Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>C(N(CC)CC)C>[CH:1]([O:4][C:5](=[O:11])[CH2:6][C@@H:7]([C:8]([OH:10])=[O:9])[NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])([CH3:3])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CC(C)OC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C[C@H](NCCCN(C)C)C(=O)O
Yield: 94.7 %

Procedure:
395.2 g (2.5 mols) of maleic acid-monoisopropyl ester, 500 ml of triethylamine and 306.5 g (2.5 mols+20% excess) of 3-dimethylaminopropylamine are reacted according to Example 1, and the reaction product is subsequently purified to yield 616.4 g (94.7% of theory) of a white crystalline aspartic acid derivative of which the melting point is 163.5°-165.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C@H:7]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:8][C:9](=[O:32])[CH2:10][N:11]([C:17](=[O:31])[C@H:18]([CH3:30])[NH:19]C(OCC1C=CC=CC=1)=O)[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>CO.[C].[Pd]>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[C:1]([O:5][C:6](=[O:40])[C@H:7]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:8][C:9](=[O:32])[CH2:10][N:11]([C:17](=[O:31])[C@H:18]([CH3:30])[NH2:19])[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1CCCC1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C[C@H](N)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1CCCC1
Yield: 97.6 %

Procedure:
N-Carbobenzoxy-L-alanyl-N-cyclopentylglycyl-L-phenylalanine tert-butyl ester (6.7 g) is dissolved in 100 ml of methanol, and according to the procedure of Reference Example 3, catalytic reduction is conducted in the presence of 1 g of oxalic acid and 1.5 g of 5% palladium-carbon (water content 50%). By the above procedure there is obtained 5.5 g of L-alanyl-N-cyclopentylglycyl-L-phenylalanine tert-butyl ester oxalate as colorless powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[Li+].CC([N-]C(C)C)C.[CH3:40][C:41]([S:44]([N:46]=[C:47]1[CH2:50][O:49][CH2:48]1)=[O:45])([CH3:43])[CH3:42]>C1COCC1>[CH3:43][C:41]([S:44]([NH:46][C:47]1([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[CH2:50][O:49][CH2:48]1)=[O:45])([CH3:40])[CH3:42]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of lithium diisopropylamine (1.8 M, 4.96 mL, 8.92 mmol) in THF (8 mL) was placed under an Argon atmosphere and was cooled to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1200 mg, 3.57 mmol) in THF (8 mL) was cooled to −78° C. and added drop wise to the LDA solution. The reaction mixture was stirred 30 minutes at −78° C. The product of Step 1 (625 mg, 3.57 mmol) in THF (8 mL) was added drop wise and the reaction was allowed to warm to room temperature overnight. The mixture was quenched with brine, diluted with ethyl acetate. The organics were washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes) to afford 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfinamide (1.10 g, 2.140 mmol, 60.0% yield). MS ESI: [M+H]+ m/z 512.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:22]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:10])[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:24][CH2:23]1
Reactant: CCOc1cc(-c2ccc(F)cc2)c(Br)cc1C(=O)OC
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A mixture of methyl 2-bromo-5-ethoxy-4′-fluorobiphenyl-4-carboxylate (7.62 g), cyclopropylboronic acid (5.56 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.33 g), a 2 M aqueous sodium carbonate solution (32.4 mL), tris(dibenzylideneacetone)dipalladium(0) (1.38 g), and toluene (50 mL) was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto. The reaction mixture was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. A THF (50 mL) solution of the obtained residue was added to a THF (50 mL) suspension of lithium aluminum hydride (0.819 g) under ice cooling. After stirring at the same temperature as above for 30 minutes, water (1 mL) and a 15% aqueous sodium hydroxide solution (1 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (3 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.65 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH3:9])[O:6][CH:7]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH2:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[N:4]=1)[CH3:9]
Reactant: CCc1nc(CCl)co1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1coc(CC)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 4-chloromethyl-2-ethyl-1,3-oxazole (3.26 g), triethyl phosphite (8.19 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (3.86 g, yield 70%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:42]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([OH:41])[C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:57][O:58][C:59]([NH:61][C@@H:62]([C:66]([CH3:69])([CH3:68])[CH3:67])[C:63]([OH:65])=O)=[O:60].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>ClCCl.C1COCC1>[CH2:1]([C@H:8]([NH:42][C:63]([C@@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]([CH3:69])([CH3:68])[CH3:67])=[O:65])[CH2:9][C@H:10]([OH:41])[C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
A solution of the product from Example 22A (7.81 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (20 mL), and the mixture was stirred at 25° C. for 1 hour. The solvent was concentrated and the reaction was partitioned between ethyl acetate and 10% Na2CO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the residue (7.81 mmol) in THF (80 mL) was treated with the product from Example 1F (1.6 g, 8.47 mmol), DEPBT (3.5 g, 11.71 mmol), and N,N-diisopropylethylamine (6.8 mL, 39.04 mmol) and the mixture was stirred at 25° C. for 5 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by chromatography on silica gel eluting with a gradient starting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate. The product was then purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA). The product was, partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (1.32 g, 23% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (s, 9 H), 0.91 (s, 9 H), 1.25 (m, 1 H), 1.51 (m, 2 H), 2.36 (m, 1 H), 2.46 (s, 3 H), 2.70 (m, 3 H), 2.96 (m, 1 H), 3.09 (m, 1 H), 3.23 (m, 1 H), 3.55 (s, 3 H), 3.65 (m, 1 H), 3.83 (d, J=9.93 Hz, 1 H), 4.14 (m, 3 H), 4.35 (m, 2 H), 4.50 (d, J=7.72 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.09 (m, 12 H), 7.47 (d, J=9.19 Hz, 1 H), 7.71 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([OH:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:32](N(CC)CC)C.CI.C(=O)([O-])[O-].[K+].[K+].[H-].[Na+]>O.ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]([O:14][CH3:32])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(C(F)(F)F)s1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1CN(c2ncn(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CC=C1c1ccc(F)cc1
Yield: 15.1 %

Procedure:
To an N,N-dimethylformamide (2.0 mL)-dichloromethane (2.0 mL) solution of 4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (50.0 mg, 0.111 mmol) synthesized in Synthesis Example 190, triethylamine (23.2 μL, 0.167 mmol) and methyl iodide (20.6 μL, 0.332 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 1 day. Next, to the reaction solution, potassium carbonate (50.0 mg, 0.362 mmol) and methyl iodide (40.0 μL, 0.643 mmol) were added and the resultant mixture was stirred at 50° C. for 1 hour. Then, to the reaction solution, sodium hydride (12.0 mg, 0.500 mmol) and methyl iodide (40.0 μL, 0.643 mmol) were added and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, to the reaction solution, water was added and extraction with chloroform from the reaction solution was performed. The organic layer was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain the title compound (7.80 mg, yield: 15%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=O.Cl>CO>[N+:19]([C:16]1[CH:17]=[CH:18][C:11]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:13][C:12]=2[CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A 2000 ml 3-necked round-bottomed flask, 250 ml pressure equalized dropping funnel, Teflon stirrer, and gas inlet were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, and allowed to cool to room temperature. The cooled flask was charged with methanol (600 ml) and methyl thioglycolate (28.6 g, 0.27 mole). Sodium methoxide (19,98 g, 0.37 mole) in methanol (125 ml) was added to the reaction mixture over 10 minutes while stirring. The reaction mixture was then warmed to 40° C. and a solution of 2-chloro-5-nitrobenzaldehyde (28.6 g, 0.27 mole) in methanol (300 ml) was added over a period of about 20 minutes. The resulting slurry was stirred at 40° C. for 1 hour, cooled to room temperature, and acidified with 2M hydrochloric acid. The resulting white solid was filtered, washed with water (2×300 ml) and air-dried to give 61 g (95%) of methyl 5-nitrobenzothiophene-2-carboxylate. See, R. A. Zambias, M. L. Hammond, Synthetic Communications, 21:959 (1991).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:27]1.C(N(CC)CC)C.CS(Cl)(=O)=O>>[O:25]=[C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH:15]=[CH:16][N:11]1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:27]2)=[CH:4][CH:5]=1
Reactant: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccncc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[2-Oxo-4-(pyridin-4-ylmethoxy)-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 10.1b from 80 mg (0.24 mmol) 1-[2-(4-hydroxymethylphenyl)-ethyl]-4-(pyridin-4-ylmethoxy)-1H-pyridin-2-one (example 10.1a), 101 mg (0.71 mmol) N-piperidin-4-yl-acetamide, 99 μL triethylamine (0.71 mmol) and subsequently 37 μL (0.48 mmol) methanesulfonyl chloride. The product is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CS(C)=O>CCOC(C)=O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccccn2)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (100 mg, 0.41 mmol), potassium carbonate (100 mg, 0.72 mmol), 2-bromopyridine (0.40 mL, 4.2 mmol), and dimethyl sulfoxide (2 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]=3[N+:19]([O-])=O)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].O.C(Cl)(Cl)Cl>CO.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine (0.2 g, 0.55 mmol) (from Example 11, Step A, supra) and NH4Cl (0.24 g, 4.43 mmol) in a mixture of MeOH, H2O and CHCl3 (50 mL, 2:1:12), was added Zn powder (0.72 g, 11 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered. The filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2 /NEt3 (1:1:0.05) as eluent to give the desired N4-(3-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine as an orange gum. (Yield 0.1 g, 55%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]>ClCCl>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:15])[C:23]2[CH:22]=[CH:21][C:20]([O:25][CH3:26])=[C:19]([F:18])[CH:24]=2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1F
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.2 %

Procedure:
To an ice-cooled slurry of AlCl3 (2.01 g, 15.1 mmol) in dichloromethane (10 mL) was slowly added 4-chlorocarbonyl-benzoic acid methyl ester (2 g, 10.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 20 min in the ice bath then 2-fluoroanisole (1.4 mL, 12.1 mmol) in dichloromethane (5 mL) was added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into ice cold 1 N HCl (10 mL) and the mixture was stirred for 15 min. The reaction mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude solid was triturated with hot hexanes, filtered and washed with hexanes to give 0.5 g (17%) of compound 173 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 3.89 (s, 3H), 3.94 (s, 3H), 7.32 (t, J=8.5 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.59-7.63 (m, 1H), 7.81 (d, J=8.2 Hz, 2H), 8.04 (s, 1H), 8.10 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15](O)[CH2:14]1>>[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14]1
Reactant: CC1CCCC(O)C1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CCC[C@@H](C)C1)C(C)=O

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3 g, 18.9 mmol) was converted into the title compound by reaction with 3-methylcyclohexanol (5.16 ml, 39.7 mmol. 60:40 cis: trans mixture) as described in Example 4a method 3, except that the reaction was complete in 2 h. After purification the title compound was obtained as a colourless oil (2.4 g; 50%); νmax (CHCl3) 1740, 1685, and 1590 cm-1 ; δH (CDCl3) 0.75-0.97 (1H, m), 0.96 (3H, d, J 6.5 Hz), 1.05 (1H, dd, J 11.7 Hz, partially obscured by d, δ 0.96), 1.32 (3H, t, J 7. 1 Hz), 1.19-1.40 (2H, m, partially obscured by t, δ 1.32), 1.40-1.73 (2H, m), 1.79-1.90 (1H, m), 2.03-2.19 (2H, m), 2.39 (3H, s), 4.23 (1H, tt, J 11.2 and 4.5 Hz), and 4.34 (2H, q, J 7.1 Hz); δ13C 14.1, 22.3, 23.6, 25.1, 31.2, 31.4, 34.0, 40.1, 61.7, 85.1, 149.9 161.5, and 193.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])([CH3:20])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 106.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.13 mg (0.131 mMol) isopropyl isocyanate, 21.9 mg of the title compound were recovered.
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[O:12]([Br:14])[Na:13].[OH-].[Na+].BrBr.C(O)(=[O:26])C1C=CC=CC=1.[Na]>O1CCOCC1.O>[O:12]([Br:14])[Na:13].[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])=[O:26])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)c1ccccc1
Agent: BrBr
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
4-methoxyacetophenone (11.5 g) was dissolved in 100 ml dioxane and freshly prepared NaOBr solution (as prepared below) was added dropwise, with constant stirring with a stir bar at room temperature. The NaOBr solution was prepared by dissolving 40 g of NaOH in 500 ml of water, cooling to 0° C. in an ice bath, and adding bromine (12.5 ml) dropwise while stirring with stir bar; bromine was added slowly so that the reaction mixture did not exceed 5° C. After overnight stirring of the 4-methoxyacetophenone, dioxane and NaOBr solution, the reaction mixture was diluted with water (200 ml). Since the reaction mixture was basic, the product, benzoic acid, was in water as its sodium salt. The resultant mixture was partitioned between ether and water. The ether layer was washed with dilute aqueous NaOH to extract any remaining product as Na salt. The aqueous layers were combined and acidified to pH 1 to precipitate the benzoic acid. The resulting acid was extracted with ether. The ether layer was washed with water a few times, dried with anhydrous MgSO4, and filtered. Rotary evaporation of the ether fraction afforded 4-methoxybenzoic acid (IV) in 85% yield.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH:9]([CH3:11])[CH3:10])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:12][Li].O>CCOCC>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(CC(C)C)=C1C=CC=C1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(C)CC(C)(C)C1=CC=CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
To a solution of 8.00 g (54.0 mmol) of 6-methyl-6-isobutylfulvene in 30 ml of ether, 54.0 ml (61.6 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 days. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (120° C./25 mmHg) to obtain 7.10 g (43.2 mmol) of a light yellow liquid (yield: 80%)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:2]=1[Cl:1])=[O:19]
Reactant: CCOC(=N)c1cc(Cl)ccc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1cc(Cl)ccc1Cl

Procedure:
starting from ethyl 2,5-dichlorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2,5-dichlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(2,5-dichlorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 60°-63° C.;