Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 59.4 %

Procedure:
1-[5-(3,4-Dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.139 mmol, 39.7 mg) synthesized in Synthetic Example 1 and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) were stirred with dimethylformamide (4 mL) and two drops of concentrated hydrochloric acid at room temperature for 22 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (39.5 mg, yield 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=3)[CH2:38][CH2:37]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cc(OC)c(OC)c(OC)c4)CC3)nc2c1
Yield: 97 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 3.55-3.87 (m, 10H), 4.12 (s, 4H), 6.67 (d, J=8.4 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.25 (s, 1H), 7.34 (s, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 8.21 (d, J=3.6 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[CH2:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=1>O1CCCC1>[CH3:1][N:2]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CNc1ccccn1
Reactant: Cn1c(CCl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1nc2ccccc2n1C)c1ccccn1

Procedure:
To a flask were added 0.6 g 2-(methylamino)pyridine and 20 ml tetrahydrofuran, and the mixture was cooled to 5 C. To this mixture were added 0.26 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 5-10 C for ten minutes, 1.0 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole was added. The reaction mixture was heated to 45 C for 16 hours, then cooled to 22 C and quenched with 40 ml water. The product was extracted with 40 ml ethyl acetate and following removal of the solvent, the product was purified by silica gel chromatography using 63% ethyl acetate, 25% hexane and 12% methanol resulting in 0.55 g of a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([CH2:11][C:12]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:26]=O>C(O)=O>[CH3:26][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][C:12]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:25]=2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: CCOC(=O)C(C)(Cc1ccc(N2CCNCC2)cc1)C(=O)OCC
Solvent: O=CO
Product: CCOC(=O)C(C)(Cc1ccc(N2CCN(C)CC2)cc1)C(=O)OCC
Yield: 86.8 %

Procedure:
A mixture of diethyl 2-(4-(piperazin-1-yl)benzyl)-2-methylmalonate (500 mg, 1.43 mmol), formaldehyde (2 ml) and formic acid (2 ml) was heated at reflux for 2 h. The reaction mixture was concentrated and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated and washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford 400 mg (86.8%) of diethyl 2-(4-(4-methylpiperazin-1-yl)benzyl)-2-methylmalonate as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH3:19]C(C)([O-])C.[K+].CI.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8](=[O:13])[N:7]([CH3:19])[C:6]=2[CH:14]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc(Cl)cc2c1OC(C)(C)C(=O)N2
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Oc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 4.2 g of methyl 6-chloro-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate in 20 ml of dimethylformamide is added 2.27 g of potassium t-butoxide, and the solution stirred at room temperature for 30 minutes. To the resultant solution is added dropwise a solution of 2.95 g of methyl iodide in 5 ml of dimethylformamide, and the solution stirred for 2.5 hours. To the resulting solution are added water and ethyl acetate to separate the organic layer followed by washing with water and drying over magnesium sulfate. After the solvent is distilled off under reduced pressure, to the residue are added 50 ml of ethanol and 50 ml of diluted aqueous sodium hydroxide solution and the system stirred at room temperature for 15 hours. To the resultant solution is added diluted hydrochloric acid and the precipitated crystals are collected by filtration and dried to give 3.9 g of 6-chloro-3,4-dihydro-2,2,4-trimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting at 235°-236° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33]Br)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])[CH3:19])=[O:16].[F-].[K+].[F:44][C:45]1[C:50]([F:51])=[CH:49][C:48]([F:52])=[C:47]([F:53])[C:46]=1[OH:54].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][O:54][C:46]1[C:47]([F:53])=[C:48]([F:52])[CH:49]=[C:50]([F:51])[C:45]=1[F:44])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])[CH3:19])=[O:16]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)n(C)c2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12

Procedure:
The titled product was prepared as described in Example 82 using N-[(1-methyl-3-isobutyl-indole-2-carbonyl)cyclohexylalaninyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (50.8 mg, 0.08 mmol), potassium fluoride (12.0 mg, 0.21 mmol), and 2,3,5,6-tetrafluorophenol (13.3 mg, 0.08 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 3/1): Rf=0.25.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]([CH3:37])([CH3:36])[CH2:20]2)[CH2:12][C:11]1([CH3:39])[CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:40]([N:49]=[C:50]=[O:51])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48]>>[CH2:1]([O:9][N:10]1[C:11]([CH3:38])([CH3:39])[CH2:12][CH:13]([N:18]([CH:19]2[CH2:20][C:21]([CH3:37])([CH3:36])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:23]([CH3:25])([CH3:26])[CH2:24]2)[C:47]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:49][C:50]([N:18]([CH:19]2[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]([CH3:36])([CH3:37])[CH2:20]2)[CH:13]2[CH2:12][C:11]([CH3:39])([CH3:38])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:15]([CH3:16])([CH3:17])[CH2:14]2)=[O:51])=[O:48])[CH2:14][C:15]1([CH3:16])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CCCCCCCCON1C(C)(C)CC(NC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(N(C(=O)NCCCCCCNC(=O)N(C2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)C2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)C2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)amine with hexamethylene diisocyanate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1/[C:25](=[N:29]/[OH:30])/[C:26]([OH:28])=[O:27].C(Cl)(Cl)(Cl)Cl.ClCCl.C(Br)(Br)Br>CS(C)=O.CCO>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][NH:5][C:3]([CH2:2][O:30]/[N:29]=[C:25](/[C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)\[C:26]([OH:28])=[O:27])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)NOC(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C(=N\O)c1ccco1
Solvent: CS(C)=O
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CO/N=C(\C(=O)O)c1ccco1)NOC(c1ccccc1)c1ccccc1
Yield: 17 %

Procedure:
This was prepared from diphenylmethyl chloroacetohydroxamate and Z-2-(fur-2-yl)-2-hydroxyiminoacetic acid by the method described in Preparation 4; m.p. 138°-140° (from carbon tetrachloride-dichloromethane), λmax (EtOH) 273.5 nm (ε13,900), νmax (CHBr3) 3350 (NH), ca 3600-2100 (bonded OH), 1750 and 1728 (CO2H), 1690 cm-1 (CONH), τ(DMSO d6) include 2.09, 3.20 and 3.30 (α-furyl), 2.4-2.8 (Ph), 4.00 (Ph2CH), 5 49 (CH2). Yield 17%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]2>CN(C=O)C>[N:3]1([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: O=C1CCCc2cc(OCCCl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.5 %

Procedure:
A suspension of NaH (0.29 g, 7.2 mmol, 60% oil dispersion prewashed with dry hexanes) in 18 mL of dry DMF under a nitrogen flow was cooled to 0° C. and imidazole (0.49 g, 7.2 mmol) was added portionwise. The ice bath was removed and the reaction stirred at room temperature 20 minutes. The reaction was cooled to 0° C. and a solution of 6-(β-chloroethoxy)-1-tetralone (1.07 g, 4.8 mmol) in 12 mL of dry DMF was added over several minutes. The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was partitioned between 20 mL of water and 200 mL of EtOAc. The organic portion was removed, and the aqueous portion was extracted with EtOAc (5×50 mL). The combined extracts were washed successively with water and brine, dried, filtered, and concentrated under vacuum to afford 1.6 g of crude product. Purification by flash chromatography (silica gel, 130 g, 8% MeOH in DCM) afforded 0.83 g (67%) of an off-white crystalline solid: CI-MS m/e 256 (M+), 257 (M++1);
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][S:12](Cl)(=[O:14])=[O:13]>ClCCl>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: COc1cccc(C)c1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
2,3-Dimethylanisole (1 cm3, 7.23 mmol) was dissolved into dichloromethane (4 cm3) and cooled to 0° C. Chlorosulfonyl chloride (2 cm3, 30.0 mmol) was then added dropwise, over 10 min and once the addition was completed the mixture was allowed to warm to room temperature and stirred for a further 45 min. The reaction was then quenched by the slow addition of ice/water (50 cm3, CARE, exotherm) before further dichloromethane (30 cm3) and water (30 cm3) were added and the organic layer was collected. The aqueous layer was washed with dichloromethane (15 cm3) and then organic extracts were combined and washed with saturated aqueous sodium chloride solution (70 cm3) before being dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford title compound (1.6 g, 6.82 mmol, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1
Product: O=C(CC1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccc1
Yield: 59.7 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (200 mg, 0.68 mmol) and aniline (200 mg, 2.15 mmol) to give 150 mg of the title compound (60%):mp >280° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (bs, 1H), 10.02 (s, 1H), 7.57 (d, 2H, J=7.8 Hz), 7.30 (t, 2H, J=7.8 Hz), 7.14 (s, 1H), 7.06 (t, 1H, J=7.8 Hz), 7.05 (s, 1H), 5.14~5.29 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.55~2.70 (m, 2H), 2.10 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:23][C:21]1[S:22][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)s1
Product: CC(CNCc1ccc(Cl)s1)Oc1ccc2ccccc2c1Cl
Yield: 69 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and 5-chlorothiophen-2-carbaldehyde in 69% yield as a yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1>Cl(O)(=O)(=O)=O>[Br:1][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CC(=O)O)s1
Agent: [O-][Cl+3]([O-])([O-])O
Product: O=C(O)Cc1ccc(CBr)s1
Reaction time: 22 h
Yield: 82 %

Procedure:
To a solution of N-bromosuccinimide (5.94 g, 33 mmol) in hexanes (16 mL) was added 5-methyl-2-carboxymethylthiophene (5.0 g, 32 mmol), prepared as in step 1, followed by 1 drop of perchloric acid. The reaction mixture was stirred for 22 hours at ambinet temperature and then partitioned between ethyl acetate and saturated aqueous HaHSO3 solution. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 6.17 g of 5-bromomethyl-2-carboxymethylthiophene as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]>C(O)(C)C.[Ni]>[C:1]([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[NH2:19])[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(OC(C)=O)C1OC(C)=O
Agent: [Ni]
Solvent: CC(C)O
Product: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2N)C(OC(C)=O)C1OC(C)=O

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (4.30 g, 9.28 mmol) in isopropanol (250 mL) was shaken with Raney nickel (Aldrich, slurry in water, 400 mg wet) under hydrogen (50 psi) on a Parr shaker for 2.75 hours. Catalyst was filtered off with Celite and the filtrate-wash (350 mL) stored at -5° C. Yellow crystals of title compound formed slowly (2.35 g, 58%), m.p. 124°-125° C.; 1H-NMR(DMSO-d6)δ: 6.70 and 6.57 (both s, 1 each, 2 aromatic CH), 5.15-4.9 (m, 5, NH2, NH, and 2 OCH), 4.2-4.0 (m, 2, CH2O), 3.9-3.75 (m, 1, NCH), 2.5-2.4 (m overlapping solvent, CH2), 2.07, 2.04, and 2.01 (all s, 9, 3 CH3), 1.4-1.2 (m, 1, CH); mass spectrum(CI): 433(M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N+:46]([CH2:49][CH2:50][CH3:51])([O-:48])=[O:47]>C(COC)OC.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]>[F:15][C:5]1[CH:4]=[CH:3][C:2]([CH:49]([N+:46]([O-:48])=[O:47])[CH2:50][CH3:51])=[CH:14][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CCC[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1F
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCC(c1ccc(F)c(C(=O)OC(C)(C)C)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To tert-butyl 5-bromo-2-fluorobenzoate (1.26 g) in dimethoxyethane (22.9 ml) solution, tris(dibenzylideneacetone)dipalladium (0.10 g), 2-(di-tert-butylphosphino)-2′-methylbiphenyl (0.14 g), tripotassium phosphate (1.07 g), and 1-nitropropane (0.82 ml) were added, the mixture was stirred at room temperature for 1 minute, then the mixture was stirred under heating and reflux for 15 hours. The insoluble compound was filtered out, then the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate: 0 to 10%) to obtain the title compound (392 mg).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C1(=O)O[CH2:28][CH2:27][O:26]1.[OH-].[K+].C(=O)=O>CN(C)C=O.O>[C:1]([C:4]1[C:5](=[O:24])[N:6]([CH2:28][CH2:27][OH:26])[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: O=C1OCCO1
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nn(CCO)c1=O
Temperature: 5 °C
Yield: 68 %

Procedure:
4-Acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one (3.1 g), ethylene carbonate (2.0 g), and potassium hydroxide (powdered) were dissolved in dimethylformamide (50 ml) and the flask placed in an oil bath (110°-120° C.) until CO2 evolution ceased (ca. 3.5 hours). The reaction mixture was poured into water (400 ml) and chilled at 5° C. for 1 hour. The resulting precipitate was separated by filtration and recrystallized from methanol (85 ml) to afford 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one (68 percent yield) as pale yellow crystals, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[CH:39])[CH:33]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:39]#[C:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([O:30][CH3:29])=[O:40])[CH:33]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#Cc1cccc(C(=O)OC)c1
Product: COC(=O)CCc1nc(C#Cc2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 79.2 %

Procedure:
Under the conditions of example 5 A, 1 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 320 mg of 3-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-15% ethyl acetate. 835 mg of 3-{6-[2-(3-methoxycarbonylphenyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH3:16].C(O)C>>[NH2:16][CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To diethyl ethoxymethylenemalonate (50.13 g, 0.232 mmol), cooled to −20° C. under nitrogen, was added a 2.0 M solution of ammonia in ethanol (232 ml, 0.464 mmol) and the resulting solution was stirred at room temperature overnight. The solution was then evaporated in vacuo to give a quantitative yield of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) 5 1.28 (3H, t, J 7.1 Hz), 1.35 (3H, t, J 7.1 Hz), 4.19 (2H, q, J 7.1 Hz), 4.26 (2H, q, J 7.1 Hz), 5.68 (1H, br s), 8.11 (1H, dd), 8.69 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH:13]([OH:12])[CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1CNC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1

Procedure:
2-Bromo-5-nitropyridine (406 mg, 2 mmol), 3-hydroxyazetidine hydrochloride (199 mg, 2 mmol), and finely ground potassium carbonate (828 mg, 6 mmol) were heated to 80° C. in 20 mL anhydrous DMF for 5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and used without further purification. ES-MS calcd for C8H9N3O3 (m/e) 195.18, obsd 196.2 (M+H).