Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4](C(OCC)=O)[C:3]([C:11]([O:13]CC)=O)=[CH:2]1.O.[NH2:17][NH2:18].[CH2:19]([OH:21])C>>[NH:1]1[C:2]2[C:19](=[O:21])[NH:18][NH:17][C:11](=[O:13])[C:3]=2[CH:4]=[CH:5]1
Reactant: CCO
Reactant: CCOC(=O)c1c[nH]cc1C(=O)OCC
Reactant: NN
Solvent: O
Product: O=c1[nH][nH]c(=O)c2[nH]ccc12
Temperature: 140 °C
Yield: 84 %

Procedure:
Diethyl pyrrole-3,4-dicarboxylate (10 g, 47.39 mmol) was heated to reflux with hydrazine monohydrate (5 mL) in ethanol (50 mL) for 24 hours. After this time, the pale yellow precipitate formed was filtered, washed with methanol (2×20 mL), air dried, resuspended in anhydrous hydrazine (20 mL), and refluxed at 140° C. for 12 hours. The clear solution was concentrated under reduced pressure. The residue was dissolved in boiling water (70 mL), acidified (pH 4) with concentrated HCl and filtered. The crystalline solid was washed with cold water (2×25 mL), ethanol (2×20 mL) and ether (20 mL), and air dried to furnish 6.06 g (84%) of pyrrolo[4,5-d]pyridazin-4(5H),7(6H)-dione. To this product (6.04 g, 40 mmol) is added hexamethyldisilazane (HMDS, 15 mL) and chlorotrimethylsilane (TMSCl, 0.5 mL), and refluxed at 150° C. for 1 hour. Excess HMDS/TMSCl is removed under vacuum and the residue dried. A mixture of this silylated product and 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride is anhydrous chloroform is stirred at room temperature under argon. CuI is added to the solution and the slurry stirred at room temperature for 3 hours. The reaction is quenched by the addition of a saturated solution of soldium bicarbonate, stirred for 15 minutes and filtered through celite. The chloroform layer is separated, washed with with saturated NaCl solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with ethyl acetate/hexanes (1:1). The product so obtained is dissolved in methanol, and sodium methoxide is added. The reaction mixture is stirred at room temperature, neutralized with Dowex-50H+ after 1 hour and filtered. The resin is washed with methanol and the combined filtrates concentrated under reduced pressure. The residue is dissolved in water, washed with chloroform and the aqueous layer freeze dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:3]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:16])[CH:5]=[C:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:3]=1
Reactant: CN(C)C(=O)c1c[nH]c(=O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CN(C)C(=O)c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (100 mg, 0.408 mmol) and iodomethane (57.9 mg, 0.408 mmol) in DMSO (3 mL) was added potassium carbonate (56.4 mg, 0.408 mmol). The mixture was stirred at room temperature overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 10-90% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product was dried under vacuum to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc(Cl)cc2)cc1
Yield: 35 %

Procedure:
Following a procedure similar to that described in Example 12, but using 2 g of 2-amino-1-(4-chlorophenyl)ethanol (prepared as described in Preparation 12), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.7 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained as crystals, melting at 78°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C1(C)C=CC(S(O[CH2:27][C@@H:28]2[O:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][CH2:29]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:33]1[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[O:30][CH2:29][C@@H:28]1[CH2:27][NH:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Reactant: COc1ccccc1N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCC(CNC[C@H]2COc3ccccc3O2)CC1

Procedure:
A stirred mixture of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine (0.84 g, prepared in a similar manner to that described in Example 2), (R)-1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate (1.2 g), potassium carbonate (1 g), and potassium iodide (catalytic amount) in acetonitrile (50 ml) was heated under reflux for 90 hours. The solvent was removed in vacuo and the residue diluted with ethyl acetate (100 ml). The product was extracted into hydrochloric acid (5M, 3×70 ml) and the extracts combined and basified by the addition of aqueous sodium hydroxide solution (5M). The product was extracted into ethyl acetate (3×150 ml), and the combined extracts were washed with water (2×100 ml), dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using ethyl acetate as the eluant. Appropriate fractions were combined and the solvent removed in vacuo to leave a yellow oil which crystallised on standing. The product was then recrystallised from ethyl acetate to yield (S)-(-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl]methylamine as light brown crystals (0.41 g), m.p. 78°-79° C., [μ]D25 -27.0° (c=1.0, CH2Cl2)
Reaction SMILES: CC(C1C=CC(O)=CC=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)C.C1[O:20][CH:19]1CCl.C(C1OC1)Cl.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>>[C:7]1([OH:10])[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1.[CH2:19]=[O:20]
Reactant: ClCC1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: C=O
Product: Oc1ccccc1

Procedure:
In the following examples Epon 828 is the reaction product of epichlorohydrin and bisphenol A having an epoxide equivalent value of 175-210 and a viscosity at 25° C. of 10,000-20,000 cps. and sold by Shell Chemical Company. D.E.N. 438 is a Dow Chemical Company epoxy resin synthesized by the reaction of epichlorohydrin and the product obtained by the reaction of phenol and formaldehyde in an acid solution having an epoxide equivalent value of 176-181 and a viscosity of 35,000-70,000 cps. at 52° C. NMA, Nadic methyl anhydride, is a mixture of methyl bicyclo (2.2.1)heptane-2,3-dicarboxylic anhydride isomers sold by Allied Chemical Corporation. BTDA, 3,3',4,4'-benzophenone tetracarboxylic dianhydride, is sold by Gulf Oil Chemicals Company. In the examples 7-inch by 7-inch strips of 181 fiber glass cloth having Linde A1100 silane finish were used. The resulting 7-inch by 7-inch laminates were cut to the proper dimension as required for the indicated ASTM test. The flexural strengths were determined at either 73° F. or 500° F., as indicated in the following examples.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[CH3:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cccc(N)c1N
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)Nc1cccc(C)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-methyl-1,2-diaminobenzene. Crystalline solid, m.p. 184-186° C.,
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]([C:16]3[CH:17]=[C:18]([Cl:21])[S:19][CH:20]=3)=[O:15])=[O:11])[CH:8]=[CH:9][C:2]1=2.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH:13]([C:14]([C:16]3[CH:17]=[C:18]([Cl:21])[S:19][CH:20]=3)=[O:15])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:11])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(CNC(=O)c1ccc2occc2c1)c1csc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)c1ccc2occc2c1)C(=O)c1csc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[(5-benzo[b]furoyl)aminoacetyl]-2-chlorothiophene (543 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (71.3 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. After ice-cooling, ethyl bromoacetate (0.21 ml) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 40 minutes. After cooling, 5% aqueous citric acid solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of ethyl 3-[(5-benzo[b]furoyl)amino]-4-(5-chlorothiophen-3-yl)-4-oxobutyrate (896 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(P(=O)(OCC)OCC)#N>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[NH:35][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: CCOP(=O)(C#N)OCC
Product: COc1ccc(CNC(=O)Cc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Yield: 78.6 %

Procedure:
[1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (70 mg, 0.19 mmol) was treated with 4-methoxybenzylamine (31 mg, 0.22 mmol), diethyl cyanophosphonate (36 mg, 0.22 mmol), and TEA (38 mg, 0.37 mmol) according to the procedure described in example 1E to give {6,7-dimethoxy-4-[(4-methoxy-benzylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester (74 mg, 80.7%). H1-NMR (CDCl3): 8.19 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 6.97 (d, 2H, J=8.8 Hz), 6.73 (d, 2H, J=8.5 Hz), 6.14 (m, 1H), 5.62 (m, 1H), 4.87 (d, 2H, J=4.3 Hz), 4.26 (d, 2H, J=6.0 Hz), 4.03 (s, 2H), 3.94, 3.91, and 3.75 (s, 3H each), 1.50 (s, 9H); MS: APCI (M+H) calc'd for C27H33N3O6+H 496.6; found 496.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([NH:1][C:4]2[C:5]3[CH:6]=[CH:7][C:8]([NH:25][C:24]4[C:18]5[O:17][C:16]([CH3:15])=[CH:20][C:19]=5[CH:21]=[CH:22][CH:23]=4)=[N:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:28][CH:29]=1
Reactant: Cc1cc2cccc(N)c2o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Fc1ccc(Br)cc1
Product: Cc1cc2cccc(Nc3ccc4c(Nc5ccc(F)cc5)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=384.1 (M+H+), was prepared in accordance with the general method of example 38 from 5-nitro-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and 1-bromo-4-fluorobenzene.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:35](O)[CH2:36][OH:37]>C1C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6]2([O:37][CH2:36][CH2:35][O:9]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2(C#N)CCC3(CC2)OCCO3)cc1OC1CCCC1
Reaction time: 1.5 h

Procedure:
A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (1.0 g, 3.19 mmol, prepared by the procedures described in PCT applications PCT/US3/01990 (WIPO publication No. WO 93/19748) and PCT application PCT/US93/02325 published as WIPO number WO 93/19750) in benzene (25 mL) was treated with p-toluenesulfonic acid (5 mg) and ethylene glycol (0.18 mL, 3.19 mmol) and was heated to reflux under an argon atmosphere; water was removed from the mixture via a Dean-Stark trap. After 1.5 h, ether (200 mL) was added, the solution was washed with aqueous 5% sodium bicarbonate and brine, was dried (potassium carbonate) and was evaporated to provide a clear colorless oil. 1H NMR(250 MHz, CDCl3) δ 7.0 (m, 2H), 6.85 (d, J=7 Hz, 1H), 4.8 (m, 1H), 4.0 (m, 4H), 3.85 (s, 3H), 1.58-2.20 (m, 16H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CCCP(=O)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: NCc1ccccc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)NCc3ccccc3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 4.5 mL CH2Cl2 at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.131 mL, 0.22 mmol). After 5 min at rt, benzyl amine (0.023 mL, 0.21 mmol) was added and the reaction stirred at rt for 23 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with aqueous NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and evaporated to a solid. The solid was chromatographed eluting with CHCl3/EtOAc plus 5% MeOH and then triturated with acetone/hexane to give the title compound as a light beige solid (20 mg, 28%). 1H NMR (Acetone-d6) δ: 8.39 (br. s., 1H), 8.12 (s, 1H), 7.58 (br. s., 1H), 7.27-7.38 (m, 5H), 7.16-7.26 (m, 2H), 4.59 (d, J=5.6 Hz, 2H), 4.30 (s, 2H), 3.66 (t, J=5.3 Hz, 2H), 2.82 (t, J=5.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([O:12][CH2:24][CH2:23][CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCCCc1cccnc1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (6.0 g; 28 mmol), 3-(3-pyridyl)-1-propanol (5.80 g; 41.8 mmol), dicyclohexylcarbodiimide (9.20 g; 44.48 mmol), camphorsulfonic acid (21.60 g; 9.26 mmol), and 4-dimethylaminopyridine (1.12 g; 9.26 mmol) in dry methylene chloride (200 mL) was stirred overnight. The reaction mixture was filtered through Celite, concentrated, and purified on a silica gel column eluting with 40 ethyl acetate in hexane to obtain 5.0 g of the product as a clear oil (53%). 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H); 1.43-1.95 (m, 6H); 2.68 (m, 2H); 3.46-3.52 (m, 2H); 4.11-4.22 (m, 2H); 4.33 (m, 1H); 7.17-7.24 (m, 1H); 7.47 (m, 1H); 8.43 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CC(=O)Nc2cccc(/C=C/c3cccc(C)c3)c2)ccc1OCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CC(=O)Nc2cccc(CCc3cccc(C)c3)c2)ccc1OCCNC(=O)OC(C)(C)C
Yield: 79.7 %

Procedure:
4-[2-(tert-Butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[(E)-2-(3-methylphenyl)vinyl]phenyl]phenylacetamide (100 mg) is dissolved in methanol (10 ml) and acetic acid (1 ml), and thereto is added 10% palladium on carbon (10 mg), and the mixture is subjected to catalytic hydrogenation at 50° C. The catalyst is removed by filtration, and the solvent is evaporated to give 4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[2-(3-methylphenyl)ethyl]phenyl]phenylacetamide (80 mg). This product is treated with 10% hydrogen chloride-methanol to give the desired compound (50 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:9]O)=[CH:3][CH:2]=1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:40]([NH2:43])[CH2:41][CH3:42]>C(O)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[N:43]([CH2:40][CH2:41][CH3:42])[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:9]=2)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(C(=NO)c1cccc(C(F)(F)F)c1)c1ccncc1
Reactant: CCCN
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Product: CCCn1c(C2CCN(C(=O)OCc3ccccc3)CC2)nc(-c2cccc(C(F)(F)F)c2)c1-c1ccncc1
Reaction time: 18 h
Yield: 23.7 %

Procedure:
To a stirring solution of 1-(pyridin-4-yl)-2-[3-(trifluoromethyl) phenyl]ethane-1,2-dione 2-oxime (83 mmol, 24.43 g), and 1-benzyloxycarbonyl-piperidine-4-carboxaldehyde [Amici et al Eur. J. Med. Chem. 26, 625-631 (1991)] (108 mmol, 26.7 g) in acetic acid (300 mL) was added propylamine (1.24 mol, 73.6 g) in a dropwise manner at ambient temperature. The reaction was heated to reflux for 3 h, cooled to ambient temperature and basified to pH8 with concentrated ammonium hydroxide/ice and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (100 mL) and treated with a solution of titanium trichloride (3×150 mL of 10-20 wt % in 20-30% HCl) and stirred for 18 h. The reaction was basified to pH 10 with saturated potassium carbonate and extracted with ethyl acetate (4×300 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of 30%-60% ethyl acetate:hexane to give a yellow oil which was rechromatographed on silica, eluting with a gradient of 25%-50% ethyl acetate:hexane to give 10.8 g of a pale yellow oil.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19]C.O>CN(C=O)C>[CH2:11]([O:14][C:3]1[C:4]2[O:8][CH:7]=[CH:6][C:5]=2[CH:9]=[CH:10][CH:2]=1)[CH2:18][CH3:19]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2ccoc2c1
Reactant: CCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc2ccoc12
Yield: 54.5 %

Procedure:
To a solution of 6-hydroxybenzofuran (1.30 g) in DMF (15 ml) was added potassium carbonate (1.88 g) and then was added dropwise bromopropane (1.44 g) under nitrogen atmosphere, and the mixture was refluxed overnight. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed with water (three times) and then washed with saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give yellow oil of 7-propoxybenzofuran (0.93 g).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH:9]=[CH:8][S:7][CH:6]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O>>[C:1]([NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1C=CSC1C(=O)c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)Nc1ccsc1C(=O)c1ccccc1
Yield: 82 %

Procedure:
Using the method described in Example 14(c), 2.47 parts of 3-acetylamino-2-benzoyldihydrothiophene, on reaction with 0.66 parts of sulfuryl chloride for one hour at 0° C., give 2.0 parts of 3-acetylamino-2-benzoylthiophene (82% of theory) of melting point 93°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([C:17]#[C:18][CH3:19])[OH:16].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:23](=[O:24])[O:16][C:15]([CH:20]4[CH2:22][CH2:21]4)([C:17]#[C:18][CH3:19])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC#CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Solvent: C1CCOC1
Product: CC#CC1(C2CC2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol (0.02 g, 0.064 mmol) and 1,1′-carbonyldiimidazole (0.016 g, 0.096 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THF was removed and the residue purified via flash chromatography (silica gel, 40% ethyl acetate/hexane) to give 6-(3-chlorophenyl)-4-cyclopropyl-4-prop-1-ynyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.014 g, 56%) as a light yellow solid: mp 178-179° C.; 1H-NMR (DMSO-d6) δ10.6 (s, 1H), 7.68 (m, 2H), 7.64 (bs, 1H), 7.59 (d, 1H, J=7.72 Hz), 7.49 (t, 1H, J=7.82 Hz), 7.42 (d, 1H, J=7.95 Hz), 7.02 (d, 1H, J=8.0 Hz), 1.86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H); MS (ESI) m/z 336 ([M−H]−, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(C1C=CC=CC=1CC)C>[OH:8][C:7]1[C:2]2=[N:1][CH:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCc1ccccc1CC
Product: CCOC(=O)c1cnc2c(O)cccn2c1=O
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Diethylbenzene Process: A mixture of 66.0 g of 2-amino-3-pyridinol, 220.0 g of diethyl ethoxymethylenemalonate, and 1.0 liter of diethylbenzene was heated so that the internal temperature reached 140° in 1 hour, was kept for 1 hour at 140°, then heated so that the temperature rose to 180° in 1 hour, and then kept 1 hour at 180°. During this entire heating period, 50 ml. of distillate was collected. The solution was allowed to cool spontaneously, was cooled at 0°, filtered, and the solid washed with diisopropyl ether to give 130.0 g of product, after drying at 56° in vacuo. The m.p. was 175°-177° and a mixture m.p. with the product isolated in (a) above was 175°-177°. The ir and pmr spectra of the two samples were superimposable. The yield was 93%.