Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1([CH3:19])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)[CH:2]=[CH2:3].Cl.CCOCC>>[CH2:1]([O:4][CH2:5][C:6]1([CH3:19])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)[CH:2]=[CH2:3]
Reactant: C=CCOCC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Product: C=CCOCC1(C)CCNCC1
Reaction time: 24 h
Yield: 117.2 %

Procedure:
tert-Butyl 4-((allyloxy)methyl)-4-methylpiperidine-1-carboxylate (300 mg, 1.114 mmol) was placed in a 25 mL RBF. A 2N solution of HCl/ether was added (7 mL) and the vessel was sealed with a septa. The colorless homogeneous solution was stirred for 24 h. An aliquot was removed and analyzed by 1H NMR which indicated that the reaction was complete. The reaction mixture was concentrated in vacuo to give 221 mg (96%) of 4-((allyloxy)methyl)-4-methylpiperidine as a white sticky solid. 1H NMR (500 MHz, DMSO-d6) δ 8.88-8.42 (m, 2H), 5.90 (ddt, J=17.3, 10.5, 5.2 Hz, 1H), 5.35-5.12 (m, 2H), 3.96 (dt, J=5.2, 1.5 Hz, 2H), 3.24-3.16 (m, 2H), 3.12-2.93 (m, 4H), 1.70 (ddd, J=14.3, 10.0, 4.3 Hz, 2H), 1.43 (dt, J=14.2, 4.4 Hz, 2H), 0.98 (s, 3H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH2:8])C.[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].Cl>CCOCC>[CH2:5]1[CH:4]2[N:8]([CH2:13][CH2:12][C:14](=[O:15])[CH2:16]2)[CH2:7][CH2:6]1
Reactant: C=CC(C)=O
Reactant: CCOC(CCCN)OCC
Agent: Cl
Solvent: CCOCC
Product: O=C1CCN2CCCC2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-aminobutyraldehyde diethyl acetal (2.51 mL, 14.3 mmol) in Et2O (5 mL) was added methyl vinyl ketone (1.21 mL, 14.3 mmol). After 1 h, concentrated HCl (5 mL) was added, and the reaction mixture was heated at 100° C. for 2 h. The mixture was concentrated to give hexahydroindolizin-7(1H)-one, which was carried forward without purification. The crude residue was diluted with EtOH (5 mL), and 3-bromophenylhydrazine hydrochloride (1.02 g, 4.47 mmol) was added followed by concentrated HCl (5 mL). The reaction mixture was heated at reflux overnight. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound (0.15 g, 12%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.43-7.42 (d, J=1.6 Hz, 1H), 7.29-7.26 (d, J=8.3 Hz, 1H), 7.03-7.03 (dd, J=8.4, 1.8 Hz, 1H), 4.10-4.05 (d, J=13.4 Hz, 1H), 3.22-3.14 (m, 2H), 2.92-2.88 (d, J=13.7 Hz, 1H), 2.57-2.40 (m, 2H), 2.32-2.22 (m, 1H), 2.09-1.98 (m, 1H), 1.88-1.75 (m, 2H), 1.57-1.53 (m, 1H); ESI MS m/z 291 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:10]=1.[CH3:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH2:33]>C(OCC)(=O)C.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:32]([CH3:33])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:14]=1
Reactant: C=C(C)c1ccccc1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3cc(C(C)(C)c4ccccc4)c(O)cc3O)n2)c(C)c1
Temperature: 175 °C
Yield: 67.7 %

Procedure:
To a 1 L three-necked, round-bottomed flask equipped with a magnetic stirrer, condenser, dropping funnel, thermometer, and a nitrogen atmosphere are charged 15.0 g (37.8 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(2,4-dimethylphenyl)-s-triazine and 390 mg of aluminum isopropoxide. The mixture is heated to 175° C. and 4.47 g (37.9 mmol) of α-methylstyrene are added dropwise at a rate of one drop every two seconds. A total of six equivalents of a-methyl styrene are added in this fashion over a 4.5 hour period. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed twice with water and once with brine, and is dried over anhydrous magnesium sulfate. Following filtration, the solvent is removed under reduced pressure to yield a yellow solid. The crude product is purified with medium pressure chromatography with 12% ethyl acetate/heptane to afford 13.2 g of the title compound as a yellow solid; mp 168°-170° C.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([NH:17][C:18]([NH:20][C:21](=[NH:23])[NH2:22])=[O:19])=[C:12]([CH3:24])[CH:11]=1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([CH3:24])[C:13]([NH:17][C:18]([NH:20][C:21](=[NH:22])[NH2:23])=[O:19])=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)NC(=N)N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(O)cc(C)c1NC(=O)NC(=N)N

Procedure:
A mixture of 1-(4-benzyloxy-2,6-dimethylphenyl)-3-amidinourea hydrochloride (7.0 g), methanolic HCl (50 ml), 5% Pd/C (1.0 g) and 150 ml of absolute ethanol are shaken under an atmosphere of H2 (50 psi) until the uptake of hydrogen ceases. The mixture is filtered through a pad of Celite and the pad washed well with methanol. The filtrate is concentrated under vacuo and the residue crystallized from methanol/acetonitrile to give, after filtering and vacuum drying, 4.7 grams of an off-white solid, M.P. 204°-206° C. Recrystallization from methanol/acetonitrile gave, after filtering and vacuum drying, 2.3 grams, M.P. 208°-210° C. of the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:6]=2[CH:21]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.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]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2([CH3:13])[C:6]3[CH:21]=[C:2]([NH:1][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[CH:3]=[CH:4][C:5]=3[N:10]([CH3:11])[C:9](=[O:12])[O:8]2)=[CH:15][CH:16]=1
Reactant: Clc1cccc(I)c1
Reactant: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(N)ccc21
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(Nc3cccc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 16.1 %

Procedure:
To a stirred solution of 6-amino-4-(4-chlorophenyl)-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.09 g, 0.30 mmol) and 1-chloro-3-iodobenzene (0.2 mL, 1.62 mmol) in THF (2 mL) was added Pd2(dba)3 (0.03 g, 0.03 mmol), BINAP (0.03 g, 0.05 mmol), sodium t-butoxide (0.07 g, 0.45 mmol), and 18-crown-6 (0.12 g, 0.45 mmol). The reaction mixture was stirred at room temperature for 2 days, quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. Flash silica gel column separation with 20% ethyl acetate/hexane followed by trituration with hexane gave the title compound as brown solid (0.02 g, 18%). 1H NMR (DMSO-d6): δ 8.43 (s, 1H), 7.46 (dd, J=6.7, 2.0 Hz, 2H), 7.31 (dd, J=6.8, 2.2 Hz, 2H), 7.28 (m, 2H), 7.10 (d, J=10.5 Hz, 1H), 7.09 (s, 1H), 6.94 (m, 2H), 6.80 (m, 1H), 3.17 (s, 3H), 1.92 (s, 3H); MS (ESI) m/z [M+H]+(413/415); MS (ESI) m/z [M−H]−(411/413); Anal. calcd for C22H18Cl2N2O2: C, 63.93; H, 4.39; N, δ 6.78. Found: C, 62.88; H, 4.72; N, 5.67.
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[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[N+:24]([C:23]1[C:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Yield: 23 %

Procedure:
(R)-5-Amino-3-(pyrrolidin-2-ylmethyl)indole and 2-chloro-3-nitropyridine were used. Sodium acetate was used as base, acetic acid was used as solvent, and the reaction was heated at reflux (116°0 C.) for 2 hours. Column chromatography afforded the title compound (23%) as a dark red foam: 1H NMR (CDCl3) δ 10.05 (br s, 1H), 9.23 (br s, 1H), 8.49 (dd, J=1.8 and 8.3 Hz, 1H), 8.39 (1.8 and 4.5 Hz, 1H), 7.70 (d, J=1.7 Hz,1H), 7.33-7.22 (m, 2H), 6.98 (s,1H), 6.73 (dd, J=4.5 and 8.3 Hz, 1H), 3.46-3.34 (m, 1H), 3.10-2.97 (m, 1H), 2.97-2.78 (m, 3H), 1.99-1.64 (m, 3H), 1.56-1.42 (m, 1H); 13C NMR (CDCl3) δ 155.7, 151.5, 135.5, 134.5, 129.2, 128.1, 127.8, 123.8, 119.4, 114.3, 113.0, 111.6, 59.5, 45.7, 31.3, 30.6, 24.7; FAB LRMS (m/z, relative intensity) 338 (6, [MH+ ]), 309 (12), 155 (49), 135 (38), 119 (100). Anal. calcd for C18H19N5O2.0.67 C2H4O2 [acetic acid]: 61.53; H, 5.79; N, 18.56. Found: C, 61.57; H, 5.74; N, 18.82.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:53]1[CH:62]=[C:61]2[C:56]([C:57]([Cl:63])=[CH:58][CH:59]=[N:60]2)=[CH:55][C:54]=1[O:64][CH3:65])(=O)=O.[N:68]1([CH2:74][CH2:75][NH2:76])[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:63][C:57]1[C:56]2[C:61](=[CH:62][C:53]([NH:76][CH2:75][CH2:74][N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[C:54]([O:64][CH3:65])[CH:55]=2)[N:60]=[CH:59][CH:58]=1
Reactant: NCCN1CCOCC1
Reactant: COc1cc2c(Cl)ccnc2cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(Cl)ccnc2cc1NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14 %

Procedure:
Palladium acetate (62 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (170 mg) were dissolved in toluene (16 ml) to prepare a solution which was then stirred at room temperature for 5 min. 4-Chloro-6-methoxy-quinolin-7-yl trifluoro-methanesulfonate (400 mg) and 2-morpholin-4-yl-ethylamine (1.12 ml) were added thereto, and the mixture was further stirred at room temperature for 5 min. Cesium carbonate (1.97 g) was added to the reaction solution, and the mixture was stirred at 90° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol chloroform to give (4-chloro-6-methoxy-quinolin-7-yl)-(2-morpholin-4-yl-ethyl)-amine (53 mg, yield 14%).
Reaction SMILES: [O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>O>[O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([NH:25][C:37](=[O:40])[CH2:38][CH3:39])[CH:26]=[CH:27][CH:28]=4)[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To a 20-mL glass vial was added 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (30.00 mg; 0.08 mmol) and pyridine (1.00 ml). The resulting mixture was cooled to 0° C. and stirred for 5 minutes. Then propanoyl chloride (0.01 ml; 0.08 mmol) was added. The ice bath was left to melt. The reaction mixture was stirred at room temperature overnight. Water was added to the mixture which was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was purified using Biotage column chromatography (50-100% EtOAc/Hexanes) to afford the title compound as a white solid (28.00 mg, 82%). HPLC (method F): 92%, RT=4.530 min. 1H NMR (DMSO-d6) δ [ppm] 7.52 (d, 1H), 7.45 (d, 1H), 6.85-6.80 (dd, 2H), 6.70-6.64 (q, 1H), 6.60-6.49 (m, 6H), 6.36-6.34 (m, 3H), 6.26 (d, 2H), 6.01 (d, 1H), 1.63 (q, 2H), 0.42 (t, 3H). MS: m/z=451 [M+H]+, RT=4.08 min.
Reaction SMILES: C(S[C:6](=[O:24])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:32][C:31]1[CH:30]=[CH:29][C:28]([OH:33])=[CH:27][C:26]=1[NH:25][C:6](=[O:24])[CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:16][CH:17]=1)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1Cl
Product: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-[4-(2,2-dimethylpropionyl)benzyl]-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-chlorophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17][CH3:18])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:35](Cl)(=[O:37])[CH3:36]>CC(C)=O>[C:35]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:16](=[N:19][O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:17][CH3:18])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:11])(=[O:37])[CH3:36]
Reactant: CCC(=NOCc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=NOCc1ccc(Cl)cc1)c1cc(Cl)ccc1N(C(C)=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a mixture of N-{4-chloro-2-[1-(4-chlorobenzyloxyimino)propyl]phenyl}trifluoromethanesulfonamide (compound 11) (150 mg, 0.33 mmol) and K2CO3 (137 mg, 0.99 mmol) in acetone (5 mL) was added acetyl chloride (70 μL, 0.99 mmol), and the reaction allowed to stir at RT for 2 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in CHCl3 (20 mL), washed with H2O (15 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with EtOAc/PE, 1:19) to afford N-acetyl-N-{4-chloro-2-[1-(4-chlorobenzyloxyimino)propyl]phenyl}trifluoromethanesulfonamide 307 (156 mg, 95%), as a pale yellow solid. M.p. 64-66° C. 1H n.m.r. (400 MHz, CDCl3) δ 7.51, d, J=2.4 Hz, 1H; 7.42, dd, J=2.4 and 8.8 Hz, 1H; 7.30, m, 4H; 7.23, d, J=2.4 Hz, 1H; 5.12, m, 2H; 2.83, m, 1H; 2.67, m, 1H; 1.91, s, 3H; 1.18, t, J=7.6 Hz, 3H.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21](=O)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>ClCCl.O1CCCC1.[Cl-].[Na+].O>[NH2:1][C:2]1([CH3:21])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: O=Cc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: CN1C(=O)C(C)(N)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 54.8 %

Procedure:
A mixture of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J. Org. Chem., 1987, 52, 3232) (1 g), benzaldehyde (408 mg) and anhydrous magnesium sulphate (3 g) in anhydrous dichloromethane (25 ml) was stirred at room temperature for 21 hours, under nitrogen. 4 Å Molecular sieves (2 g) were added to the above mixture and it was refluxed for 19 hours and finally stirred at room temperature for a further 23 hours. Solids were filtered off, washed with anhydrous dichloromethane (15 ml) and the solvent was removed under vacuum. The remaining residue was azeotroped with toluene (2×15 ml) and further dried under high vacuum to give a yellow foam. This material was dissolved in anhydrous tetrahydrofuran (10 ml) and it was added via cannula to a cooled (-72° C.) and stirred solution of sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran; 4.2 ml) in anhydrous tetrahydrofuran (10 ml) over 7 minutes, under a nitrogen atmosphere. The resulting dark blue solution was stirred at -72° C. for 5 minutes before iodomethane (0.27 ml) was added dropwise and stirring was continued at -70° C. for 2 hours and at room temperature for 17 hours. Brine (20 ml) was added and the organic solvent was removed under vacuum. The aqueous residue was diluted with 2N hydrochloric acid (10 ml) and methanol (5 ml) and it was stirred at room temperature for 10 minutes before it was extracted with diethyl ether (2×25 ml). The acidic aqueous solution was basified with 2N sodium hydroxide and products were extracted with ethyl acetate (3×65 ml). The combined organic solutions were washed with brine (1×25 ml), dried (Na2 SO4) and concentrated. Flash chromatography (silica gel, dichloromethane-methanol, 92:8) of the residue gave the title compound (577 mg) as a solid; δH (250 MHz, CDCl3) 7.66-7.26 (8H, m, Ar--H), 7.15 (1H, dt, J=8.0 and 1.1 Hz, Ar--H), 3.52 (3H, s, --NMe), 1.00 (3H, s, --Me); m/z (CI) 280 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH:20]1([C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.C1COCC1.O>[CH:20]1([C:23]2[O:6][N:5]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21]1
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reaction time: 1 h
Yield: 7.6 %

Procedure:
To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solutions were stirred while in the water bath for approximately 20 min and the outside the bath for approximately 1 hour. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclopropyl-3-oxopropanoate (2.17 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (289 mg, 8%). 1H-NMR (400 MHz, DMSO-d6) δ 7.62-7.53 (m, 3H), 4.04 (q, J=7 Hz, 2H), 2.84-2.82 (m, 1H), 1.35-1.25 (m, 4H), 0.93 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[C:24]([F:26])[CH:25]=3)[NH:22][C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[C:24]([F:26])[CH:25]=3)[NH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3cc(F)c4[nH]c(CCC(=O)O)cc4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
To a suspension of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D166) (720 mg) in isopropanol (20 mL) was added 20% sodium hydroxide (1.52 g) solution, then the reaction mixture was stirred at room temperature overnight. The mixture was acidified with HCl (2 M) to pH 4. The solvent of the reaction was removed by evaporation. The residue was dissolved in DMF (5 mL). The precipitation was filtered and the filtrate was purified by Mass Directed Auto Prep to afford 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoic acid (E114) (41 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.32 (6H, s), 2.65 (2H, t), 2.94 (2H, t), 5.38 (1H, m), 6.38 (1H, s), 7.43 (1H, d), 8.01 (1H, s), 8.48 (1H, d), 8.85 (1H, d), 11.78 (1H, s); δF (DMSO-d6, 376 MHz): −132.6; MS (ES): C21H18ClFN4O4 requires 444. found 445.2 (M+H+).
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])([O:3][CH3:4])=[O:2].[OH-].[Ba+2].[OH-]>CO>[CH3:4][O:3][C:1]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:2]
Reactant: COC(=O)CCC#CCCC(=O)OC
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCC#CCCC(=O)O
Temperature: 5 °C
Yield: 80.1 %

Procedure:
1,6-Dicarbomethoxy-3-hexyne (20.0 g, content; 83.9 0.0847 mole) is dissolved in methanol (40 g) and the mixture is cooled to 5° C. To the mixture is added 2 N anhydrous barium hydroxide (33.9 g) and the mixture is stirred. After stirring for 17 hours, the reaction mixture is filtered, and dried under reduced pressure. The resulting crystal is suspended in 1,2-dichloroethane (100 g) and thereto are added 10 % hydrochloric acid (16 g) and water (50 g). The reaction temperature is raised to 40°-45° C., and the mixture is stirred for 2 hours and then separated. The organic layer is washed with water (50 g) and concentrated under reduced pressure to give 6-methoxycarbonyl-1-carboxy-3-hexyne [VI-1] (12.5 g, yield; 80.2%),
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)#[N:12]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: NCCSCc1ccon1
Product: CNC(NCCSCc1ccon1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 3-[(2-aminoethyl)thiomethyl]isoxazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(Br)cc1
Product: COc1ccc2c(Cl)cc(-c3ccc(C)cc3)nc2c1

Procedure:
The title compound, m. p. 129-131° C., MS: m/e=283 (M+), was prepared from 4-chloro-7-methoxy-quinoline and 4-bromotoluene.