Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:30](=[O:41])[C:29]=1[C:42](Cl)=[O:43])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH:13][C:42]([C:29]3[C:30](=[O:41])[N:31]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[CH:32]=[CH:33][C:28]=3[O:27][CH2:25][CH3:26])=[O:43])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of Example A2 (29 g, 113 mmol) and triethylamine (23 g, 226 mmol) in THF (400 mL) was added freshly prepared 4-ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (33.5 g, 113 mmol) and the mixture was stirred at RT overnight. The mixture was concentrated in vacuo, and the residue was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (51 g, 87% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[C:20]([OH:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:21][C:20]2[C:19]([F:22])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=2[F:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 10.8 g of 4-acetoxybenzoyl chloride in dry acetonitrile was treated with 10 g of pentafluorophenol, and stirred at 0° C. whilst 4.4 ml of pyridine was added dropwise. The solution was permitted to warm to room temperature then heated to reflux temperature until the reaction was complete. Solvent was evaporated in vacuo and the residue obtained partitioned between ethyl acetate and water. The organic solution was washed with further portions of water and brine and dried over magnesium sulphate. Evaporation afforded 18 g of the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][NH:21][CH2:22]C)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNCCO>>[Si:1]([O:18][CH2:19][CH2:20][NH:21][CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CNCCO
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 49 %

Procedure:
The title compound (4.1 g, yield: 49%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 23 utilizing 2-(methylamino)ethanol (2.0 g, 26.6 mmol) as starting material. The title product was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% DCM/10% MeOH in DCM with 1% NH4OH).
Reaction SMILES: CC#N.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)#[N:5].Cl.[NH2:20][OH:21].C([O-])(O)=O.[Na+]>CO>[OH:21][NH:20][C:4](=[NH:5])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:13])(=[O:14])[NH:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccc(S(=O)(=O)NCCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 49.9 %

Procedure:
To a solution of 4-cyano-benzenesulfonyl chloride (1.00 g, 4.96 mmol) in THF, ethanolamine (454 mg, 7.44 mmol) is added. The mixture becomes slightly warm (30° C.) and turbid. The mixture is stirred at rt for 3 h before it is diluted with EA, washed with sat. aq. NH4Cl solution and water, dried over MgSO4, filtered and concentrated to give crude 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.26 g) as a white solid; LC-MS: tR=0.34 min, [M+1+CH3CN]+=268.13. b) A mixture of 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.25 g, 5.56 mmol), hydroxylamine hydrochloride (773 mg, 11.1 mmol) and NaHCO3 (934 mg, 11.1 mmol) in methanol is stirred at 60° C. for 7 h. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in EA (250 mL) and washed with water (5 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (720 mg) as a white solid; LC-MS: tR=0.23 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[O+](C)C
Reactant: COC(=O)c1c(F)ccc2n[nH]cc12
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)ccc2nn(C)cc12
Reaction time: 5 h
Yield: 84.9 %

Procedure:
To a solution of methyl 5-fluoro-2H-indazole-4-carboxylate (4.50 g, 23.2 mmol) in ethyl acetate (93 mL) was 25 added trimethyloxonium tetrafluoroborate (4.46 g, 30.1 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (4.10 g, yield 85%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[CH3:16][C:17]1([CH3:23])[CH2:21][NH:20][C:19](=[O:22])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH3:16][C:17]1([CH3:23])[CH2:21][N:20]([C:2]2[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=2)[C:19](=[O:22])[CH2:18]1
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: CC1(C)CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)nn2)C1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 14.7 %

Procedure:
To a solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (180 mg, 839 μmol) and 4,4-dimethylpyrrolidin-2-one (CAS 66899-02-3) (142 mg, 1.26 mmol, 1.5 equiv.) in 2 ml of DMF were added cesium carbonate (546 mg, 1.68 mmol, 2 equiv.). The suspension was heated 16 hours at 120° C. and then allowed to cool to room temperature. Ethyl acetate (10 ml) were added and the unsoluble salts were filtered off. After concentration in vaccuo, the residue was dissolved in 10 ml of ethyl acetate. Silicagel (4 g) were added and the suspension was evaporated to dryness. The silicagel with the adsorbed crude mixture was loaded onto a 20 g silicagel flash chromatography column and eluted three min. with heptane followed by a heptane to 45% ethyl acetate/heptane gradient over 25 min to yield 36 mg (15% yield) of the title compound as a cristalline yellow solid, MS: m/e=292.3 (M+H+).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:17])[CH2:13][C@@H:14]([OH:16])[CH:15]=1)([O:3][CH3:4])=[O:2].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:16][C@@H:14]1[CH2:13][C:12](=[O:17])[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])=[CH:15]1
Reactant: COC(=O)CCCCCCC1=C[C@H](O)CC1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCCC1=C[C@H](OC2CCCCO2)CC1=O

Procedure:
A vigorously stirred, ice-cold solution of 10 g. of 2-(6-carbomethoxyhexyl)-4(R)-hydroxy-cyclopent-2-en-1-one [R. Pappo, et al., Tetrahedron Letters, 943(1973)] and 15 g. of dihydropyran in 215 ml. of methylene chloride is treated with 85 mg. of p-toluenesulfonic acid monohydrate. After stirring for 5 minutes at 0° C. and 60 minutes at 25° C., the solution is poured into a stirred mixture of 40 ml. of saturated sodium chloride solution, 40 ml. of saturated sodium bicarbonate solution and 80 ml. of water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated to give an oil, λmax (film) 1730 (ester carbonyl), 1710 (ketone carbonyl), and 1030 cm-1 (tetrahydropyranyloxy group).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[F:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc2c(F)cccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2c(F)cccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 4-fluoro-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 318.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:50])[N:33]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:34]1[S:35][C:36]([CH:40]=[O:41])=[C:37](Cl)[N:38]=1)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:50])[N:33]([C:34]1[S:35][C:36]([CH:40]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:41])=[CH:37][N:38]=1)[CH2:42][C:43]1[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cnc(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)s2)c2cc(Cl)cnc21
Temperature: 0 °C
Yield: 29.5 %

Procedure:
To a solution of 5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (626, 300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at −20° C. was added dropwise iso-propyl-magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was allowed to warm to 0° C. over 10 minutes and then cooled to −40° C. To this reaction mixture was added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (625, 211 mg, 0.63 mmol) in tetrahydrofuran (5 mL). The reaction mixture was allowed to warm to 0° C. over 30 minutes and then quenched with brine (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material which was purified by silica gel column chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120 mg, 30%), consistent with structure by 1H-NMR.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]1([CH:7]([NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cccc2ccccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccccc1)c1cccc(N)c1)c1cccc2ccccc12
Yield: 93.9 %

Procedure:
Following a procedure similar to that described in Example (1b), 1.56 g of N-[phenyl-(3-nitrophenyl)methyl]-N-[(R)-1-(napthalen-1-yl)ethyl]amine [prepared as described in step (a) above], 2.23 g of nickel chloride hexahydrate and 650 mg of sodium borohydride were reacted, to obtain 1.35 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:30]2([CH3:31])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9][C@@H:8]([O:33][C:34]([O:36][CH3:37])=[O:35])[CH2:7]1)=[O:4].BrN1C(C)(C)C(=O)N(Br)C1=O.CC1C=C(C)N=C(C)C=1>CCCCCC.C1(C)C(C)=CC=CC=1.C(OC(=O)C)C>[CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:30]2([CH3:31])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9][C@@H:8]([O:33][C:34]([O:36][CH3:37])=[O:35])[CH2:7]1)=[O:4]
Reactant: COC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCCC
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 1α,3β-dimethoxycarbonyloxycholest-5-ene (518 mg, 1 m mole) in dry hexane (10 ml), 1,3-dibromo-5,5-dimethylhydantoin (172 mg, 0.6 m moles) was added dropwise under stirring and heating at oil bath temperature of 95° C., and the mixture was continued to react under the irradiation of infrared rays for 15 minutes. The reaction mixture was cooled, and the resulting precipitate was removed by filtration, the filtrate was concentrated at reduced pressure at 40° C. to afford a residual product. Xylene was added to this substance to form a solution. The resulting solution was added dropwise to a solution held at 170° C. of s-collidine (2.5 ml) in dry xylene (3 ml), and the reaction was carried out for additional 20 minutes. After the reaction, the resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure at 40° C. to give residual product. The product was dissolved in ethylacetate (20 ml). The ethylacetate solution was washed with 1 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 479 mg of residual product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26](OCC)=[O:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[CH3:31][Mg]Cl.[Cl-].[NH4+].C(Cl)Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26](=[O:27])[CH3:31])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: -30 °C
Reaction time: 0.42 h

Procedure:
In a 100 mL round-bottomed flask, ethyl 6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (2.00 g, 4.87 mmol) was suspended in THF (30 mL) and cooled to about −30° C. A solution of methylmagnesium chloride (3 M in THF, 6.50 mL, 19.5 mmol) was added over about 10 min to the suspension. The mixture was stirred for about 25 min at about −30° C., followed by slow addition of a saturated solution of ammonium chloride (15 mL). The suspension was diluted with the addition of water (20 mL) and then DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give a solid that was triturated with Et2O (15 mL) and collected by vacuum filtration as a slightly off-white powder (1.50 g, 81%): LC/MS (Table 1, Method g) Rt=2.06 min; MS m/z: 380.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.[CH2:24]([N:26]([CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>>[CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]1([C:30]2[CH:31]=[CH:32][C:27]([N:26]([CH2:24][CH3:25])[CH2:34][CH3:35])=[CH:28][C:29]=2[CH3:33])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:11])[O:10]1
Reactant: CCN(CC)c1cccc(C)c1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(C)c1

Procedure:
Condensation of 2-(2,4-bis(dimethylamino)benzoyl)-benzoic acid and N,N-diethyl-m-toluidine in the presence of acetic anhydride also afforded 3-(2,4-bis(dimethylamino)-phenyl-3-(2-methyl-4-(diethylamino)phenyl)phthalide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[N:6]([CH2:19][C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]2=[O:27]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[N:6]([CH2:19][C:20]([NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:5]2=[O:27]
Reactant: CC(C)(C)NC(=O)CN1C(=O)c2cc(Br)ccc2NC1c1cccc(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(Br)cc2c1=O
Temperature: 70 °C
Yield: 100 %

Procedure:
In a capped 20 mL scintillation vial, a mixture of 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-N-tert-butylacetamide (0.51 g, 1.13 mmol) and manganese(IV) dioxide (0.44 g, 5.10 mmol) in chloroform (10 mL) was heated at 70° C. for 3 h. The black suspension was cooled to room temperature, filtered through a pad of celite and concentrated in vacuo to provide 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-4H-quinazolin-3-yl]-N-tert-butylacetamide (INTERMEDIATE VI.1) (0.51 g, 1.13 mmol, 100%) as a white solid. Data for 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-4H-quinazolin-3-yl]-N-tert-butylacetamide (INTERMEDIATE VI.1): 1H NMR (300 MHz, CDCl3): δ 9.44 (d, 1H), 7.86 (dd, 1H), 7.65-7.54 (m, 2H), 7.53-7.4 (m, 3H), 5.47 (s, 1H), 4.46 (s, 2H), 1.34 (s, 9H) ppm; MS (ESI) m/z: 448/450 ([M+H]+).
Reaction SMILES: [CH2:1]([Si:4]([CH2:9][CH2:10][CH3:11])([CH2:6][CH2:7][CH3:8])Cl)[CH2:2][CH3:3].[C:12]([NH:20][CH:21]1[C:35](=[O:36])[N:23]2[C:24]([C:32]([OH:34])=[O:33])=[C:25]([CH2:30][Br:31])[CH:26]([Br:29])[S:27](=[O:28])[C@H:22]12)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCCl>[C:12]([NH:20][CH:21]1[C:35](=[O:36])[N:23]2[C:24]([C:32]([O:34][Si:4]([CH2:9][CH2:10][CH3:11])([CH2:6][CH2:7][CH3:8])[CH2:1][CH2:2][CH3:3])=[O:33])=[C:25]([CH2:30][Br:31])[CH:26]([Br:29])[S:27](=[O:28])[C@H:22]12)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Reactant: CCC[Si](Cl)(CCC)CCC
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCC[Si](CCC)(CCC)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
123 mg of tri-n-propylchlorosilane were added to a suspension of 312 mg of 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylic acid-1-oxide (prepared by the process of Step D of Example 1) in 25 ml of 1,2-dichloroethane under a nitrogen atmosphere and then a solution of 64 mg of triethyl-amine in 4 ml of 1,2-dichloroethane was dropwise added over 15 minutes under cooling in an ice-bath. The clear, slightly yellow colored solution was stirred for two hours at room temperature and after removal of the solvent under vacuo, 7 ml of diethyl ether was added. The obtained suspension was centrifuged and the clear liquid layer was separated and evaporated to dryness under vacuo. The residue was kept at a pressure of 0.5 mm of mercury for half an hour to obtain 210 mg of tri-n-propylsilyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate-1-oxide having the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCCBr
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Yield: 103.2 %

Procedure:
Part A. A suspension of 4,5-bis(4-methoxyphenyl)-2-mercapto-1H-imidazole (10.4 g, 33.2 mmol), ethyl 5-bromovalerate (5.00 mL, 31.6 mmol), potassium carbonate (5.50 g, 39.8 mmol), and tetra-n-butylammonium iodide (2 g) in tetrahydrofuran (100 mL) was heated to reflux for 20 hours. The mixture was cooled, and poured into water (400 mL). This was extracted with methylene chloride (2 ×400 mL), and the extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was purified by elution through a short plug of silica gel with ethyl acetate, and evaporation afforded ethyl 5-[4,5-bis(4-methoxyphenyl)-1H-imidazole-2-ylthio]pentanoate (14.4 g, 32.6 mmol, 98%) as a waxy, low-melting solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.P(=O)(O)(O)O>O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[CH:15][C:14]([OH:18])=[O:17])[C:7]2=[O:12]
Reactant: O=CC(=O)O
Reactant: O=C1CCCc2c(F)cccc21
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)C=C1CCc2c(F)cccc2C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 5-fluoro-3,4-dihydro-1(2H)-naphthalenone (10 g), glyoxylic acid monohydrate (6.2 g) and 85% phosphoric acid (10 ml) was stirred at 90° C. for three hours. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to give (5-fluoro-3,4-dihydro-1-oxo-2(1H)-naphthalenylidene)acetic acid (13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[Br:14]Br>C(O)(=O)C>[Br:14][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=1[NH:9][C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)Nc1ccc(F)c(Cl)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCC(=O)Nc1cc(Cl)c(F)cc1Br
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 97.2 %

Procedure:
The solid (10 g, 49.60 mmol) from step 1 dissolved in acetic acid (70 mL) was added with Br2 (12.7 mL, 247.93 mmol) dropwise for 2 h. Then the reaction mixture was kept stirring at rt for 5.5 h. The resulting mixture was poured to ice water (1 L) and quenched with excess of NaHSO3 until the solution became clear with yellow suspension. The quenched solution was filtered to get title compound (13.52 g, 97.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.07 (t, J=7.6 Hz, 3H), 2.36 (q, J=7.6 Hz, 2H), 7.80 (d, J=7.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 9.50 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 10.1, 29.3, 117.3, 117.4, 119.0, 119.2, 121.0, 121.2, 128.4, 134.45, 134.49, 153.4, 155.9, 173.0;