Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(CN1CCCCC1)C(O)=O.[CH3:14][C:15]([CH3:34])([CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:16]([O:18]CC1C=CC=CC=1)=[O:17]>>[CH3:14][C:15]([CH3:34])([CH2:26][N:27]1[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]1)[C:16]([OH:18])=[O:17]
Reactant: CN1CCN(CC(C)(C)C(=O)OCc2ccccc2)CC1
Agent: CC(C)(CN1CCCCC1)C(=O)O
Product: CN1CCN(CC(C)(C)C(=O)O)CC1

Procedure:
The procedure for 2,2-dimethyl-3-piperidin-1-ylpropanoic acid was followed except for replacing benzyl-2,2-dimethyl-3-piperidin-1-ylpropanoate with benzyl 2,2-dimethyl-3-(4-methylpiperazin-1-yl)propanoate. The compound was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.24 (s, 6H), 2.33 (s, 3H), 2.44-2.92 (m, 10H).
Reaction SMILES: C([S-])#N.[K+:4].[CH3:5][C:6]1([S:9]([O:12]CC2C=CC=CC=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1>COCCOC.O>[CH3:5][C:6]1([S:9]([O-:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.[K+:4]
Reactant: CC1(S(=O)(=O)OCc2ccccc2)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1(S(=O)(=O)[O-])CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
KSCN (2.48 g, 25.5 mmol) was added to a solution of Benzyl 1-methylcyclopropane-1-sulfonate (4.9 g, 25.5 mmol) in DME/H2O (1:1, 120 mL) and continued stirring at 100° C. for 16 h. Reaction mixture was concentrated under reduced pressure and the residue was washed with n-pentane and dried to afford potassium 1-methylcyclopropane-1-sulfonate (Int-49) (4.44 g, 100% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O.[OH-].[Na+].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
19 g (67 mmol) of 7-methoxy-4-(4-methoxyphenyl)-2H-phthalazin-1-one are dissolved in 100 mL of phosphoryl chloride. The solution is heated at 80° C. for 2 hours. The reaction medium is cooled to room temperature and then poured slowly into 500 mL of water at 40-50° C. with stirring. The mixture is then stirred at 5° C., basified by addition of 35% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water and then with brine and dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure, 19.3 g of a beige-coloured powder are obtained (yield=96%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N+:10]([O-])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OCC)(=O)C>[Pd].CO>[NH2:10][C:5]1[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCNc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNc1cccnc1N

Procedure:
A mixture of 3-ethylamino-2-nitro-pyridine (400 mg), 10% palladium on carbon (40 mg) and 1:1 ethyl acetate:methanol (30 mL) were placed in a Parr apparatus under hydrogen (50 psi) for 50 min. The mixture was filtered through Celite, concentrated, and the product triturated with hexane to give 2-Amino-3-ethylaminopyridine as a brown solid. More material was recovered from the filtrate. 1H NMR (CDCl3): δ 7.59 (d, J=4.94 Hz, 1H), 6.81 (d, J=6.32 Hz, 1H), 6.71 (dd, J=4.94, 7.69 Hz, 1H), 3.12 (q, J=7.14 Hz, 2h), 1.31 (t, J=7.14 Hz, 3H).
Reaction SMILES: C(OC(N1C2SC(C(O)=O)=CC=2C([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=N1)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1(NN)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH2:17])=[O:27])=[CH:20][CH:21]=1
Reactant: CCOC(C)n1nc(NC(=O)c2ccc(OC)cc2)c2cc(C(=O)O)sc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: NNc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(N)=O)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
1-(1-Ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (0.3 g, 0.77 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.247 g, 0.77 mmol, 1 eq.), dimethylformamide (3.85 mL) and phenylhydrazine (0.151 mL, 1.54 mmol, 2 eq.) are successively introduced into a 20 mL round-bottomed flask under argon. Triethylamine (0.322 mL, 2.31 mmol, 3 eq.) is added to the reaction mixture. The mixture is stirred at a temperature in the region of 60° C. for 15 hours. The solvent is then evaporated off under vacuum and the residual oil is diluted with 15 mL of ethyl acetate and 10 mL of water. The aqueous phase is isolated and then acidified to pH 4-5, after which it is extracted with ethyl acetate (3×15 mL). The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel, eluting with a 1:1 ethyl acetate/heptane mixture. The product obtained in oil form (0.310 g, 84%, Rf=0.47 (1:9 MeOH/dichloromethane)) is placed without further purification in 5 mL of tetrahydrofuran and 2.5 mL of 2.5 N hydrochloric acid. The reaction mixture is then heated at a temperature in the region of 50° C. for 2 hours and is then cooled to room temperature. 15 mL of water are then added to the mixture. A precipitate forms. The tetrahydrofuran is evaporated off and the aqueous phase is neutralized with 5 N NaOH. The precipitate formed is filtered off and then washed with water. The beige-colored solid is dried in an oven at a temperature in the region of 60° C. under vacuum. The dry solid is then dissolved in acetone and precipitated from heptane. The 5-(N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-methoxybenzamide thus obtained (86 mg, 33%) has a purity of 95%. Overall yield=28%. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): 3.85 (s, 3H); 6.72 (broad t, J=7.5 Hz, 1H); 6.76 (broad d, J=8.0 Hz, 2H); 7.05 (broad d, J=8.0 Hz, 2H); 7.15 (broad t, J=7.5 Hz, 2H); 7.85 (broad s, 1H); 8.09 (broad d, J=8.0 Hz, 2H); 8.19 (broad s, 1H); 10.45 (broad m, 1H); 11.0 (broad m, 1H); 12.9 (broad m, 1H). LC/MS: m=407. ES m/z=408 MH+
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=12.[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(C)n(CC=Cc2ccccc2)c2c(Cl)nncc12
Product: Cc1c(C)n(CC=Cc2ccccc2)c2c(OCc3ccccc3)nncc12
Yield: 85.4 %

Procedure:
The title compound (trans) was prepared as pale brown crystals in 85.4% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d]pyridazine (trans) and benzyl alcohol.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Yield: 93.2 %

Procedure:
Sodium iodide (10.32 g, 68.88 mmol) was added to a solution of 1-methanesulfonyloxy-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.5 g, 22.96 mmol) in acetone (300 ml), followed by heating under reflux for 12 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.6 g, Yield 93%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)o1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-furancarboxylate (0.70 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylate as colorless crystals (0.41 g, yield 46%) from a fraction eluted with acetate-hexane (9:1, v/v). Recrystallization from ethyl ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].C(O[CH2:21][CH:22]=[CH2:23])(=O)C.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>CN(C)C=O>[CH2:23]([C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH:22]=[CH2:21]
Reactant: C=CCOC(C)=O
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1Br
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CN(C)C=O
Product: C=CCc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
Under nitrogen atmosphere, 1.00 g (3.54 mmol) of methyl 3-bromo-4,7-dimethylindole-2-carboxylate and 0.31 g (5.23 mmol) of dichloro [1,1-bis(diphenylphos-phino)ferrocene]palladium (PdCl2 (dppf)) were suspended in 4 ml of anhydrous dimethylformamide (DMF). Thereto were added 0.57 ml (5.32 mmol) of allyl acetate and 2.7 ml (5.32 mmol) of hexabutylditin. The reaction mixture was stirred at 120° C. for 90 minutes and then subjected to Celite filtration. The filtrate was extracted with chloroform. The extract was purified by silica gel column chromatography (chloroform:n-hexane=1:1 to 3:1) to provide 0.75 g of white crystals. Yield: 87%
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:29]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH2:16]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 (105 mg) was reacted with 2-ethylbenzimidazole and sodium-tert-butoxide (instead of cesium carbonate) via General Procedure C to afford 15.2 mg of 131 following reverse phase HPLC purification. MS (Q1) 515.3 (M)+
Reaction SMILES: Br[C:2]1=[CH:3][C:4](=[O:9])[O:5]/[C:6]/1=[CH:7]\Br.[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2=[CH:3][C:4](=[O:9])[O:5]/[C:6]/2=[CH:7]\[C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)=[CH:11]1
Reactant: O=C1C=C(Br)/C(=C/Br)O1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(c2ccsc2)/C(=C/c2ccsc2)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture containing (Z)-4-bromo-5-(bromomethylene)furan-2(5H)-one (0.502 g, 1.977 mmol), 3-thiopheneboronic acid (0.553 g, 4.322 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.068 g, 9.688×10−2 mmol), tetrabutylammonium iodide (0.037 g, 1.137×10−1 mmol) and cesium fluoride (1.221 g, 8.038 mmol) in toluene (10 mL) and water (10 mL) was stirred at room temperature for 72 h under nitrogen. Brine (50 mL) was added and the product extracted with ethyl acetate (3×50 mL). The organic fractions were combined, washed with brine (3×20 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a dark brown solid. The resulting solid was subjected to recrystallization to give (Z)-4-(thiophen-3-yl)-5-(thiophen-3-ylmethylene)furan-2(5H)-one 18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][CH:8]([NH:13][C:14](=[O:39])[C@@H:15]([N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:40])[CH2:7][CH:8]([NH:13][C:14](=[O:39])[C@@H:15]([N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](=[O:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(=O)CF
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A stirred solution of 3(R,S)-[2(S)-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionylamino]-5-fluoro-4(R,S)-hydroxy-pentanoic acid tert-butyl ester (1.23 g, 2.23 mmol) in anhydrous DCM (25 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (1.13 g, 2.67 mmol) at 0° C. The resulting mixture was kept at 0° C. for 2 hours, diluted with ethyl acetate, then poured into a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (Magnesium sulfate) and concentrated. The residue was purified by flash chromatography (40-60% ethyl acetate/petrol ether) to afford the title compound as a red gum (776 mg, 64%); 1H NMR (400 MHz, CDCl3) δ 1.32-1.40 (3H, s), 2.60 (1H, m), 2.92 (1H, m), 3.27 (1H, m), 3.61 (1H, m), 4.78-4.88 (1H, m), 4.97-5.05 (2H, m), 5.77 (1H, m), 6.43 (1H, m), 7.22-7.38 (7H, m), 7.54-7.65 (3H, m), 7.95 (2H, m), 8.62 (1H, m), 9.22 (1H, m).
Reaction SMILES: [C:1]1([C:7](=[N:13][NH2:14])[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(OO)(=O)C>CN(C)C(=O)C.C(O)(=O)C>[C:1]1([C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N+:13]=[N-:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN=C(c1ccccc1)c1cccs1
Agent: CC(=O)OO
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: [N-]=[N+]=C(c1ccccc1)c1cccs1
Reaction time: 0.67 h

Procedure:
To a mixture of phenyl-2-thienyl ketone hydrazone (20.2 g; 0.1 mole), and pyridine (24.8 ml; 0.307 mole) in N,N-dimethylacetamide (100 ml) stirred and cooled to 15° was added peracetic acid (17.7 ml of a 38% w/w solution in glacial acetic acid; 0.1 mole) during 40 minutes, the temperature being maintained at +15° throughout.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:8])([O-])=O.O=NC1C=CC=CC=1.CO.C(Cl)(Cl)Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:8]
Reactant: O=C1Cc2cc(C(=O)c3cccc([N+](=O)[O-])c3)ccc2N1
Agent: [Pd]
Agent: O=Nc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reaction time: 0.08 h

Procedure:
5-(3-Nitro-benzoyl)-1,3-dihydro-indol-2-one (2.0 g, 7.09 mmol) was dissolved in MeOH (600 mL). 10% Pd/C (0.20 g) was added to the flask and then placed under vacuum to remove any O2(g). The reaction mixture was kept under reduced pressure for ˜5 min and was then charged with H2(g) at atmospheric pressure. This evacuation/H2(g) fill procedure was repeated twice. The reaction mixture was stirred for 2 h at which point the starting material had been completely consumed. As the desired ketone product was prone to over-reduction to the alcohol, stopping the reaction immediately upon complete consumption of the starting material limited the amount over-reduction that occurred. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo resulting in a solid that contained the desired keto-aniline product plus ˜5% of the overreduced alcohol-aniline. Flash silica gel chromatography (5% MeOH/CHCl3) of the crude solid provided pure 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one in 72% (0.957 g, 3.80 mmol) yield.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].N1C=CN=C1.CN(C)C=O.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCl>[Si:17]([O:6][CH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0° C. solution of (S)—(+)-1,3-butanediol (2.1 g, 23.3 mmol), imidazole (1.74 g, 25.6 mmol), and N,N-dimethylformamide (1.0 mL) in dichloromethane (40 mL) was treated with tert-butyl-dimethylsilyl chloride (3.68 g, 23.3 mmol). The reaction mixture was warmed to room temperature, stirred overnight, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined dichloromethane layers were dried (MgSO4), filtered and concentrated to afford of the desired product of sufficient purity for subsequent use without further purification in near quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:14]([O:17][C:18](=O)C)(=O)C>>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([C:6](=[CH:14][O:17][CH3:18])[C:7]#[N:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)c1ccc(Cl)cc1Cl
Product: COC=C(C#N)C(=O)c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 104.5 %

Procedure:
A mixture of 8.8 g of 2,4-dichloro-benzoylacetonitrile, 69.2 g of methyl o-formate and 10.5 g of acetic anhydride is refluxed at a bath temperature of 150° C. for 3 hours. The volatile constituents are then distilled off in vacuo and finally under a fine vacuum at a bath temperature of 120° C. 11 g of 2-(2,4-dichloro-benzoyl)-3-methoxy-acrylonitrile are obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:27])[CH:3]([N:8]1[C:11](=[O:12])[CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:9]1[S:24](Cl)=[O:25])[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=O>>[C:17]1(=[O:18])[N:13]([CH:10]2[C:11](=[O:12])[N:8]3[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:2](=[CH2:27])[CH2:1][S:24](=[O:25])[C@H:9]23)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC

Procedure:
A solution of 0.29 g. of methyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate in 10 ml. of trifluoroacetic acid was refluxed for 30 minutes and then was evaporated in vacuo to dryness. The product was dissolved in 20 ml. of ethyl acetate. The resulting solution was washed successively with aqueous sodium bicarbonate (3X), water, and brine, dried (MgSO4), and evaporated in vacuo to dryness to provide methyl 7-phthalimido-3-methylenecepham-4-carboxylate 1-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[CH:4][CH:3]=1.N[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].N>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([C:8]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[N:9]=2)([CH3:10])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn+2]
Product: CC1(C)COC(C(C)(C)Oc2ccc(Cl)cc2)=N1
Reaction time: 34 h
Yield: 88 %

Procedure:
19.57 g. (0.1 moles) of 2-(p-chloro-phenoxy)- 2-methyl-propionitrile are reacted under stirring for 34 hours with 17.83 g. (0.2 moles) of 2-amino-2-methyl-1-propanol in the presence of 0.66 g. (0.003 moles) of zinc acetate catalyst at a temperature of 140°-150°C. The reaction takes place under an intensive development of ammonia gas. When the development is finished, the mixture is cooled, dissolved in 300 ml. of chloroform and the solution washed with water to neutral reaction. After drying the solution over anhydrous magnesium sulphate it is evaporated to dryness. The green-yellow colored oil (26.5 g.), is subjected to fractional distillation in vacuo. The main fraction is a product of 23.6 g. (yield 88%), mp.: 98°-100°C/0.02 mmHg. The distilled product crystallizes after standing for 48 hours, Mp. 59°-61°C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[N:6]=1.O1CCCC1.CO.[OH-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2csc(N)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reaction time: 1 h

Procedure:
At room temperature, methyl 4-(2-aminothiazol-4-yl)benzoate (300 mg) was suspended in a mixed solvent of tetrahydrofuran (5 ml) and methanol (5 ml), followed by the addition of a 1N aqueous sodium hydroxide solution (10 ml). The resulting mixture was stirred for one hour. To the reaction mixture, N,N-dimethylformamide (5 ml) was added, followed by heating under reflux for 6 hours. After completion of the reaction, the solvent was distilled off. To the residue, water and 1N hydrochloric acid were added successively and the pale yellow solid so precipitated was collected by filtration, whereby the title compound (229 mg, 69%) was obtained as a pale yellow solid.