Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:13])(C)(C)C.[H-].CO.O>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[O:5]
Reactant: CC(C)(C)OC(=O)CCCCCCBr
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=CCCCCCCBr
Yield: 85.3 %

Procedure:
To 8.5 g of 7-bromoheptanoic acid t-butyl ester (prepared as described in Reference Example 1) in 80 ml of methylene chloride was added dropwise 18.2 ml of a 25% solution of diisobutyl alminium hydride in toluene at -78° C. over a period of 1 hours. The solution was stirred at the same temperature, to which was added 5 ml of methanol at from 0° C. to 10° C. and then added 10 ml of water, and the mixture was stirred at 30° C. to 40° C. for 1 hour. The deposited crystals were filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene and chloride and cyclohexane (1:1) as an eluent to give 5.28 g of the title compound having the following physical characteristic:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[NH2:20]N>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][NH:15][N:20]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)C=CN(C)C)cc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc[nH]n2)cc1Cl
Temperature: 77.5 °C

Procedure:
To a suspension of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester (13.67g) in ethanol (53 ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80° C. for one hour. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield the title compound as a crude solid (12 g). A purified sample had a melting point of 130-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9]O.CCN(S(F)(F)[F:17])CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][F:17]
Reactant: OCc1cc(I)ccc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCc1cc(I)ccc1F
Temperature: 25 °C

Procedure:
To a stirred solution of (2-Fluoro-5-iodo-phenyl)-methanol (1.0 g, 3.97 mmol) in dry methylene chloride (10 mL) at −78° C. and under a nitrogen atmosphere was added DAST (0.63 mL, 4.76 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 1 h, and then quenched with sat sodium bicarbonate (4 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo to a clear oil (0.999 g, 99%) and used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:27]4[CH:35]=[CH:36][C:37]([C:39]([OH:41])=[O:40])=[CH:38][C:26]=4[N:25]=3)[CH:14]=2)[N:9]=1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[C:3]([C:8]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:24]5[N:28]([CH:29]6[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]6)[C:27]6[CH:35]=[CH:36][C:37]([C:39]([OH:41])=[O:40])=[CH:38][C:26]=6[N:25]=5)[CH:14]=4)[N:9]=3)=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4Br)c(-c4ccccc4)cc3c1)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4-c4ccc(Cl)cc4)c(-c4ccccc4)cc3c1)n2C1CCCCC1
Yield: 7.6 %

Procedure:
Compound 424 (50 mg, 0.083 mmol), 4-chlorophenylboronic acid (20 mg, 0.125 mmol), and CsF (143 mg, 0.94 mmol) were added to degassed dioxane (6 mL). A solution of 2-(dicyclohexylphosphino)biphenyl (5 mg, 0.0125 mmol) and palladium acetate (2 mg, 0.0083 mmol) in degassed dioxane (3 mL) was added to the reaction solution. The reaction was then refluxed under argon for 3 hours. The reaction was then evaporated to dryness and purified via HPLC resulting in the title compound (4 mg, 10% yield).
Reaction SMILES: [CH2:1]([O:3]CC)[CH3:2].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.C(OC(=O)C)(=O)C>O>[C:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2.4 h

Procedure:
Into 40 ml of anhydrous ethyl ether, was dissolved 7.1 g of 4-hydroxy-2-methylbenzoic acid followed by 21.3 g of acetic anhydride. The solution was stirred for 2.4 hours at room temperature. The reaction mixture was freed from the solvent under reduced pressure. The residue was admixed with hot water, then allowed to cool, and extracted with ethyl ether. The organic layer was washed with 2% hydrochloric acid, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure. The residue was recrystallized from an ethyl ether-petroleum ether mixture to obtain 7.5 g of 4-acetyloxy-2-methylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:29](O)=[O:30])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:38])=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:48]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:29]([NH2:48])=[O:30])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:38])=[CH:6][CH:7]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1c(C(=O)N2CCC(C(=O)O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(C(N)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 44 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxylic acid (1 eq., 12.7 mg, 0.024 mmol), ammonium chloride (10 eq., 12.7 mg, 0.24 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 10.5 mg, 0.024 mmol), and triethylamine (10.1 eq., 0.03 mL, 0.024 mmol) was stirred in tetrahydrofuran (5 mL) for 3 d. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide (6 mg, 44%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.92-2.31 (m, 5H) 2.46 (d, J=13.94 Hz, 2H) 3.65 (t, J=10.36 Hz, 1H) 3.75-3.90 (m, 1H) 4.02 (d, J=13.38 Hz, 1H) 4.23 (d, J=13.00 Hz, 1H) 5.24 (br. s., 2H) 7.07 (d, J=8.38 Hz, 2H) 7.12-7.20 (m, 1H) 7.20-7.49 (m, 9H).
Reaction SMILES: [F-].C([N+](CC)(CC)CC)C.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]([C:36]3[C:44]4[C:39](=[CH:40][C:41]([CH2:45][O:46][Si](C(C)C)(C(C)C)C(C)C)=[CH:42][CH:43]=4)[N:38]([CH3:57])[CH:37]=3)[C:21]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[CH2:34][CH3:35])(=[O:26])=[O:25])=[O:22])=[CH:19][C:14]=2[O:13][CH2:12]1.Cl>C(#N)C>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]([C:36]3[C:44]4[C:39](=[CH:40][C:41]([CH2:45][OH:46])=[CH:42][CH:43]=4)[N:38]([CH3:57])[CH:37]=3)[C:21]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[CH2:34][CH3:35])(=[O:26])=[O:25])=[O:22])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: CCc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc12
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [F-]
Solvent: CC#N
Product: CCc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Yield: 84.5 %

Procedure:
Tetraethylammonium fluoride (312 mg, 2.18 mmol) was added to a stirred solution of the compound of step (g) (380 mg, 0.55 mmol) in acetonitrile (6 ml) at room temperature under a nitrogen atmosphere. After 12 h the mixture was poured into 1M hydrochloric acid (50 ml) and extracted into ethyl acetate (2×50 ml). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give a yellow foam. Flash column chromatography (eluting with 98% dichloromethane/2% methanol) gave the product as a white solid (242 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([Cl:20])[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([Cl:20])[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)c1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile (from the previous step) (1 eq) in ethanol (0.1 M) was added Platinum Oxide (30 mol %). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 0.5 hour. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give 5-(4-acetylphenethyl)-3-chloropicolinonitrile as an off-white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[I:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1.CCOC(C)=O.[OH-].[Na+]>C1COCC1.O>[I:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: O=C(CN1CCCC1)Nc1ccc(I)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1ccc(NCCN2CCCC2)cc1
Reaction time: 0.33 h

Procedure:
2.25 mL (2.25 mmol) 1 M lithium aluminium hydride solution are added to a solution of 500 mg (1.51 mmol) N-(4-iodo-phenyl)-2-pyrrolidin-1-yl-acetamide in 10 mL THF at 0° C. and the reaction is stirred for 20 min at this temperature. EtOAc is added and then 85 μL water, 85 μL 15% NaOH solution and finally 256 μL water are added. The precipitate is removed by suction filtering and the filtrate is diluted with 50 mL EtOAc. The organic phase is washed with 30 mL saturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH:6]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(Br)C=C.O>C1COCC1>[CH2:3]([C:17]1([C:19]([OH:21])=[O:20])[C:18]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH2:1]
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C(=O)O)c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
42 ml (0.096 mol) of a 2.5M butyl lithium solution are added dropwise at 0° C. under nitrogen to a solution of 10 g (0.048 mol) of 9-fluorenecarboxylic acid in 150 ml of THF and the mixture is stirred for 30 minutes. Then 4.67 ml (0.054 mol) of allyl bromide are added and the solution is stirred for four hours at ambient temperature. The reaction solution is poured into water and extracted with diethyl ether. The aqueous phase is acidified with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulphate and freed from solvent.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=C[C@H]4O)CC2)C)OC1>>[CH3:35][N:33]([CH3:34])[C:32]([O:31][C@@H:15]1[CH:16]=[C:17]2[C@:22]([CH3:23])([C@H:21]3[O:29][C@H:20]3[C@H:19]([OH:30])[CH2:18]2)[C@@H:24]2[C@@H:14]1[C@H:13]1[C@:27]([CH3:28])([CH2:26][CH2:25]2)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]1)=[O:36]
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(=O)N(C)C)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(=O)N(C)C)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 69.5 %

Procedure:
The procedure of Example 36 was repeated except that 2.5 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7α-(N,N-dimethylcarbamoyloxy)-1α,2α-epoxypregn-5-en-3β-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol to give 1.5 mg of 7α-(N,N-dimethylcarbamoyloxy)-1α,2α-epoxy-3β-hydroxypregn-5-ene-20-carbaldehyde (yield: 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH:12]([OH:16])[CH2:13][O:14][CH3:15].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[CH:12]([OH:16])[CH2:13][O:14][CH3:15])=[CH:20][CH:21]=1
Reactant: CCC(c1ccc(Cl)cc1)(C(O)COC)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(c1ccc(Cl)cc1)(C(O)COC)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of the product from Step B (39 mg, 0.108 mmol) and NMM (22 mg, 0.216 mmol) in DCM (8 mL) was added methylsulfonyl chloride (18 mg, 0.163 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by PREP-TLC eluting with PE/EA (1/1, v/v) to get the title compound as a colorless amorphous solid. LC/MS m/z=437.1[M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+].Cl.C[N:37](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([NH2:37])=[O:30])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (300 mg, 0.69 mmol) was combined with ammonium chloride (55 mg, 1.04 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (159 mg, 0.83 mmol), 1-hydroxybenzotriazole (103 mg, 0.76 mmol), and triethylamine (0.38 ml, 2.76 mmol) in 5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 219 mg of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([O-:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 91.8 %

Procedure:
A solution of 5.40 mmol .COPYRGT.f ceftizoxime sodium salt (equivalent to 2 g of ceftizoxime) in 20 ml of water was acidified with 5.40 ml of 1 N acetic acid. The resulting solid was collected and washed with ice water to give 1.90 g of ceftizoxime. A suspension of 1.85 g of ceftizoxime (dried at 80° C./0 1 mm) in 60 ml of methylene chloride was stirred overnight under argon with 2.03 g of N,O-bis(trimethylsilyl) acetamide and 1.73 g of diethyl chlorophosphate, whereupon the solid had dissolved. After a month the reaction mixture was evaporated to dryness and the residue was washed with water. The aqueous washes were extracted with chloroform, back-washing the chloroform extracts with water. Evaporation of the dried (MgSO4) chloroform extracts left 0.049 g of a colorless gum; NMR (CDC13, 80 MHz) δ 1.37 (t, CH3) δ 1.41 (t, CH3), 4.17 (OCH2, NOCH3); IR (KBr) 1032 (P=0), 1787 (β-lactam).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:23]=[C:24]([C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=3)[C:18]=2[N:17]=1>>[Br:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:16]3[NH:17][C:18]4[C:24]([C:25]5[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=5)=[CH:23][C:22]([C:34]([F:37])([F:35])[F:36])=[CH:21][C:19]=4[N:20]=3)[C@@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: C[C@H]1CN(c2ncccc2Br)CCN1
Product: C[C@H]1CN(c2ncccc2Br)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
The piperazine from step (a) above (51 mg, 0.2 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (53 mg, 0.15 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1
Reactant: CCC(C)n1cc(C)c2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCC(C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Added sequentially to a reaction flask were 6-bromo-1-(sec-butyl)-3-methyl-1H-indole-4-carboxylic acid (1.33 g, 4.29 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (1.213 g, 6.43 mmol), 1-hydroxy-7-azabenzotriazole (0.875 g, 6.43 mmol), EDC (1.233 g, 6.43 mmol), followed by DMSO (30 mL, via syringe) and then N-methylmorpholine (1.886 mL, 17.15 mmol, via syringe). The contents were sealed and stirred at room temperature and the solids gradually dissolved. The contents were stirred at room temperature for 32 h, and then slowly diluted into 220 mL of ice-water with stirring. The contents were stirred for 10 min, and then allowed to stand for an additional 10 min. The contents were filtered and the filtered solid was washed with additional water (50 mL). The solid was then air dried for 10 min, and then in a vacuum oven at 50° C. for 23 h total. The product was collected as 1.75 g (87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H), 1.36 (d, J=6.57 Hz, 3H), 1.77 (dq, J=10.29, 7.09 Hz, 2H), 2.12 (d, J=9.09 Hz, 6H), 2.21 (s, 3H), 4.30 (d, J=5.05 Hz, 2H), 4.43-4.56 (m, 1H), 5.86 (s, 1H), 6.99 (d, J=1.52 Hz, 1H), 7.30 (s, 1H), 7.77 (d, J=1.77 Hz, 1H), 8.25 (t, J=4.93 Hz, 1H), 11.49 (br. s., 1H); LCMS=444.1 (MH+).
Reaction SMILES: [C:1]1([CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OC(C(=O)OCc2ccccc2)c2ccccc2)cc1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(C(=O)OCc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g, 15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) and N,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for 7 hours. The reaction was allowed to cool to ambient temperature and the volatile component was removed in vacuo. The residue was partitioned between ethylacetate and water, and the organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel, ethyl acetate) to provide benzyl 2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscous oil (4.56 g). Chiral HPLC analysis (Chiralcel OD-H) indicated that the sample is a mixture of enantiomers in a 38.2 to 58.7 ratio. The separation of the enantiomers were effected as follow: the product was dissolved in 120 mL of ethanol/heptane (1:1) and injected (5 mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20 μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at 220 nm. Enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) were retrieved as viscous oil. 1H NMR (CDCl3, δ=7.26, 500 MHz) 7.44-7.40 (m, 2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08 (d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H). RT=2.10 (Cond. 3); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C20H25N2O2: 325.19; found 325.20.