Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.I.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](SC)=[NH:23].ClCCl>C(O)C.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[NH:23])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCn1ccc2cc(N)ccc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCn1ccc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A solution of compound 92 (0.104 g, 0.512 mmol) in absolute ethanol (3 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.290 g, 1.02 mmol) at room temperature and the resulting mixture was stirred for 3 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (5 mL) followed by dichloromethane (30 mL) and transferred to a separatory funnel. The aqueous was extracted twice more with dichloromethane (2×30 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 5:95). Product was dried under high vacuum. HPLC revealed a 10% impurity. A second purification by column chromatography using less polar solvent conditions (2M ammonia in methanol:dichloromethane, 0:100-2.5:97.5) afforded pure product 93 (35 mg, 22%) as a yellow oil. 1H NMR (CDCl3) δ 7.43 (d, J=4.5 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.13 (d, J=3.0 Hz, 1H), 7.08 (t, J=4.2 Hz, 1H), 6.67 (dd, J=1.8, 8.7 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 4.22 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.31 (s, 6H); ES-MS (m/z, %): 313 (M+1); ESI-HRMS calculated for C17H21N4S (MH+): 313.1481, Observed: 313.1467.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[C:25]2[O:26][C@H:27]([CH2:30]C3C=C(C)C=CC=3S([O-])(=O)=O)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:18][O:19][C:20]1[C:25]2[O:26][CH:27]([CH2:30][N:1]3[CH2:2][CH:3]=[C:4]([C:7]4[C:15]5[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=5)[NH:9][CH:8]=4)[CH2:5][CH2:6]3)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: COc1cccc2c1O[C@H](Cc1cc(C)ccc1S(=O)(=O)[O-])CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CN1CC=C(c3c[nH]c4ccc(C#N)cc34)CC1)CO2
Yield: 56.6 %

Procedure:
3-(1,2,3,6-Tetrahydro-4-pyridinyl)1H-indole-5-carbonitrile (0.70 g, 3.1 mmole) and [(2R)-8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl-4-methylbenzenesulfonate (040 g, 1.1 mmole) were dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 50 mL) and sodium bicarbonate (1.0 g) added. The reaction mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuum and the residue partitioned between 400 mL each of methylene chloride and water. The organic phase was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuum to give a solid which was purified by column chromatography on silica gel. Elution with 2% methanol in chloroform, concentration of the product fractions in vacuum and treatment of an ethereal solution of the residue with 4 N isopropanolic HCl gave the (S)-enantiomer of the title compound (250 mg, 54%) as a yellow solid hydrochloride, one-quarter hydrate, m.p. 235–238° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=1
Reactant: C=CCOc1cccc(C=CC(=O)c2c(O)cc(C)oc2=O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1cccc(C=CC(=O)c2c(OC)cc(C)oc2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.7 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.00 g of 4-hydroxy-3-[3-(3-allyloxyphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, 1.85 g of triphenylphosphine and 0.23 g of methanol, and to the mixture was added dropwise a solution of 1.23 g of diethyl azodicarboxylate in 12 ml of tetrahydrofuran. The mixture was stirred at room temperature for 18 hours, and the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.12 g of 4-methoxy-3-[3-(3-allyloxyphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (5a)] as a yellow oil.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]([CH3:13])=O.O>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:11](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([CH3:13])[CH3:10]
Reactant: CC(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C(=O)OC)=C(C)C
Reaction time: 24 h

Procedure:
A solution of 51 grams (0.39 mol) of dimethyl malonate, 30 grams of acetone, and 2.5 grams of zinc chloride in 50 mL of acetic anhydride was refluxed with stirring for 24 hours. The solution was poured into ice and water, then extracted with 200 mL of dichloromethane. The organic phase was washed 2×150 mL water, dried over sodium sulfate and concentrated to a brown oil. After two distillations the 41 gram fraction collected at 25°-34° C. (0.1 mm Hg) gave satisfactory analytical for dimethyl isopropylidenemalonate.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:25][C:26](=[O:47])[C:27]([C:30]4[N:31]=[C:32]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[S:33][C:34]=4[F:35])=[N:28][OH:29])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:51])=[N-]>ClCCl.CCOCC>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:25][C:26](=[O:47])[C:27]([C:30]4[N:31]=[C:32]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[S:33][C:34]=4[F:35])=[N:28][O:29][CH3:51])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=CCS[C@H]23)c(F)s1)OCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)OCc2ccccc2)sc1F
Reaction time: 0.5 h

Procedure:
To a solution of 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (180 mg) in dichloromethane (3 ml) is added a solution of diazomethane in ether until yellow color of the solution does no more fade out. After 30 minutes, the reaction mixture is concentrated to give 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (153 mg). Similarly prepared are compounds of Table 1.
Reaction SMILES: [C:1]([Cu])#[N:2].[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[CH2:5][CH2:6][CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:1]#[N:2])[C:9]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=1)[CH2:5][CH2:6][CH3:7]
Reactant: N#C[Cu]
Reactant: CCCCc1nc(C)nc(I)c1Cc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C)nc(C#N)c1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
A mixture of 800 mg (8.94 mmol) CuCN and 10 mL pyridine was heated to 110° C. until all of the CuCN went into solution (7 minutes). To this mixture was added a solution of 440 mg (0.894 mmol) 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 3 mL pyridine. After 5 minutes, the reaction mixture was cooled to room temperature, diluted with CH2Cl2, filtered through powdered cellulose flock, stripped of solvent in vacuo, and was medium pressure chromatographed on silica gel using 13% EtOAc/hexane to give 306 mg of the title compound, 87% yield. Rf 0.29 in 15% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain; 1H-NMR (300 MHz, CDCl3): δ 7.63 (m, 2H), 6.84 (m, 2H), 4.16 (s, 2H), 2.73 (s, 3H), 2.68 (3 line m, 2 H), 1.53 (m, 2H), 1.31 (m, 2H), 0.87 (3 line m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]2[NH:18][CH:17]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:16][S:15]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:30]1([CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19]([CH:17]3[CH2:16][S:15][CH:14]([CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[NH:18]3)=[O:20])[CH2:22][CH2:23]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C2NC(C(=O)N3CCN(CCCc4ccccc4)CC3)CS2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CSC(C2CCCNC2)N1)N1CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
1-[2-(1-tert-Butoxycarbonyl-3-piperidinyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine (430 mg) was dissolved in 3 ml of dichloromethane, followed by addition of 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 ml of saturated aqueous solution of sodium hydrogen carbonate, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 280 mg of 1-(3-phenylpropyl)-4-[2-(3-piperidinyl)thiazolidin-4-ylcarbonyl]piperazine. This compound was dissolved in 8 ml of ethyl acetate, and 1 ml of 4N hydrogen chloride solution in dioxane was added. After 30 minutes of stirring, the resultant solid was collected by filtration and dried to give 200 mg of 1-(3-phenylpropyl)-4-[2-(3-piperidinyl)thiazolidin-4-ylcarbonyl]piperazine trihydrochloride. Melting point 174°-178° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23](=[O:25])[CH3:24])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Yield: 86 %

Procedure:
Using the procedure of example 66, compound 13 (24 mg) and acetic anhydride (7.7 μL) were used to provide compound 68 (24 mg, 86%). 1H NMR (300 MHz, CDCl3) δ 8.85 (d, 1 H), 8.52 (d, 1 H), 8.40 (d, 1 H), 8.28 (d, 1 H), 7.35 (dd, 1 H), 6.90 (d, 1 H), 5.15 (m, 1 H), 3.92 (m, 1 H), 2.15 (m, 2 H), 1.85 (m, 2 H), 1.70 (m, 2 H), 1.50 (m, 2 H), 1.30 (m, 2 H). MS (ESI) m/z: 336 (M+H)+.
Reaction SMILES: Br[C:2]1[CH2:3][NH:4][C:5]2[C:9]([CH:10]=1)=[CH:8][C:7]([P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22])([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])[CH:6]=2.C([Li])CCC>C1COCC1.CCCCCC>[N:4]1[C:5]2[C:9](=[CH:8][C:7]([P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22])([P:11]([O:12][CH2:13][CH3:14])(=[O:15])[O:16][CH2:17][CH3:18])[CH:6]=2)[CH:10]=[CH:2][CH:3]=1
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(Br)CNC2=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=c2cccnc2=C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of dihydro-3-bromo-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (10 mmol) [prepared as described in Example E (part I) hereinbefore] in THF (10 ml) cooled to -78° C. is added a solution of n-butyllithium (2.1 equivalent) in hexane over 30 minutes. The reaction is kept at -78° C. for an additional 30 minutes. To this solution is added 4-iodobutanol trimethylsilyl (TMS) ether (2.5 equivalent) and the reaction is allowed to warm to room temperature over 30 minutes. After standard aqueous work-up, dihydro-3-(4-butanol, TMS ether)-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester is isolated and used in the next reaction without purification.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:24]2[N:25]=[C:26]([NH:29]C=O)[S:27][CH:28]=2)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.CO>O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 86.5 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.6 g), conc.hydrochloric acid (1.1 g), methanol (20 ml) and tetrahydrofuran (15 ml) was stirred for 2 hours at room temperature. The reaction mixture was evaporated. The residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was adjusted to pH 3.0 with hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.3 g). mp. 201° to 213° C. (dec.).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH2:25][N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH:24]=2)[O:21][C:20]([CH3:32])([CH3:31])[CH2:19][C:18]3([CH3:34])[CH3:33])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].CO.O1CCCC1.[OH-].[Na+]>>[CH:28]1([N:26]([CH2:25][C:23]2[CH:24]=[C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:35])=[O:2])=[CH:8][CH:9]=3)[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([CH3:32])([CH3:31])[CH2:19][C:18]3([CH3:33])[CH3:34])[CH3:27])[CH2:30][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(C#Cc2ccc(C(C)(C)C(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Yield: 0 %

Procedure:
A solution of 2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-2-methyl-propionic acid methyl ester (Intermediate 15, 0.040 g, 0.084 mol) in methanol (2.5 mol) and tetrahydrofuran (2.5 mol) was treated with a 2M solution of sodium hydroxide (1 mol, 2 mol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Preparative reverse phase HPLC on a partisil 10 ODS-3 column using 10% water in acetonitrile as the mobile phase afforded the title compound (0.008 g, 27%).
Reaction SMILES: Br[N:2]1[CH2:5][C:4]([CH2:8][Br:9])([CH2:6][Br:7])[C:3]1=[O:10].C1(C)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:7][CH2:6][C:4]1([CH2:8][Br:9])[CH2:5][NH:2][C:3]1=[O:10]
Reactant: O=C1N(Br)CC1(CBr)CBr
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCC1(CBr)CBr

Procedure:
A 22.4 g (0.067 mole) sample of the 1-bromo-3,3-bis(bromomethyl)-2-azetidinone was dissolved in 450 ml carbon tetrachloride. The insoluble residue (2.0 g) was discarded. A 7 ml (6.07 g, 0.067 mole) portion of toluene was added to the stirred solution. The reaction mixture was irradiated by a 275 watt General Electric Sunlamp and allowed to reflux for one hour. The reaction mixture was decanted hot from a small amount of residue on the stirrer and flask wall and then cooled in ice. White crystals were collected on a filter and dried in vacuo to yield 12.1 g of product. Mother liquor with a few seed crystals was kept cold overnight to yield a second crop of 1.0 g. Total yield of 13.1 g or 76.6% of 3,3-bis(bromomethyl)-2-azetidinone was recovered.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](/[CH:16]=[C:17](\[O:23][CH2:24][CH3:25])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:10]=1[F:26])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([CH2:16][CH:17]([O:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[C:10]([F:26])[C:9]=1[OH:8]
Reactant: CCOC(=O)/C(=C/c1cc(F)c(OCc2ccccc2)c(F)c1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(F)c(O)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution (Z)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-ethoxyacrylate (680) (1.3 g, 3.59 mmol) in ethanol (25 mL) was added Pd/C (140 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-ethoxypropanoate (0.81 g) (681).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40])[CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)COCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 48 h
Yield: 73.7 %

Procedure:
(2S)-1-(Benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-amine (1.55 g, 5.25 mmol) was dissolved in 60 mL of dry CH2Cl2. Triethylamine (1.46 mL, 10.5 mmol) and 4-chloro-3-nitroquinoline (1.09 g, 5.25 mmol) were then added and the reaction was stirred under N2 for 2 days. The reaction mixture was then concentrated and the resulting material was partitioned between 50 mL of CH2Cl2 and 50 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-10% ethyl acetate/CH2Cl2) gave 1.81 g of N-[(1S)-2-(benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH2:4]C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COP(C)(=O)c1cc(Sc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
To a mixture of ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol) and thiophenol (40.0 mmol) in 20 ml of ethanol is added sodium hydroxide (60.0 mmol) in 1 ml of water. The mixture is heated under reflux for 24 hours. The reaction mixture is poured into water, acidified with dilute HCl and extracted with methylene chloride (2×). The combined extracts are washed with brine, dried and evaporated to dryness. The resulting oily residue is treated with diazomethane in methanol, concentrated and purified by preparative TLC to yield methyl P-methyl-2-nitro-5-phenylthiophenylphosphinate.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:27])[C:16]([C:18]2C3C(=NC=CC=3)[NH:20][CH:19]=2)=[O:17])[C@H:11]([CH3:28])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[N:38][C:37]([O:40][CH3:41])=[C:36]2[C:32]=1C(C(=O)C([O-])=O)=CN2.[K+]>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:27])[C:16]([C:18]2[C:32]3[C:36](=[C:37]([O:40][CH3:41])[N:38]=[CH:39][C:31]=3[O:30][CH3:29])[NH:20][CH:19]=2)=[O:17])[CH:11]([CH3:28])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Agent: [K+]
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3C)c[nH]c12

Procedure:
Compound 5ap, ®-N-(benzoyl)-3-methyl-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine (white solid) was prepared using the same method used to prepare compound 5a except that Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was used as the starting material. MS m/z: (M+H)+ calcd for C23H25N4O5: 437.18; found 437.24. HPLC retention time: 1.37 minutes (column B).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)[S:10][CH:11]=2)=[CH:5][N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[CH:5]=[C:6]([C:7]3[N:8]=[C:9]([NH:12][C:13]4[N:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=4)[S:10][CH:11]=3)[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:3]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4nccc(C)n4)n3)c(Br)n2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3csc(Nc4nccc(C)n4)n3)c(-c3ccccc3)n2)cc1
Yield: 51.5 %

Procedure:
According to Scheme 12 Step 1: A solution of 4-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine (0.33 mmol, 150 mg), phenylboronic acid (0.39 mmol, 48 mg), Pd(PPh3)4 (49 μmol, 57 mg) and a saturated aqueous solution of NaHCO3 (0.5 mL) in dioxane (0.5 mL) was stirred at 120° C. for 2 hours under microwave heating. The crude mixture was filtered through celite pad and washed with DCM. The filtrate was washed with water. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using DCM/AcOEt (100:0 to 70:30) to yield 4-(1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine (0.17 mmol, 77 mg, 52%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:11]([O:14][C:15](Cl)=[O:16])([CH3:13])[CH3:12]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:15](=[O:16])[O:14][CH:11]([CH3:13])[CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Product: CC(C)OC(=O)Nc1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-52, using 1H-indol-5-amine and isopropyl-chloro-formate (0.72 g, 52%); MS: 219(M+1).