Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:12][CH2:11][CH2:10][CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccc(O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCSc1ccc(O)cc1
Yield: 68.4 %

Procedure:
2-[3-(4-Hydroxy-phenylsulfanyl)-propyl]-isoindole-1,3-dione (10.5 g) was dissolved in ethanol (450 ml) and treated with hydrazine monohydrate (17 ml) at 100° C. for 2 h in argon gas. Filtration and evaporation then crystallization from ethanol gave 4-(3-amino-propylsulfanyl)-phenol (4.2 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 102.3 %

Procedure:
A solution of nitrile 20B (3 g, 11.3 mmol) in diethyl ether (30 mL) was added in small amounts to a mixture of LiAlH4 (0.9 g, 2 mol eq) in diethyl ether (35 mL) and stirred at 0° C. After the addition was completed, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed at 0° C. by addition of small amount of water (30 mL), the solid formed was filtered off and the organic filtrate separated, washed with brine (50 mL) and dried over Na2SO4. The organic phase was evaporated under reduced pressure to obtain 21B as a yellow oil (3.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 308 (s, 2H), 3.8 (bs, 2H), 7.33 (dd, 1H, J=1.8), 7.47 (dd, 2H, J=2), 7.96 (s, 1H), 8.20 (dd, 2H, J=1.8), 8.57 (dd, 1H, J=1.2).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[O:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.C(N(CC)C(C)C)(C)C.[CH2:23]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[NH:43][C:44]([C:46]1[CH:55]=C(O)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]=1[OH:57])=[O:45])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CCCCCC.O1CCCC1>[CH3:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][C:8]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([OH:57])=[C:46]([C:44](=[O:45])[NH:43][C:37]2[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=2[O:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:55]=1)=[O:6]
Reactant: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(O)c2ccccc2c1O
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(OC(=O)c2ccccc2NC)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-Methylisatoic anhydride (18.00 g, 90% technical grade containing mineral oil) was suspended in hexane (300 ml) and stirred for 0.75 hr at room temperature. The solid was filtered under suction, washed with petroleum ether (40–60° C.) and dried briefly before use. 1,4-Dihydroxy-naphthalene-2-carboxylic acid (2-dodecyloxy-5-methyl-phenyl)-amide was recrystallised from a mixture of petroleum ether (60–80° C.) and toluene before use. N,N-Diisopropylethylamine (16.20 g, 0.125 mol) was added to a stirred suspension of 1,4-dihydroxy-naphthalene-2-carboxylic acid (2-dodecyloxy-5-methyl-phenyl)-amide (29.14 g, 0.061 mol) and N-methylisatoic anhydride (12.00 g {of 90%}, 0.061 mol) in tetrahydrofuran (150 ml, dried over 4 Å molecular sieves) under an atmosphere of argon. The reaction was heated to reflux overnight. An aliquot was removed, added to dilute hydrochloric acid and extracted with ethyl acetate. Thin layer chromatography indicated the presence of a small amount of residual starting naphthol. A further quantity of N-methylisatoic anhydride (1.1 g) was added and the reflux continued for a further 18 hr. The reaction was allowed to cool and then the solvent was removed under reduced pressure. The residue was taken-up in a mixture of dilute aqueous (2 M) hydrochloric acid (500 ml) and warm ethyl acetate (1000 ml). Some material failed to dissolve and collected at the interface. The buff solid was filtered, washed with ethyl acetate and dried in vacuo (27.3 g). The organic solution was separated and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Methanol (100 ml) was added and the mixture stirred and boiled under reflux for 15 min and then allowed to cool. A further quantity of a solid precipitated which was filtered and dried in vacuo (3.8 g). The solids were analysed and the results were consistent with the desired 2-methylamino-benzoic acid 3-(2-dodecyloxy-5-methylphenylcarbamoyl)-4-hydroxy-naphthalen-1-yl ester. The total yield of product was 31.1 g (83%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Na].CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:3]1[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1ncccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Bromo-2-methylpyridine (500 mg) and tert-butyl piperazine-1-carboxylate (650 mg) were dissolved in toluene (7.5 ml), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one_palladium (3:2) (40 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (18 mg), and 2-methylpropan-2-ol sodium (391 mg) were added thereto in this order under a nitrogen atmosphere, followed by warming to 100° C. and stirring overnight. The reaction mixture was subjected to liquid separation with CHCl3 and water, the organic layer was dried over Na2SO4, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CHCl3 to 5% MeOH/CHCl3) to obtain tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (790 mg) as a pale yellow oil.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([Cl:16])=[CH:9][C:7]=1[NH2:8].[OH-].[Na+].O.NN>O.C1(=O)C2C(=CC=CC=2)C(=O)C=C1>[Cl:5][C:6]1[CH:12]=[C:11]([NH2:13])[C:10]([Cl:16])=[CH:9][C:7]=1[NH2:8]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: NN
Agent: O=C1C=CC(=O)c2ccccc21
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Cl)c(N)cc1Cl
Temperature: 5 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A reaction vessel was charged with 60 g of isopropyl alcohol, 50 g of water, 41.4 g of 2,5-dichloro-p-nitroaniline, 6 g of sodium hydroxide and 0.3 g of 1,4-naphthoquinone. The temperature of the mixture was controlled to be 75° to 80° C., and 22 g of an 80% solution of hydrazine hydrate in water was added dropwise to the mixture over 2 hours. After the addition, the reaction mixture was refluxed with stirring for 3 hours to complete the reaction. After cooling to 5° C., the reaction product was filtered, washed with water and dried, to give 32.2 g of 2,5-dichloro-p-phenylenediamine.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@H:2]([CH3:4])[OH:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.ClC[C:27]([O:29][CH2:30]OC)=C.C(=O)([O-])O.[Na+]>C1(C(F)(F)F)C=CC=CC=1>[CH3:27][O:29][CH2:30][O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C)O
Reactant: C=C(CCl)OCOC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Product: COCO[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
Methyl L-lactate (208 mg, 2 mmol) was dissolved in benzotrifluoride (2.0 mL), pyridinium p-toluenesulfonate (PPTS, 50 mg, 0.2 mmol) was added and then 2-(chloromethyl)-3,5-dioxahexa-1-ene (manufactured by Tokyo Kasei Kogyo Co., Ltd., 327 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for 24 hrs. Saturated aqueous sodium hydrogencarbonate solution (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (4 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (2 mL) and dried over anhydrous magnesium sulfate (0.5 g), and the solvent was evaporated under reduced pressure to give methyl (S)-2-(methoxymethoxy)propionate (248 mg, yield 84%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)=[CH:17][C:16]([C:29]2[S:33][C:32]([C:34](O)=[O:35])=[N:31][C:30]=2[CH3:37])=[CH:15][CH:14]=1.Cl.[CH3:39][NH:40][O:41][CH3:42].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:42][O:41][N:40]([CH3:39])[C:34]([C:32]1[S:33][C:29]([C:16]2[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:23][CH:24]=3)[C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:30]([CH3:37])[N:31]=1)=[O:35]
Reactant: COc1ccc(-c2sc(C(=O)O)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc(C(=O)N(C)OC)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Yield: 37.2 %

Procedure:
HOBT (0.62 g, 4.62 mmol) was added to a solution of 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-4-methylthiazole-2-carboxylic acid (8b, 1.70 g, 4.20 mmol) in DMF (15 ml) at room temperature under stirring. N,O-dimethylhydroxylamine hydrochloride (0.82 g, 8.40 mmol) was then added to the reaction mixture. The reaction mixture was cooled to 0° C. and to this were added EDC (1.20 g, 6.31 mmol) and triethylamine (1.69 g, 2.34 ml, 16.80 mmol). The reaction mixture was stirred at room temperature for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was mixed with ethyl acetate (100 ml). The mixture obtained was washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The separated organic layer was dried over anhydrous sodium sulphate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography using 50% ethyl acetate in hexanes as an eluent to obtain the title compound 8c (0.70 g, 37.23%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)=[O:4]>[Pd].CC(O)C>[CH3:25][O:24][C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][C:13](=[O:26])[CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:21][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(C=CC(=O)C=Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)c1ccc(CCC(=O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 50 °C

Procedure:
A heterogeneous mixture of 71.7 g of 1,5-bis-(4'-methoxycarbonyl-phenyl)-1,4-pentadien-3-one, 3.8 grams of 5% Pd on carbon, and 650 mL of 2-propanol was prepared in a 1 L 3-necked flask. The mixture was stirred mechanically and heated to 50° C. The system was flushed with hydrogen, and hydrogen was then supplied on a continuous basis at about 20 psi. The hydrogen uptake was initially very rapid, but gradually slowed. When hydrogen uptake nearly ceased, the hydrogen source was removed. The vessel was heated to 75°-80° C. and purged thoroughly with nitrogen. The hot product was filtered through a steam-jacketed Buchner funnel which contained a pad of filter-aid. The hot filtrate immediately began to precipitate the product.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)=[N:14][CH:15]=[N:16]2)=[C:11]([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2C(OC(C)(C)C)=O)[CH:10]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[N:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 70 °C
Yield: 19.9 %

Procedure:
tert-Butyl (2R)-2-[({7-(benzyloxy)-4-[3-chloro-4-fluoroanilino]quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (1.5 g) was taken up in trifluoroacetic acid (15 ml) and the solution was heated at 70° C. for 18 hours. The solution was cooled to room temperature and then concentrated in vacuo to leave a brown residue. Saturated aqueous sodium hydrogen carbonate was added to the residue and the aqueous mixture was extracted with ethyl acetate. The layers were separated and the organic layer was dried (MgSO4) and concentrated in vacuo to leave a brown oil. Purification by flash chromatography, using 5:1:84 methanol:7N ammonia in methanol:DCM→20:1:79 methanol:7N ammonia in methanol:DCM as eluent, followed by trituration with ether gave 4-[3-chloro-4-fluoro-anilino]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-7-ol as an off-white solid (200 mg, 20%); NMR Spectrum (DMSO-d6) 10.40 (brs, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.95 (m, 1H), 7.40 (m, 1H), 6.75 (m, 2H), 4.30 (m, 1H), 4.05 (m, 1H), 3.60-3.50 (m, 1H), 3.0-2.80 (m, 2H), 1.95-1.80 (m, 1H), 1.75-1.65 (m, 2H), 1.50-1.40 (m, 1H); Mass spectrum MH+ 391.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:5])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:30].[CH2:31]([O:33]CC)[CH3:32]>O.O1CCCC1>[ClH:30].[CH2:32]1[O:14][C:11]2([CH2:10][CH2:9][C:8]([N:7]([CH2:6][CH2:4][OH:5])[CH3:21])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:12]2)[O:33][CH2:31]1
Reactant: CCOC(=O)CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CCOCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)C1(c2ccccc2)CCC2(CC1)OCCO2
Yield: 58 %

Procedure:
A solution consisting of 4.52 gm. (0.0136 mole) of 4-[[(ethoxycarbonyl)methyl]methylamino]-4-phenylcyclohexanone, ethylene ketal, p-toluenesulfonate (prepared in Example 35, above), and 100 ml. tetrahydrofuran is added to a suspension of 0.52 gm. lithium aluminum hydride in 10 ml. tetrahydrofuran. This reaction is heated at the reaction mixture is heated at the reflux temperature for four (4) hours, after which heating it is allowed to cool and then chilled in an ice bath. To the chilled solution is added 0.52 ml. water followed by 0.52 ml. of 14% aqueous sodium hydroxide, and finally followed by another 1.56 ml. water. A gel forms and the gelatinous liquid is poured through a filter. The filtrate is collected and the liquids removed by evaporation under reduced pressure. The residue thus obtained is chromatographed on a 400 ml. column of silica gel and the chromatogram is developed by elution with a 3% solutin of methanol in methylene chloride which has been saturated with ammonia. The fractions containing the prospective product, as determined by thin layer chromatography, are combined and the solvents removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and then hydrogen chloride saturated diethyl ether is added. A precipitate forms which is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 2.56 gm. (58% yield) of 4-[(2-hydroxyethyl)methylamino]-4-phenylcyclohexanone ethylene ketal hydrochloride having a melting range from 184° to 186° C. A second crop of crystals obtained by removing some of the solvent mixture from the mother liquors by evaporation under reduced pressure weighs 0.56 gm. and has a melting range from 176° to 182° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([NH:34][NH2:35])=[O:33])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:35][NH:34][C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NNC(=O)CN1CCOCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)CN1CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in CH2Cl2:EtOAc (20 mL, 2:1) and cooled to −60° C. where 2-morpholinoacetohydrazide (0.23 g, 1.0 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.27 mL, 1.5 eq.) was added dropwise followed by DIPEA (0.96 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-morpholinoacetyl)acrylohydrazide (0.1 g, yield: 14%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH2:20]([C@H:27]([O:38][C:39]1[CH:55]=[CH:54][C:42]([C:43]([NH:45][NH:46]C(OC(C)(C)C)=O)=[O:44])=[CH:41][CH:40]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:46][NH:45][C:43]([C:42]1[CH:54]=[CH:55][C:39]([O:38][C@@H:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:40][CH:41]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(1S)-1-benzyl-2-(benzyloxy)-2-oxoethoxy]benzoyl}hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 15 hrs gave 164 mg of the title compound (76%) as a yellow solid in 98.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(O[Cl:6])(C)(C)C.[CH2:7]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17])[CH:8]=[CH2:9]>CO>[Cl:6][C:10]1([CH2:7][CH:8]=[CH2:9])[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]1=[O:16]
Reactant: C=CCC1C(=O)CCCC1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: C=CCC1(Cl)C(=O)CCCC1=O
Yield: 91.1 %

Procedure:
t-Butylhypochlorite (104.6 g, 0196 mol) was added dropwise to a solution of 2-allyl-1,3-cyclohexanedione (132 g, 0.87 mol) in 650 ml of methanol at 0° C. The temperature was not allowed to rise above 20° C. The methanol was removed at reduced pressure in a 40° water bath and the residual oil was taken up in benzene. The benzene solution was washed with 5 percent sodium thiosulfate (3×250 ml), 5 percent sodium bicarbonate (3×250 ml) and water (1×250 ml). Evaporation of the benzene gave 148 g (91 percent) of 2-chloro-2-allyl-1,3-cyclohexanedione as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([NH2:60])=[CH:57][CH:58]=2)[CH:53]=[N:52]1>ClCCCl.C(#N)C>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:60][C:56]1[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=1)[N:51]([CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=1)[N:52]=[CH:53]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (783 mg, 3 mmol), triphenylphosphine (2.35 g, 9 mmol) and carbon tetrachloride (8.62 ml, 90 mmol) in 1,2-dichloroethane (20 ml) was stirred at 45° C. for 2 hours. The mixture was cooled and the solvents were evaporated under vacuum. 1-(Pyridin-2-ylmethyl)-1H-indazol-5-amine (706 mg, 3.15 mmol) and acetonitrile (15 ml) were added. The mixture was stirred at 75° C. for 1 hour. After cooling, the solvents were evaporated under vacuum. The residue was diluted in DCM and extracted with 2N hydrochloric acid. The aqueous layer was neutralised by addition of 6N aqueous ammonia and extracted with DCM. The DCM layer was dried over magnesium sulfate and the solvents were evaporated under vacuum. The residue was purified twice by chromatography on silica gel (first eluant: 3% 6N methanolic ammonia in DCM; second eluant: 3% methanol in DCM) to give the title compound as a white foam (600 mg, 43%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum 468.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][NH:11][C:10]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[N:9]1.[ClH:18]>>[Cl:18][C:6]1[CH:5]=[CH:4][C:3]([CH:8]2[CH2:12][NH:11][C:10]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[N:9]2)=[CH:2][CH:7]=1
Reactant: COC(=O)NC1=NC(c2ccccc2Br)CN1
Reactant: Cl
Product: COC(=O)NC1=NC(c2ccc(Cl)cc2)CN1

Procedure:
4-(2-bromophenyl)-4,5-dihydro-2-methoxycarbonylamino-imidazole, m.p. 203°-204° C., HCl salt m.p. 156°-159° C.;
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCCCl)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCCl)C(=O)O)cs1
Yield: 85.3 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 30.5 g.), 1 N aqueous solution of sodium hydroxide (220 ml.), methanol (110 ml.) and tetrahydrofuran (140 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 23.4 g.), mp 201° C. (dec.).