Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:22])[NH:7][C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)#[N:4].[Cl:23][C:24]([Cl:28])([Cl:27])[S:25]Cl>O.ClCCl>[C:3]([C:5]1[C:6](=[O:22])[N:7]([S:25][C:24]([Cl:28])([Cl:27])[Cl:23])[C:8](=[O:21])[N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[CH:10]=1)#[N:4]
Reactant: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(=O)n(SC(Cl)(Cl)Cl)c1=O
Reaction time: 2 h

Procedure:
To 290 mg of NaOH in 15 ml of water, cooled in an ice bath, is added 1.0 g (3.56 mol) of 5-cyano-1-(4-trifluoromethylphenyl)uracil. Then 15 ml of dichloromethane is added, followed by 0.725 ml of trichloromethanesulfenyl chloride in 1.5 ml of dichloromethane. The mixture is stirred for approximately 2 hr at 5°. Then dichloromethane and ice cold water are added and the layers separated. The organic phase is washed with ice cold water, dried over MgSO4 and evaporated. The product is taken up with ether, filtered and washed again with ether to yield 5-cyano-3-trichloromethanesulfenyl-1-(4-trifluoromethylphenyl)uracil, m.p. 167°-168.5°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:25]=[O:26])C.Cl>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:25]=[O:26])[C:9]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (−78° C.) solution of (2,4-difluoro-phenyl)-carbamic acid tert-butyl ester (5 g) in THF (50 ml) under an argon atmosphere was added dropwise a 1.6 M solution of BuLi in hexanes (28.6 ml) for 20 min (temperature below −68° C. during the addition). When addition was complete, the mixture (turning to orange, then to light red) was stirred at −78° C. for 1 h 30. DMF (7.55 ml) was then added for 10 min (temperature below −70° C.) and stirring at −78° C. was continued for 15 min. As the mixture had turned to a compact mas (no more stirring), it was allowed to warm to room temperature. Water (50 ml) was added and the pH was set to 3 by the dropwise addition of 3 N HCl. EtOAc (50 ml) was added. The organic phase was washed with water and brine dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 85:15) to give (2,4-difluoro-3-formyl-phenyl)-carbamic acid tert-butyl ester (1.75 g) as an off-white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=O.C(O)C>O>[CH3:19][O:18][C:13]([C:14]1([CH3:16])[NH:2][CH2:3][CH2:4][S:5]1)=[O:17]
Reactant: COC(=O)C(C)=O
Reactant: NCCS
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)NCCS1
Yield: 70.5 %

Procedure:
A mixture of 36.6 g of cysteamine hydrochloride, 32.6 g of triethylamine, 32.9 g of methyl pyruvate and 500 ml of ethanol was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a residue which was, after addition of water, extracted with ethyl acetate. The extract was vacuum distilled to give 36.6 g (yield 70.4%) of 2-methylthiazolidine-2-carboxylic acid methyl ester with a boiling point of 76° C./2 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br/[CH:19]=[CH:20]/[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:19]=[CH:20]/[C:21]([F:24])([F:23])[F:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)/C=C/Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 74.3 %

Procedure:
A mixture of 4-(benzyloxy)phenylboronic acid (1026 mg, 4.50 mmol, Alfa Aesar), (E)-1-bromo-3,3,3-trifluoroprop-1-ene (262 mg, 1.5 mmol, SynQuest), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (122 mg, 0.15, Combiphos Catalysts, Inc.) and cesium carbonate (2444 mg, 7.50 mmol, Aldrich) in Water (0.5 mL) and DMF (3.0 mL) was heated under microwave conditions (90° C., 20 min). The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residual was purified by flash chromatography on silica gel (0 to 100% EtOAc/hexanes) to yield the title compound (310 mg, 74%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1>C(#N)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A solution of 4-Hydroxybenzaldehyde (20.1 grams, 0.164 moles), potassium carbonate (67.9 grams, 0.492 moles) and t-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (70 grams, 0.197 moles) in acetonitrile (1000 mL) was stirred for 18 hours at 80° C. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was cooled to room temperature and quenched on to chilled water (1000 mL). The compound was extracted with dichloromethane (3×500 mL). The resulting dichloromethane layer was washed with 10% lye solution (100 mL), water (100 mL) and brine solution (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (50.3 grams).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(OCC)C>CO>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: OCc1cccc(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
3-Benzylbenzaldehyde (5.5 g) was dissolved in methanol (75 cm3) and cooled to 0° C. Sodium borohydride (1.29 g) was added gradually in small portions, and stirring was continued for one hour. The reaction mixture was cautiously poured into a water/diethyl ether mixture, and the resulting ethereal solution was washed with water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzylbenzyl alcohol as a pale yellow oil (5.2 g). The product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:29])[CH3:28].[C:41]([O-])(=[O:43])C.[Na+]>>[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH:40][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=1)=[O:43])=[S:39])([CH3:29])[CH3:28]
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(NC(N)=S)c(C(C)C)c1
Agent: [Na+]
Product: Cc1ccc(NC(=S)NC(=O)NCCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C(C)C)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(2-isopropyl-4-methylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.123 g, 37%): 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.04 (s, 1H), 9.41 (s, 1H), 8.12-8.04 (m, 2H), 8.02-7.91 (m, 2H), 7.61 (ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.13 (d, J=1.9 Hz, 1H), 7.09 (t, J=5.6 Hz, 1H), 7.04-6.97 (m, 1H), 3.17 (q, J=6.5 Hz, 2H), 2.95 (hept, J=7.0 Hz, 1H), 2.82-2.64 (m, 2H), 2.30 (s, 3H), 1.91-1.77 (m, 2H), 1.14 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 597 ([M+H]+), 595 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[F:11][C:12]1([CH:19]=[C:18]([F:20])[CH:17]=[N:16][CH2:15]1)C#N.C1C[O:24][CH2:23]C1>>[F:20][C:18]1[C:17]([C:23]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:24])=[N:16][CH:15]=[C:12]([F:11])[CH:19]=1
Reactant: C1CCOC1
Reactant: COc1ccccc1[Mg]Br
Reactant: N#CC1(F)C=C(F)C=NC1
Product: COc1ccccc1C(=O)c1ncc(F)cc1F
Temperature: 25 °C

Procedure:
2-Methoxyphenyl magnesium bromide (53.3 mL of 1.75 M solution in THF was cooled to 0° C. 3,5-Difluoronicotinonitrile (5.0 g, 35.6 mmol) was added over 20 minutes to the reaction mixture at 0° C. The reaction was quenched by addition of of 60 mL of 2M H2SO4, and the mixture was allowed to warm to room temperature. The reaction mixture was extracted with 40 mL 50 mL EtOAc, and the aqueous phase was basified by addition 12 mL of 5M NaOH. The aqueous phase was then extracted twice with 70 mL of EtOAc, and the combined organic layers were washed with water, and dried (MgSO4). The MgSO4 was removed by filtration and solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 mm×15 cm) with hexanes/EtOAc (0:1 to 4:1) to yield 7.9 g of (3,5-difluoro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone. Mass Spec. M+H=250.
Reaction SMILES: C([NH:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)C(C)(C)NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)N

Procedure:
To the solution of tert-butyl 2-(benzylamino)-2-methylpropanoate (20 g, 0.08 mol) in ethyl acetate (1 L), was added the catalyst Palladium-carbon (10%, 2.2 g). The resulting mixture was put under the hydrogen pressure of 5 Kg/cm2, at RT for 18 h. The reaction mixture was filtered. The filtrate was concentrated affording the title compound as pale green liquid. 1H NMR (DMSO-d6, 400 MHz) δ 1.38 (brs, 2H), 1.14 (s, 9H), 1.14-1.11 (d, J=10.7 Hz, 6H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5](CC)[C:6]([NH:9][C:10](=O)[CH3:11])=[CH:7][CH:8]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](=O)([O-])[O-:23].[K+].[K+].II>[Cu]>[CH3:22][O:23][C:16]1[CH:17]=[CH:18][C:19]([CH2:11][CH2:10][NH:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:20][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccccc1
Reactant: CCc1cc(OC)ccc1NC(C)=O
Agent: [Cu]
Agent: II
Agent: [K+]
Product: COc1ccc(CCNc2ccccc2)cc1
Temperature: 200 °C
Yield: 66 %

Procedure:
19.3 g. of 3-methoxy-6-acetylamino-1-ethylbenzene, 22 g. of bromobenzene, 7.78 g. of potassium carbonate, 0.43 g. of copper powder and 0.01 g. of iodine were refluxed under ordinary pressure for 48 hours on the oil bath. Then excess bromobenzene was recovered by means of steam distillation, and the remaining solid [crude 3-methoxy-6(N-acetylanilino)ethylbenzene] was filtered off, mixed, without purifying, with 140 ml. of a 10 percent aqueous solution of caustic soda and heated in the autoclave to 200° C. for 8 hours. After cooling, an oil layer was separated from it and purified by means of distillation under reduced pressure. Then 14.8 g. (66.0 percent of theoretical) of 3-methoxy-6-anilinoethylbenzene was obtained as a light yellow oily substance having a boiling point of 185° to 215° C./13 mmHg, and the formula: ##STR16##
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30]CC4C=CC=CC=4)[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)C.CO>C(OCC)(=O)C.[Pd]>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Reaction time: 16 h
Yield: 99 %

Procedure:
3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide (3.9 g, 7.9 mmol) was dissolved in ethyl acetate (200 mL) and ethanol (200 mL) then 10% palladium on charcoal added. The reaction was stirred under an atmosphere of hydrogen for 16 hours. Methanol (150 mL) was added to aid solubilisation of the material and the suspension filtered, the residue taken up in DMF, filtered and the combined filtrates evaporated to dryness to give the desired material (3.17 g). 1H NMR δ (d6-DMSO): 2.33 (quin, 2H), 2.53 (s, 3H), 4.13 (t, 2H), 4.64 (t, 2H), 6.81 (s, 1H), 7.31 (s, 1H), 7.34 (s, 1H), 7.62 (d, 1H), 8.05 (d, 1H), 8.40 (s, 1H), 8.47 (s, 1H), 9.26 (s, 1H), 10.35 (s, 1H), 11.02 (s, 1H); m/z 406 (M+H)+
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:16])([F:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1>>[Cl:3][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([F:16])([F:15])[F:5])=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CCl)cc1

Procedure:
Thionyl chloride (15.0 g) was added to 4-(trifluoromethyl)benzenemethanol (15.0 g) over 30 min. The mixture was heated at reflux for 2 hr and then evaporated. The residue was distilled to afford the product as a colourless liquid b.p. 88°-92°/14 mm (11.0 g).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:21]1CCOCC1.ClC(OCC)=O.[OH-].[NH4+]>O1CCCC1>[C:16]([O:15][C:13]([NH:1][C@H:2]([C:10]([NH2:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a solution of Boc-Phe-OH (30.1 g, 113 mmol, 1 eq.) in tetrahydrofuran (378 mL, 0.3 M) cooled to −10° C. were added N-methylmorpholine (13.6 mL, 124 mmol, 1.09 eq.), and ethyl chloroformate (11.8 mL, 124 mmol, 1.09 eq.). After 20 minutes, a 30% aqueous ammonium hydroxide solution (45 mL, 350 mmol, 3.1 eq.) was added. The mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The residue was diluted with ethyl acetate and washed sequentially with 1 N aqueous potassium bisulfate solution, water and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The white solid was dissolved (this required heating with stirring) in ethyl acetate (about 400 mL); the solution was then allowed to cool to room temperature before adding hexane (1000 mL). After a few minutes, a white material started to precipitate from the reaction mixture. The solid was collected by filtration, washed with heptane (2×˜150 mL), and dried under vacuum for 18 hours to give #12 (24.50 g, 82%) as a solid. LC-MS: m/z 263.2 [M−H+], 309.2 [M+HCO2−], retention time=1.85 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 7.35 (br s, 1H), 7.22-7.30 (m, 5H), 7.00 (br s, 1H), 6.78 (d, J=8.6 Hz, 1H), 4.09 (ddd, J=10, 9, 4.5 Hz, 1H), 2.95 (dd, J=13.8, 4.4 Hz, 1H), 2.72 (dd, J=13.7, 10.1 Hz, 1H), 1.30 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:17]1([CH3:16])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-hexanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0747 g, 50%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=2)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C[CH2:40][N:41](C(C)C)C(C)C>ClCCl.CN.ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=2)=[N:41][CH3:40])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 140 °C
Yield: 14.8 %

Procedure:
Part B: A stirred mixture of N-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (2.36 gram, 5 mmol), PCl5 (1.15 g, 5.5 mmol) and chlorobenzene (50 ml) is heated for 90 minutes at 140° C. After cooling the mixture to room temperature the residue is dissolved in dichloromethane and methylamine.HCl (0.34 g, 5 mmol) and DIPEA (1.74 ml, 10 mmol) are successively added. The resulting mixture is stirred for 16 hours at room temperature, twice washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is further purified by flash chromatography (silica gel, dichloromethane/acetone=99/1 (v/v/), followed by crystallization from diisopropyl ether to give N-[(4-chlorophenyl)sulfonyl]-N′-methyl-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (0.36 gram, 15% yield). Melting point: 134-144° C. Rf (silica gel, diethyl ether=0.4).
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].[OH:7][C:8](CBr)=[C:9]([N:13]1[C:16](=[O:17])[CH:15]([NH:18][C:19](=[O:43])[CH:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:21]([O:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:14]1[S:44][CH:45]=O)[C:10]([O-:12])=[O:11].[CH2:49](S)[CH2:50][CH3:51]>C1(C)C=CC=CC=1>[CH:24]([O:23][C:21]([CH:20]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:19]([NH:18][CH:15]1[C:16](=[O:17])[N:13]2[C:9]([C:10]([O:12][CH:1]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:2]3[CH:4]=[CH:51][CH:50]=[CH:49][CH:3]=3)=[O:11])=[C:8]([OH:7])[CH2:45][S:44][C@H:14]12)=[O:43])=[O:22])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCS
Reactant: CC(C)C(=O)O
Reactant: O=CSC1C(NC(=O)C(C(=O)OC(c2ccccc2)c2ccccc2)c2ccccc2)C(=O)N1C(C(=O)[O-])=C(O)CBr
Solvent: Cc1ccccc1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(O)CS[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N12
Temperature: 18 °C
Reaction time: 0.33 h

Procedure:
To 0.391 g. (1 mmol.) of mercuric acetate in a mixture of 15 ml. of toluene and 15 ml. of isobutyric acid are added 0.739 g. (1 mmol.) of 3-hydroxy-4 -bromo-2-[2-formylthio-4-oxo-3-(α-benzhydryloxycarbonylphenylacetamido)-1-azetidinyl]-2-butenoate, benzhydryl ester, as a neat solid. The mixture is stirred for 20 minutes at 18° C., after which time the solution becomes cloudy. n-Propyl mercaptan is added to the mixture, and the mixture then is filtered through activated charcoal and a filter aide. The resulting filtrate is evaporated, and a residue comprising benzhydryl 7-(α-benzhydryloxycarbonylphenylacetamido)-3-hydroxy-3-cephem-4-carboxylate is obtained.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].[K+].I[CH:15]([CH3:17])[CH3:16]>C1COCC1.CC(OC)(C)C>[CH:15]([O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10])([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc(C)c1OC(C)C

Procedure:
4-Hydroxy-3,5-dimethylbenzaldehyde (2.5 g, 16.6 mmol) in THF (100 mL) was treated with KOH (1.5 eq. of 1 N aq. solution, 25 mL) and 2-iodopropane (2.0 eq.) and heated at reflux for 5 days. The reaction was then cooled, transferred to a separatory funnel, diluted with MTBE, washed with H2O, 1 N NaOH (twice), 0.5 N HCl (aq.), brine, dried over MgSO4 and concentrated. The product was purified over silica gel on an ISCO combiflash to yield 1.99 g (10.34 mmol) 4-isopropoxy-3,5-dimethylbenzaldehyde as a colorless liquid. H1 NMR (300 MHz, CDCl3) 9.89 (s, 1H), 7.55 (s, 2H), 4.41-4.26 (m, 1H), 2.32 (s, 6H), 1.32 (d, J=6 Hz, 6H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCC(=O)O
Yield: 88 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 106 mg 5-bromo-2-oxindole, and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 171 mg (88%) of the title compound as an orange solid.