Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[F:17][C:16]([F:19])([F:18])[C:3]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([OH:13])[OH:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(O)(O)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a mixture of 4-nitro-benzoic acid methyl ester (1.8 g, 9.9 mmol), trimethyl-trifluoromethyl-silane (2.0 ml, 12.8 mmol) and anhydrous dichloromethane (20 ml), cooled at −78° C., was added a solution of tetrabutylammonium fluoride in dichloromethane (1 M, 0.5 ml) previously dried over 4A molecular sieves. After stirring for 72 hours, hydrochloric acid (1 M, 50 ml) was added. The mixture was treated with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (100 ml). The organic extract was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) providing 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethane-1,1-diol (1.1 g, 47% yield).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: OCCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCCO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 3-mercapto-1-propanol to provide 5-[2-[(3-hydroxypropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one; 1H NMR (CDCl3) δ1.40 (br s, 1H), 1.65 and 1.68 (singlets, 3H), 1.68-1.82 (m, 2H), 2.42-2.57 (m, 2H), 3.10-3.27 (m, 2H), 3.67 (m, 2H), 4.42 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.27-7.40 (m, 6H); MS (HR-FAB) m/z 375.1113 (M+H calcd. for C20H23O3S2 375.1089).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][O:18][CH3:17])=[CH:27][CH:26]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: COCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(OCc2cc(Cl)ccc2Br)cc1
Yield: 94.7 %

Procedure:
1.42 g (5 mmol) of the compound obtained in Step 1 was dissolved in 20 ml of acetonitrile, 1.38 g (10 mmol) of K2CO3 and 0.84 g (5 mmol) of 4-(2-methoxyethoxy)phenol were added thereto, which was refluxed for 15 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added thereto. The resulting mixture was washed twice with water, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The concentrate was subjected to column chromatography using 20% ethyl acetate/hexane to obtain 1.76 g (yield 95%) of 1-(2-bromo-5-chlorobenzyloxy)-4-(2-methoxyethoxy)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.P(Br)(Br)[Br:12]>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: OCc1c(Cl)cncc1Cl
Solvent: ClC(Cl)Cl
Product: Clc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
To a solution of (3,5-dichloropyridin-4-yl)methanol (470 mg, 2.6 mmol) in anhydrous chloroform (10 mL) was added dropwise a solution of phosphorus tribromide (250 μL, 2.6 mmol) in anhydrous chloroform (2 mL) at 0° C. The mixture was stirred for 1.5 hours at room temperature. The solid was filtered and washed with dichloromethane to afford 4-(bromomethyl)-3,5-dichloropyridine (471 mg, 75% yield), which was used for next step without further purification; 1H NMR (400 MHz, MeOD4): δ 4.76 (s, 2H), 8.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C(COC)OC>[NH2:1][C:2]1[N:3]=[C:4]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccco1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a stirred suspension of 300 mg (1.14 mmol) 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile in 9 ml dimethoxyethane were added 0.41 ml (4.0 mmol) benzyl alcohol and 0.25 ml (1.7 mmol) DBU and the mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 2/1) followed by trituration in ether/hexane afforded 185 mg (56%) 2-amino-4-benzyloxy-6-furan-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 292 (M+, 40), 91 (C7H7+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>BrC(Br)(C(OCC)=O)C(OCC)=O.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@H](c4cccc(Cl)c4)OC3=O)cc2O1
Yield: 66.1 %

Procedure:
A mixture of 0.8 g of the above oxazolidinone, 0.74 g of diethyl dibromomalonate, 1.2 g of anhydrous potassium carbonate and 20 ml of acetone are stirred overnight with the addition of a few drops of diethyl dibromomalonate. The mixture is filtered, washed with acetone and the combined filtrate and wash are evaporated to a yellow oil. The oil is purified by flash chromatography, eluting with 5 percent acetone in toluene. The pure fractions are combined and evaporated, giving 766 mg of (R*,S*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2 -dicarboxylic acid, diethyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1cccs1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
1-(4-Nitro-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester was prepared from 3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 1.02 (t, J=7.2 Hz, 3H), 4.15 (q, J=7.2 Hz, 2H), 7.20 (dd, J=6.9, 3.4 Hz, 1H), 7.24 (dd, J=6.2, 0.8 Hz, 1H), 7.25-7.27 (m, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.37-7.43 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.68 (dd, J=5.2, 1.2 Hz, 1H), 7.71 (d, J=4.1 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H); MS (ESI) m/z 407 (MH+); 405 ([M−H]−); Anal. calcd for C22H18N2O4S: C, 65.01; H, 4.46; N, 6.89 Found: C, 65.04; H, 6.62; N, 6.82.
Reaction SMILES: Cl[C:2]1C=C(Cl)C(S(Cl)(=O)=O)=CC=1C(O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([NH2:30])[C:20](=[CH:24][C:25]=1[S:26](Cl)(=[O:28])=[O:27])[C:21]([OH:23])=[O:22]>>[CH3:16][C:17]1[CH:18]=[C:19]([NH2:30])[C:20](=[CH:24][C:25]=1[S:26]([CH3:2])(=[O:28])=[O:27])[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: Cc1cc(N)c(C(=O)O)cc1S(=O)(=O)Cl
Product: Cc1cc(N)c(C(=O)O)cc1S(C)(=O)=O

Procedure:
This product is prepared by replacing the 2,4-dichloro-5-chlorosulfonylbenzoic acid employed in Example 1, Step A, by an equimolecular proportion of 4-methyl-5-chlorosulfonylanthranilic acid and then following substantially the same procedure described in Example 1, Steps A and B, there is obtained 4-methyl-5-methylsulfonylanthranilic acid employed in the following step without purification. The compound thus obtained is combined with excess furfural and heated on a water bath at about 80° C. The water formed during the reaction is removed by azeotropic distillation with the excess furfural at about 15 mm. Hg. pressure over a one hour period. The 2-furfurylideneamino-4-methyl-5-methylsulfonylbenzoic acid formed is stirred while cooling in acetic acid while a mixture of trimethylamine-borane complex in acetic acid is added over a 10 minute period. The reaction mixture then is heated on the steam bath for 5-10 minutes, then quenched in ice water to give 2-furfurylamino-4-methyl-5-methylsulfonylbenzoic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:13]([Cl:31])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[Cl:31][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][N:19]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[C:20]1=[O:30]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
Treat a solution of 3′,5′-dichloro-4′-(3-cyclohexyl-2-oxo-pyrrolidin-1-ylmethyl)-biphenyl-4-carboxylic acid methyl ester (0.6 g) in THF (15 mL) with 5N NaOH (5 mL) and stir at 50° C. for 12 hours. Quench the reaction with HCl (1N, 25 mL). Partition the mixture between ethyl acetate and water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 0.56 g (96%) of the title compound. MS (m/z): 446 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1Br)CCC(=O)N2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1CCc2cc(Br)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (1.11 g, approx. 3.54 mmol, crude) in DCE (17 mL) was added 1-naphthalen-1-yl-piperazine hydrochloride (0.882 g, 3.54 mmol) followed by Et3N (1.0 mL, 7.1 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (1.05 g, 4.96 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as an off-white foam (1.37 g, 2.69 mmol, 76%). The HCl salt was formed by dissolving the title compound (138 mg, 0.27 mmol) in Et2O/CH2Cl2 followed by the addition of 1N HCl in Et2O (0.3 mL). The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (125 mg). MS: APCI: M+1: 509.1, 511.1 (Exact Mass: 508.15).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:28][NH2:29])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:29][CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1cnc(CN)c(C)c1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(CNc2nc(N)nc(-n3cccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-(3,5-dimethyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CC(C)=O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:16]
Reactant: Sc1cccc(Cl)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1cccc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirring mixture of 20.0 gm (0.138 mol) 3-chlorothiophenol and 21.0 gm (0.15 mol) potassium carbonate in 220 mL acetone were added dropwise 1.1 equivalents of bromoacetaldehyde diethyl acetal. After stirring for 17 hours at ambient temperature, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was partitioned between diethyl ether and water. The organic phase was separated, washed with saturated sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to give 35.1 gm (97%) of the desired. compound as a rust colored oil.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.CO.[OH-].[Na+]>C1COCC1.Cl>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of methyl 4-(4-biphenylylcarbonylamino)benzoate (1.998 g) in THF (60 ml)/methanol (20 ml) was added 1N aqueous sodium hydroxide (8 ml) and stirring was continued at room temperature for 18 hr. The reaction mixture was diluted with 1 N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The resulting crude crystals were washed with diethyl ether to obtain the titled compound (1.760 g).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[CH:24][S:25][C:19]=4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:30]([N:18]1[C:19]2[S:25][CH:24]=[CH:23][C:20]=2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])[CH2:31][CH2:32][CH3:33]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3sccc3c2=O)CC1
Reactant: CCCCBr
Product: CCCCn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccsc21
Yield: 33.8 %

Procedure:
The title compound was prepared by the procedure of Example 14 using 2.0 g (5 mmol) of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[2,3-d]pyrimidine-2,4-dione from Example 2 and bromobutane (819 mg, 6 mmol). There was obtained 774 mg (34% yield) of the title compound as a yellow solid after recrystallization from CH2Cl2 /hexane, mp 124°-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[CH3:11][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ncc(Br)cn1
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(Br)cn1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-(5-bromopyrimidin-2-yl)ethanone (100 mg, 0.5 mmol) in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.4M solution, 3.6 mL, 5 mmol). The reaction mixture was stirred for an additional 20 minutes until LC/MS analysis indicated that the reaction was complete. Quenching with saturated NH4Cl, extraction with EtOAc and drying over MgSO4, afforded the crude residue which was taken forward as is in the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (5 g, 24.9 mmol), 3,5-difluorobenzyl bromide (2.9 ml, 22.7 mmol) and diisoproylethylamine (5.9 ml, 34.03 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane, and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D5 (4.5 g, 90%) as a solid. C12H16F2N2 requires 226. Found 227 (MH+)
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N+]=[N-])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>CO.O1CCOCC1>[C:23]1([CH:29]([O:19][C:18]([C:14]2[N:13]3[C:21](=[O:22])[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C@H:12]3[S:17][CH2:16][CH:15]=2)=[O:20])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12

Procedure:
A solution of 1.275 g of 7β-phenylacetylamino-ceph-3-em-4-carboxylic acid in 5 ml of methanol and 20 ml of dioxane is treated with an excess of diphenyldiazomethane and allowed to stand at room temperature. The red-coloured reaction mixture is treated with a small amount of acetic acid and then evaporated to dryness under reduced pressure. The oily yellowish residue is taken up in a small amount of methylene chloride, the solution is treated with diethyl ether at an elevated temperature. The colourless precipitate (felt-like needles) is filtered off, washed with diethyl ether, then with pentane and dried to yield the 7β-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethylester of the formula ##STR28## m.p. 163.5°-164.5°; [α]D20 =+30°±1° (c=0.968 in dioxane); thin-layer chromatogram (silica gel): Rf=0.55 (system: toluene/acetone 4:1), Rf=0.35 (system: toluene/acetone 9:1) and Rf=0.40 (system: toluene/ethyl acetate 4:1); ultraviolet absorption spectrum: λmax =258 mμ (ε=6100) and λmin =240 mμ (ε=5250) (in methylene chloride) and λmax =259 mμ (ε=6050) and λmin =239 mμ (ε=4950); (95% ethanol) infrared absorption spectrum: characteristic bands at 2.90μ, 5.57μ, 5.76μ, 5.91μ, 6.09μ, 6.66μ, 7.13μ, 8.12μ, 8.63μ, 9.07μ, 10.43μ and 12.22μ (in methylene chloride) and at 3.01μ, 5.60μ, 5.82μ, 6.04μ, 6.08μ (shoulder), 6.51μ and 7.13μ (in mineral oil).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](OC)(OC)OC>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([CH3:10])([CH3:11])[O:12][C:17]([O:18][CH3:19])=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(c1cccc(Br)c1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 500 mg of 1-(3-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide in 2 ml of tetramethoxymethane and 0.5 ml of acetic acid was stirred at 100° C. for 3 hours. After the removal of the solvent under reduced pressure, the residue (565 mg) was used in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:15][OH:16])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>[Pd].CO>[OH:2][CH2:3][CH:4]1[NH:5][C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:12][C:15]1=[O:16]
Reactant: COC(=O)C(CO)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2NC1CO
Reaction time: 3.5 h

Procedure:
A mixture of N-(2-nitrophenyl)-DL-serine methyl ester (XI, EXAMPLE 286, 0.506 g, 4.30 g), palladium on carbon (10%, 506 g) and 150 ml of methanol is shaken under hydrogen at 40 psi for 3.5 hr. The catalyst is then removed by filtration and the filtrate is concentrated under reduced pressure. The residue is then chromatographed on silica gel (400 ml) using eluting with methanol/methylene chloride (6/94), the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 2.70, 3.90, 4.00-4.18, 6.75, 6.92, 8.23. δ.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[Cl:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=[C:21]3[Cl:20])[N:15]=[CH:14][N:13]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1cccc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)c1
Temperature: 407.5 °C

Procedure:
[3-(4-Chloro-[1,3,5]triazin-2-ylamino)phenyl]acetic acid methyl ester (3.530 g, 12.67 mmol) is combined with 2-chlorobenzimidazole (1.933 g, 12.67 mmol) and K2CO3(2.101 g, 15.20 mmol) in AcCN (50 ml) and heated at 65-750° C. for 2 to 20 hours. The reaction mix is cooled to RT. The inorganic salts are filtered off. The AcCN solution is concentrated down under reduced pressure. The crude is purifired by chromatography with an EtOAc/hexane elution gradient, giving {3-[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-ylamino]phenyl}acetic acid methyl ester.