, m), 7.21-7.09 (2H, m), 5.95 (1H, br), 4.71-4.57 (1H, m), 4.14-4.04 (1H, m), 4.00-3.86 (1H, m), 3.83-3.71 (1H, m), 3.55-3.43 (1H, m), 3.16 (0.5H, d, J=4.68 Hz), 2.56-2.43 (0.5H, m), 2.36-2.23 (0.5H, m), 2.02 (0.5H, br), 1.83-1.72 (4H, m), 1.56 (0.5H, bd, J=13.68 Hz), 1.24-1.08 (0.5H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:30]>>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][N:10]2[CH2:11][CH2:12][C:13]3[C:14]([CH3:16])([CH3:17])[O:15][C:6]4[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[C:2]([OH:1])[C:7]=4[C:8]=3[CH2:9]2)=[CH:37][CH:36]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)Nc2ccc(Cl)cc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1] benzopyrano[4,3-c]pyridine with 2-chloro-N-(4-chlorophenyl)acetamide according to the method of Example 1; m.p. 159-160°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O:26]CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1.[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:26])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCC#Cc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 13.3 g (0.0736 mole) of 4-(4-chlorophenyl)-3-butyn-1-ol in 70 ml pyridine and cool to 0° C. Add 16 g (0.0837 mole) of p-toluenesulfonyl chloride and stir in ice bath for one hour. Store in freezer over night. Add 200 ml diethyl ether and then wash with 3×150 ml 1N hydrochloric acid. The organic layer is then washed with 50 ml saturated aqueous sodium bicarbonate solution and then dried over magnesium sulfate. Evaporate solvent to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13](F)=[C:14]([N+:16]([O-])=O)[CH:15]=3)=[N:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33].[H][H]>C(#N)C.[C].[Pd].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[F:29])=[C:14]([CH:15]=3)[NH2:16])=[N:7][C:6]=2[CH:20]=1
Reactant: [H][H]
Reactant: NCCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(-c2nc3cc(Cl)ccc3o2)ccc1F
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a suspension of 5-chloro-2-(2-fluoronitrobenzen-5-yl)benzoxazole (see Working Example 100-1) (815 mg, 2.79 mmol) in acetonitrile (10 mL) was added triethylamine (847 mg, 8.37 mmol) and 3,3,3-trifluoropropylamine hydrochloride (500 mg, 3.34 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a solution of the crystals obtained in ethanol/tetrahydrofuran (1:2, 15 mL) was added 10% palladium-carbon (100 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 18 hours. After the reaction was finished, this was filtered through Celite, and the filtrate was concentrated to yield the title compound (993 mg, 100% yield) as orange crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH3:42])[C:29]([O:31][CH2:32][CH3:33])=[O:30].CCN(CC)CC>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (135 mg, 0.28 mmol) and ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (78 mg, 0.29 mmol) was added Et3N (0.1 mL, 0.72 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtoAc, washed successively with 0.5N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 160 mg (q.y.) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an oil. 1H-NMR (CDCl3) d 1.13-1.23 (m, 3 H), 1.37-1.40 (m, 3 H), 2.90-3.89 (m, 12 H), 4.09-4.28 (m, 2 H), 4.33-4.39 (m, 2 H), 6.70-8.21 (series of m, total 12 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([C:23]([O:25]C)=[O:24])=[C:20]([CH3:27])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].C1COCC1.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([C:23]([OH:25])=[O:24])=[C:20]([CH3:27])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)c(C(=O)OC)s3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 35.9 %

Procedure:
Methyl cis(±)-5-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-3-methylthiophene-2-carboxylate obtained in Example (245d) (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL). A 2 N aqueous lithium hydroxide solution (0.74 mL, 1.47 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. THF (1 mL) was added, and the mixture was stirred for 19 hours, and then further stirred at 40° C. for 6.5 hours and at 70° C. for two hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (2.5 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 23 mg of the title compound as a pale blue solid (37%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.Cl.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-benzylpiperazine dihydrochloride as starting raw materials, to produce an intended compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[Br:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1Br
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccccc3Br)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) (described in a previous experimental) and 2-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product chromatographed on silica gel (1-5% EtOH/EtOAc) to give 7-amino-4-(2-bromobenzylamino)pyrido[4,3-d]pyrimidine (175 mg, 45%) as a light brown solid. 1H NMR (DMSO) δ 9.16 (1H, s), 8.85 (1H, t, J=5.7 Hz), 8.24 (1H, s), 7.64 (1H, d, J=7.8 Hz), 7.34 (1H, dd, J=7.7, 7.1 Hz), 7.31 (1H, dd, J=7.7, 2.4 Hz), 7.21 (1H, ddd, J=7.8, 6.9, 2.4 Hz), 6.50 (2H, brs), 6.39 (1H, s), 4.74 (2H, d, J=5.7 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([CH3:3])=[CH2:2].[H][H]>CO.CCOC(C)=O.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(O)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cc(O)cc(C(F)(F)F)c1
Yield: 99 %

Procedure:
A mixture of 3-isopropenyl-5-trifluoromethyl-phenol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 3-isopropyl-5-trifluoromethyl-phenol (120 mg, 99%).
Reaction SMILES: O.[C:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[OH-].[K+].[CH3:10][N:11]([CH3:15])[CH2:12]CO>CO>[CH3:10][N:11]([CH2:15][CH2:4][O:3][C:2](=[O:7])[O:5][CH2:6][CH2:10][N:11]([CH3:15])[CH3:12])[CH3:12]
Reactant: COC(=O)OC
Reactant: CN(C)CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCOC(=O)OCCN(C)C
Temperature: 80 °C

Procedure:
Into a flask equipped with a reflux cooler, a water separator and a dropping funnel, there were charged 113.5 grams (1.25 moles) of dimethyl carbonate. The substance was heated to 80° C. A solution of 1.4 grams (0.025 moles) of potassium hydroxide in 225.0 grams (2.5 moles) of dimethylethanolamine was then added in drops over a period of 30 minutes. The methanol formed during the reaction was removed by azeotropic distillation using cyclohexane as an entraining agent.
Reaction SMILES: C(O)(C)C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1.[O:19]1[CH2:21][C@@H:20]1[CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]>O>[OH:19][C@H:20]([CH2:21][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:10][CH:11]=1)[CH2:22][N:23]1[C:24](=[O:33])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]1=[O:32]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Solvent: CC(C)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Temperature: 27.5 °C

Procedure:
In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-1H-isoindole-1,3(2H)dione ((11.6 g) and water (15 ml) at 25 to 30° C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30° C. after completion of the reaction. Reaction mass then maintained at 25 to 30° C. for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:6]2
Reactant: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 92.8 %

Procedure:
Ethyl ester (115) (0.48 g, 0.97 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.42 g (93%) of the title compound (116) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=6.8 Hz, 3H), 1.10-1.25 (m, 4H), 1.40-1.55 (m, 2H), 2.53 (t, J=7.8 Hz, 2H), 3.93 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.58 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.19-7.30 (m, 5H), 7.58 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 467 (M+H)+, m/z 465 (M−H)−.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O>>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(I)ccc21
Reactant: OB(O)c1ccco1
Product: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(-c3ccco3)ccc21
Yield: 8 %

Procedure:
Prepared from 3-(7-iodo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 11 using the same conditions used to prepare Example 1 but using 2-furanboronic acid instead of benzene boronic acid. The title compound (10 mg) was obtained as a brown solid, (yield=8%).