Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH2:8][CH2:7][CH2:6]1)=[O:4].C1COCC1.CO.O[Li].O>O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8]1)(=[O:12])=[O:11])([O-:21])=[O:20]
Reactant: COC(=O)C1(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
methyl-1-(2-nitrophenylsulfonamido)cyclobutanecarboxylate (500 mg, 1.59 mmol) was charged, and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 1-(2-nitrophenylsulfonamido)cyclobutanecarboxylic acid (468 mg, 1.56 mmol, 98%).
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:18]>C(O)C.O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:1])=[C:8]([NH2:18])[C:10]([F:13])([F:12])[F:11])[CH3:7]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)=C(N)C(F)(F)F
Temperature: 25 °C
Yield: 104.3 %

Procedure:
Ethyl α-methyl-4,4,4-trifluoroacetoacetate (24.5 g, 124 mmol) and ammonium acetate (28.6 g, 372 mmol) were dissolved in ethanol (50 ml) and water (2.5 ml). The solution was heated under reflux for 16 hours, allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to give the product as a pale brown liquid (25.5 g, 100% yield) which was used without further purification.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[N:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[C:10]=[O:11].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:9][C:10]([NH:2][CH:3]2[CH2:8][CH2:7][O:6][C:4]2=[O:5])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(CN=C=O)cc1
Reactant: NC1CCOC1=O
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)NC2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.6 %

Procedure:
A 0° C. slurry of α-amino-γ-butyrolactone hydrobromide (25 g, 0.137 mol) in THF (200 mL) was combined with 1-isocyanatomethyl-4-methyl-benzene (20.6 g, 0.139 mol) and then treated dropwise with N,N-diisopropylethylamine (19.5 g, 0.151 mol). The reaction mixture was stirred for at room temperature for 2 h. The solvent was removed in vacuo to give 48.5 g crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea that was utilized directly in the next reaction without purification. MS (ES30 ) Calc'd for C13H17N2O3 (M+1) 249. Found m/z 249 (100%). 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[CH:24]([CH3:33])[CH:25]=[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:27]=1)=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=4[CH3:33])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1C=C(CCC(=O)O)N=C1C=O
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(CCC(=O)O)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-4-methyl-4H-pyrrol-2-yl)-propionic acid (62 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) stirred at 80° C. for 2 hours to give 31 mg (20%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.14 (br s, 1H, NH), 9.14 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.30-7.40 (m, 3H), 6.08 (s, 1H), 3.32 (s, 3H, CH3), 2.89 (m, 2H, CH2), 2.53 (m, 2H, CH2), 2.16 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[N:10]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17])[O:26][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:24][CH:23]=1
Reactant: O=C(CCCCCBr)NC(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc(CCCCCBr)oc2-c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Yield: 87 %

Procedure:
4,5-Bis(4-chlorophenyl)-2-(5-bromopentyl)oxazole is prepared in the following manner: 39.5 g of 1,2-bis(4-chlorophenyl)-2-(6-bromohexanamido)ethanone in 80 cm3 of toluene containing 40 g of phosphorus oxychloride are stirred for 3 hours at 80° C. After evaporation to dryness under vacuum, 100 cm3 of ice-cold water are added. The mixture is extracted with diethyl ether (3 times 120 cm3) and the ethereal solutions are washed successively with water (3 times 50 cm3) and saturated aqueous sodium bicarbonate solution (twice 100 cm3). The organic phase is dried and concentrated to dryness. The solid residue is dissolved in 400 cm3 of hexane, the solution is treated with animal charcoal and filtered through kieselguhr, the filtrate is cooled to 10° C. and the precipate is drained and dried. 33 g (87%) of 4,5-bis(4-chlorophenyl)-2-(5-bromopentyl)oxazole are obtained in the form of white crystals, melting point 98° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[C:26]([F:27])=[CH:25][C:24]([C:28]#[N:29])=[C:23]([Cl:30])[N:22]=1>CS(C)=O.O>[F:27][C:26]1[C:21]([N:4]2[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]2=[O:13])=[N:22][C:23]([Cl:30])=[C:24]([C:28]#[N:29])[CH:25]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2nc(Cl)c(C#N)cc2F)c1=O
Temperature: 130 °C

Procedure:
A mixture of 0.776 g 1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidin-dione, 0.760 g potassium carbonate and 0.768 g 2,6-dichloro-3-fluoro-5-cyanopyridin in 40 ml dimethylsulfoxide is stirred under nitrogen at 130° C. until conversion is complete. Then the reaction mixture is cooled down and diluted with ice and water. The pH of the mixture is adjusted to neutral and the mixture is extracted several times with ethyl acetate. The organic layers are washed with water, dried, evaporated and the residue is purified by silicagel chromatography (hexane/ethyl acetate 7/3) to yield the title compound as a solid of m.p. 146-148° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([Cl:15])[N:7]=1>C(OCC)C.C1COCC1.C(Cl)(Cl)Cl.[Br-].[Zn+2].[Br-].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>[Cl:5][C:6]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH2:1][CH3:2])[N:7]=1.[Cl:15][C:8]1[N:7]=[C:6]([CH2:1][CH3:2])[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=1
Reactant: CN(C)c1cc(Cl)nc(Cl)n1
Reactant: CC[Mg]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(N(C)C)nc(Cl)n1
Product: CCc1nc(Cl)cc(N(C)C)n1
Temperature: -65 °C
Reaction time: 1.17 h

Procedure:
A mixture of zinc bromide (2.6 g) and THF (15 mL) was cooled to −60 to −70° C., a solution (3.8 mL) of 3 M ethylmagnesium bromide in diethyl ether was added dropwise, the mixture was stirred at −75° C. for 70 min and then at room temperature for 1 h, followed by addition of a solution of Pd(PPh3)4 (0.60 g) and (2,6-dichloropyrimidin-4-yl)dimethylamine (2.0 g) in THF (8 mL), and the mixture was heated to reflux for 17 h. The mixture was cooled to room temperature, then the reaction mixture was diluted with chloroform, washed with saturated aqueous ammonium chloride, and then extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=15:1) to obtain the title compound (0.18 g) and (6-chloro-2-ethylpyrimidin-4-yl)dimethylamine (0.46 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([CH2:31][N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]1([CH2:31][N:32]2[CH:36]=[C:35]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:34]=[N:33]2)[CH2:30][CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(CC3CCC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: O
Solvent: CO
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CC4CCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.9 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (6.2 mg). LCMS (M+H)+: m/z=473.3.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[CH2:13]([NH:20][C:21]1[C:22]([NH2:34])=[CH:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:22]=1[NH:34][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCN(c2ccc(N)c(NCc3ccccc3)c2)CC1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (210.000 mg; 1.256 mmol), N2-Benzyl-4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine E-1.1 (363.000 mg; 1163.422 μmol) and triethylamine (0.435 ml; 3.141 mmol) in THF (3.000 ml) is added N-propylphosphonic acid anhydride, cyclic trimer (0.880 ml; 1.508 mmol). The mixture is stirred for 5 h at RT. The reaction is quenched with 1M NaOH, diluted with 50 ml water and extracted twice with ethyl acetate (50 ml). The combined organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is used in the next step without further purification
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[NH:26][C:25]2=[CH:27][CH:28]=[CH:29][C:24]2=[C:23]([Cl:30])[N:22]=1>CN(C)C=O>[ClH:30].[CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]1[N:22]=[C:21]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[NH:26][C:25]2=[CH:27][CH:28]=[CH:29][C:24]=12
Reactant: CC1c2ccccc2CCN1c1nc(Cl)c2cccc-2[nH]1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)[nH]c2cccc1-2
Product: Cl
Yield: 11.8 %

Procedure:
After 2-methyl-4-fluoroaniline(0.46 ml, 4.2 mmol) was added to a mixture solution of 2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chlorocyclopenta[d]pyrimidine(0.6 g, 2.0 mmol) and dimethylformamide(10 ml), 0.10 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [C:1]([OH:17])(=[O:16])[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:18]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[CH3:18][O:16][C:1](=[O:17])[C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90 g (0.394 mol) of benzilic acid are dissolved in 900 mL acetonitrile and at 5° C. 109.6 g (0.72 mol) of DBU are added dropwise. After the addition of 204.4 g (1.44 mol) of methyl iodide, the mixture is stirred for 24 hours at ambient temperature (about 20° C. to 23° C.). The solution is evaporated down to the residue, the residue is taken up in diethyl ether and extracted with water. The organic phase is washed with 5% aqueous sodium carbonate solution and water, dried, and the solvent is distilled off. The product is purified by recrystallization from cyclohexane. Yield: 77.19 g of white crystals (81% of theoretical yield); melting point: 74° C.-76° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][N:13]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:29]1[N:37]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.O.NN>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:29][NH2:37])=[O:17])=[CH:14][N:13]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cn2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
To a solution of 6-(1-tert-butoxycarbonylamino-cyclopropyl)-nicotinic acid (0.50 g, 1.8 mmol) in DMF (3 mL) was added HATU (0.68 g, 1.8 mmol), Et3N (0.25 mL, 1.8 mmol) and the mixture allowed to stir at room temperature for 20 min. Hydrazine monohydrate (0.09 mL, 1.8 mmol) was then added and the reaction stirred for 1 h. The mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give [1-(5-hydrazinocarbonyl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.51 g, 1.7 mmol) as a yellow solid, m/z 293.7 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([N:19]3[CH2:18][CH2:17][CH:16]([OH:15])[CH2:21][CH2:20]3)(=[O:24])=[O:23])=[CH:33][CH:32]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 114 mg of 4-(4-hydroxypiperidin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide. MS (Q1) 472.3 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(F)cc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(-c2cccnc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
3-Fluoro-5-(pyrid-3-yl)aniline (1.05 g, 0.0050 mole) in dry dichloromethane was treated under argon with triethylamine (1.12 ml, 0.0080 mole) followed dropwise by phenyl chloroformate (0.97 ml, 0.0077 mole) and stirred at ambient temperature for 18 hours. The reaction mixture was washed (×2) with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.1 g, 71%) as an off white solid.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:42])=[C:7]([C:9](=[N:32][O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[NH2:3][C:4]1[S:5][C:6]([Cl:42])=[C:7]([C:9](=[N:32][O:33][CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
A mixture of 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g) in methanol (36 ml) and conc. hydrochloric acid (1.1 g) was stirred for 3.0 hours at ambient temperature. The reaction mixture was added to water and ethyl acetate, and adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 3.0 with 10% aqueous hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.62 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].O>CCOCC.CCCCCCC>[F:13][C:14]1[CH:15]=[C:16]([CH:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:18])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: O
Product: OC(c1cccc(F)c1)c1ccccn1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
A solution of 17.4 g of 2-bromopyridine in 40 ml of ether is added slowly with stirring to 75 ml of commercial n-butyl lithium in heptane and 100 ml of ether at -50° to -40° C. under a nitrogen atmosphere. After stirring another 0.25 hours at -40° C., a solution of 12.5 g of 3-fluorobenzaldehyde in 30 ml of ether is added dropwise and the mixture is allowed to warm to room temperature. After stirring 3 hours, 100 ml of water is added, the organic layer is separated, dried over MgSO4 and the solvent is evaporated. The residue is chromatographed over silica gel in acetonitrile to obtain alpha-(3-fluorophenyl)-2-pyridinemethanol; mp 80°-82° C., after recrystallization from cyclohexane. The alpha-(3-fluorophenyl)-2-pyridinemethanol is hydrogenated at about 50 lbs. p.s.i. in methanol-acetic acid in the presence of 10% Rh/C. The reaction mixture is filtered, the solvent evaporated from the filtrate, and the residue dissolved in methylene dichloride and shaken with concentrated sodium hydroxide. The organic layer is separated, dried, and concentrated to obtain the desired alpha-(3-fluorophenyl)-2-piperidinemethanol; mp 146°-148° C.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19](=O)[C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])=[CH:13][CH:12]=1.C[O-].[Na+]>C(#N)C>[C:11]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2([C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: C=CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reaction time: 96 h
Yield: 80.4 %

Procedure:
A solution of 41.9 ml (0.567 mol) of dimethyl sulphide in 50 ml of acetonitrile was added dropwise to a solution of 49.4 ml (0.518 mol) of dimethyl sulphate in 250 ml of acetonitrile at 25° C., in the course of 2 hours, with external cooling. After the mixture had stood for 4 days at room temperature, 87.4 g (0.31 mol) of 5-(biphenyl-4-yloxy)-3,3-dimethylpent-1-en-4-one, dissolved in 90 ml of acetonitrile, were stirred in in the course of 1 hour. Thereafter, 31.6 g (0.58 mol) of sodium methylate were introduced at 25° C. After the mixture had been stirred for twelve hours at room temperature, the precipitated salt was filtered off, and the filtrate was concentrated. The oily residue was taken up in 500 ml of ethyl acetate, and the solution was washed with twice 500 ml of water and dried over anhydrous sodium sulphate. After the solution had been concentrated in vacuo, 73.4 g (80.4% of theory) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane were obtained as a colorless waxy mass. ##STR23##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:14])[C:11]([OH:13])=[O:12].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]O.Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:14])[C:11]([O:13][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH3:20])=[O:12]
Reactant: COc1ccccc1CO
Reactant: COc1ccc(CCNCC(O)C(=O)O)cc1OC
Agent: Cl
Solvent: c1ccccc1
Product: COc1ccccc1COC(=O)C(O)CNCCc1ccc(OC)c(OC)c1
Yield: 23 %

Procedure:
To 3 g of the 3-(3,4-dimethoxyphenethyl)amino-2-hydroxypropionic acid prepared in Example I was added 200 ml of benzene and 20 ml of 2-methoxybenzyl alcohol. About 0.5 ml of concentrated HCl was added to catalyze the reaction. The reaction mixture was heated to reflux for 6 hours and the water was collected by a moisture trap. The reaction mixture was extracted with 200 ml of 0.5% HCl in water. The aqueous layer was basified with NaHCO3 and extracted with CHCl3. Evaporation of the CHCl3 gave an oily residue which after chromotography on a column (silica gel/Et2O:EtOH=5:1) gave 1 g (23%) of white solid: m.p. 79.5°-82.5° C. The NMR, IR and mass spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C21H27O6N.