Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:20]1([C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23])[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:14]1([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:21][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[OH:23])=[CH:4][CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccc(OCCCCc2ccccc2)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccccc1OCc1ccc(OCCCCc2ccccc2)cc1
Yield: 48.5 %

Procedure:
In 1.5 ml of N,N-dimethylformamide were stirred 390 mg of 4-chloromethyl-1-(4-phenylbutoxy)benzene, 180 mg of catechol and 270 mg of potassium carbonate at room temperature overnight. The reaction mixture was dispersed in water and ethyl acetate and the dispersion was separated. The ethyl acetate layer washed subsequently with water and an aqueous saline solution, dried and concentrated. The obtained residue was applied to silica gel column chromatography and eluted with toluene to obtain 240 mg of o-[p-(4-phenylbutoxy)benzyloxy]phenol.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].[CH2:27]1[C:35]2[C:30](=[CH:31][C:32](B(O)O)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[CH2:27]1[C:35]2[C:30](=[CH:31][C:32]([C:2]3[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=3)[C:7]([NH:9][CH2:10][C:11]3[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=3)=[O:8])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: OB(O)c1ccc2c(c1)CCC2
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc3c(c2)CCC3)c1

Procedure:
The title compound was synthesized in analogy to Example 83 using 5-bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (example BP) and B-(2,3-dihydro-1H-inden-5-yl)-boronic acid (CAN 196861-31-1) as starting materials; LC-MS (UV peak area/ESI) 100%, 485.1016 (M−H)−.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([Cl:16])[CH:18]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Nc1ccc(Cc2ccccc2)cc1-c1ccc(F)c(Cl)c1

Procedure:
4-benzyl-2-bromo-aniline and 3-chloro-4-fluorobenzene boronic acid were combined to form 4-benzyl-2-(3-chloro-4-fluorophenyl)-aniline,
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][CH2:5][C:6]([OH:10])([C:8]#[CH:9])[CH3:7].[OH-].[Na+].[CH:14]([Cl:17])(Cl)[Cl:15]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:15][C:14]1([Cl:17])[C:2]([CH3:1])([CH3:11])[CH:3]1[CH2:4][CH2:5][C:6]([CH3:7])([OH:10])[C:8]#[CH:9]
Reactant: C#CC(C)(O)CCC=C(C)C
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C#CC(C)(O)CCC1C(C)(C)C1(Cl)Cl
Reaction time: 21 h
Yield: 97 %

Procedure:
Dehydrolinalool (400 g, 2.6 mol) and 5.26 g of triethylbenzylammonium chloride are added to a reaction flask. Chloroform (469.6 g, 3.9 mol) is added dropwise. To this solution 223.2 g (2.79 mol) of 50% sodium hydroxide solution are added dropwise within 50 minutes while cooling with ice, whereby the temperature of the reaction mixture rises to 34°. In time the initially viscous mass becomes fluid. After 21 hours of stirring and then again after 37 hours, there are added in each case within 20 minutes while cooling with ice, 160 ml of chloroform, 2.63 g of triethylbenzylammonium chloride and 111.6 g of 50% NaOH. The mixture is stirred at room temperature for a further 60 hours, poured onto ice-water, extracted with methylene chloride, washed neutral, dried over magnesium sulphate and evaporated. In this manner there are obtained 603.7 g (97%) of 5-(2',2'-dichloro-3'3'-dimethylcyclopropyl)-3-methyl-1-pentyn-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=O)[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16][O:17][CH2:18][F:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O1CCCC1.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[S:40])[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16][O:17][CH2:18][F:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCNC(=S)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Yield: 56.2 %

Procedure:
A mixture of 380 mg (0.920 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 420 mg (1.01 mmol) of Lawesson's Reagent and 5 ml of anhydrous tetrahydrofuran was refluxed by heating for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was washed with aqueous sodium hydroxide solution, aqueous ammonium chloride solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=3:1) to give 222 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylthioamide (the present compound 1160).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[C:21]1[S:25][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[N:28]=2)=[C:23]([C:35]([NH2:37])=[O:36])[CH:22]=1>>[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:14]=[CH:13][C:12]=1[C:21]1[S:25][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH:1][CH2:2][CH:3]3[CH2:4][CH2:5][C:6](=[O:9])[N:7]3[CH3:8])[N:28]=2)=[C:23]([C:35]([NH2:37])=[O:36])[CH:22]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Reactant: CN1C(=O)CCC1CN
Product: CN1C(=O)CCC1CNCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 106, Step 2 using the oxalate salt of 5-(aminomethyl)-1-methylpyrrolidin-2-one (21 mg, 0.096 mmol) and 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-formylpyridin-2-yl)amino]thiophene-3-carboxamide (39 mg, 0.096 mmol) as starting materials.
Reaction SMILES: NCC[N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.N1C=CC=CC=1.BrCCC(Cl)=O>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: O=C(Cl)CCBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
To a chilled solution (0° C.) of 4-[(2-amino)ethyl]-1-(2-methoxyphenyl)piperazine (10.46 mmol) in 40 mL of dichloromethane were added pyridine (12.55 mmol) and a solution of 3-bromopropionyl chloride (11.51 mmol) in 10 mL of dichloromethane. After addition, the reaction mixture was warmed to room temperature, and stirred for 1 hour. The reaction mixture was quenched with saturated sodium carbonate, extracted with dichloromethane. The organic phase was washed with brine, water, and dried over magnesium sulfate Filtration and evaporation of the solvents gave a residue that was purified by flash chromatography using 3-5% of methanol and 0.5% of ammonium hydroxide in ethyl acetate to give 4-[2-(3′-bromo)propionamido)ethyl]-1-(2-methoxyphenyl)piperazine (2.16 g, 56%).
Reaction SMILES: [Br:1]Br.[C:3]1([CH3:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1>[Fe]>[Br:1][C:7]1[CH:8]=[C:3]([CH3:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: BrBr
Agent: [Fe]
Product: Cc1cc(Br)ccc1C(=O)O
Reaction time: 2 h

Procedure:
Chill a mixture of 140 gm. (0.875 mole) of bromine and 2.45 gm. of iron powder in an ice-bath and add portionwise during 15 minutes 93.31 gm. (0.7 mole) of o-toluic acid. Remove the reaction flask from the ice-bath and stir for 2 hours. Allow the resulting mushy solid to stand at room temperature overnight. Flush the reaction mixture with nitrogen. Finely grind the resulting solid cake, wash with water, aqueous sodium thiosulfate solution, water and dry to obtain the title compound together with the 3-bromo isomer (yield 144.7 gm., m.p. 112°-148° C.). The product is employed in the next step without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=3[O:24]C)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.C(Cl)Cl.O>B(Br)(Br)Br>[OH:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)(=[O:14])=[O:13]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(O)c1
Temperature: 25 °C

Procedure:
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-methoxy-4-nitro-benzenesulfonamide (200 mg, 0.55 mmol) was dissolved in 1 M BBr3 in CH2Cl2 (5.0 mL, 5.0 mmol) and the resulting soln was stirred at rt O/N. H2O was the resulting precipitate was isolated by filtration to give the title compound as a white solid: yield; 160 mg (83%). mp 198-199° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.98 (s, 1H), 10.22 (s, 1H), 9.18 (s, 1H), 7.89-7.87 (m, 1H), 7.67-7.63 (m, 2H), 7.48 (s, 1H), 7.23-7.18 (m, 2H), 4.84 (s, 2H); MS (ESI) m/z=349 (M−1, negative); HPLC purity: 95.49% (MaxPlot 200-400 nm), 95.48% (220 nm).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][CH3:13])[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[CH2:12]([C:9]1[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:19])[N:5]2[C:10]=1[CH:11]=[C:2]([N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[CH:3]=[CH:4]2)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)c2cc(Cl)ccn2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CC)c2cc(N3CCN(C)CC3)ccn2c1=O
Temperature: 85 °C
Yield: 99.9 %

Procedure:
Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (279 mg, 1.0 mmol), the product of Step 3 of Example 62, was dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture was heated at 85° C. for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated in vacuo in order to remove all of the pyridine. The residue was dissolved in 50 mL of methylene chloride and the methylene chloride solution was washed with 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3×50 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 343 mg of the title compound, m.p. 94°-96° C.; MS DCI-NH3 : 344 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH2:11][N:12]1[C:24]2[CH:23]=[CH:22][C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=2)=O.O.O1CCCC1.[OH-].[Na+]>O1CCCC1>[OH:8][CH2:9][CH2:11][N:12]1[C:24]2[CH:23]=[CH:22][C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=2
Reactant: CCCCCCc1ccc2c(c1)c1cc(CCCCCC)ccc1n2CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1ccc2c(c1)c1cc(CCCCCC)ccc1n2CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension, cooled to 0° C., of 0.88 g (22.4 mmol) of 97% lithium aluminum hydride in 30 ml of tetrahydrofuran (THF) was added dropwise, under argon, a solution of 8.00 g (19.6 mmol) of N-methoxycarbonylmethyl-3,6-di-n-hexylcarbazole in 30 ml of THF within 15 min, in the course of which the temperature was kept at 0-5° C. The reaction mixture was allowed to warm to room temperature and stirred for a further 30 min. After the dropwise addition of 20 ml water/THF, the solution was stirred at room temperature for 15 min and then admixed with 2 ml of 10% NaOH, which precipitated a solid which was filtered off. The filtrate was admixed with 200 ml of diethyl ether/water (1:1). The aqueous phase was removed and extracted by shaking twice with 100 ml each time of diethyl ether. The combined organic phases were twice washed to neutrality with 100 ml of water each time and with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. 7.5 g (100% of theory) of colorless solid were obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:1][C:2]1[C:3]([C:8]([O:10][CH2:8][CH2:3][CH2:2][CH2:7][CH2:6][CH3:5])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)c1ncccc1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)c1ncccc1OCCCCCC
Temperature: 100 °C
Yield: 40.5 %

Procedure:
To a mixture of 2.80 g (20 mmol) of 3-hydroxypicolinic acid, 4.13 g (25 mmol) of n-hexyl bromide and 30 ml of N,N,-dimethylformamide was added 2.8 g (0.02 mmol) of anhydrous potassium carbonate, and the mixture was stirred under heating at 100° C. for 4.5 hours. After cooling, 60 ml of ice-water was added, and the mixture extracted with ethyl acetate. The solution was subjected to evaporation under a reduced pressure and the residue separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to obtain 2.60 g of a colorless oily substance (yield 40.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)csc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(O)cc2)csc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To compound 47B (1.1 g, 3.59 mmol) in DCM (80 mL) was added 1.0 M BBr3 (36 mL, 36 mmol) in DCM at rt. A precipitate formed upon addition and gradually disappeared after stirring at rt for 2 hours. The solvent was removed, and the residue was partitioned between water and EtOAc. The organic layer was isolated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 3:2/hexanes:EtOAc to provide 0.65 g of the desired product 47C: 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 7.35 (d, J=8.73 Hz, 2H), 7.15 (s, 2H), 6.80 (d, J=8.73 Hz, 2H), 6.34 (s, 1H); MS (ESI(+)): m/z 217 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]([C:20](=[CH:26]OCC)[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>C(O)C>[NH2:19][C:18]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:10]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a stirred suspension of 4-fluorophenylhydrazine hydrochloride (9.76 g, 60 mmol) in ethanol (250 ml) was added triethylamine (9.2 ml, 62 mmol) and to the resulting amber solution was added ethyl 2-cyano-3-ethoxyacrylate (10.15 g, 60 mmol). The solution was heated at reflux temperature for 3.5 hours. The solution was allowed to cool to room temperature and after standing overnight the resultant solid was filtered off, washed with small amount of ethanol and then ether before being dried under vacuum to give the title compound (12.1 g) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12](Br)=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.B(O)(O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2c1sc1cc(Br)ccc12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(N)c2c1sc1cc(-c3cccc(C(F)(F)F)c3)ccc12
Temperature: 120 °C

Procedure:
A mixture of 1-amino7-bromo[1]benzothieno[3,2-c]pyridine-4-carboxamide (Example 12, Step 10), 3-trifluoromethylboronic acid (1.5 equiv), PdCl2dppf (0.1 equiv), Na2CO3 1 M (3.0 equiv) in DMF (0.15 M) was heated in the microwave reactor at 120° C. for 10 min. The reaction mixture was partitioned between EtOAc and H2O with the addition of DMSO. The organic phase was separated, dried over Na2SO4, filtered, evaporated and purified by flash chromatography (10% MeOH in CH2Cl2) to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH3:8])=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[O:19][CH3:20])[CH:3]=1>CO>[CH3:20][O:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[C:4]1[CH:3]=[CH:2][N:7]=[N:6][C:5]=1[CH3:8]
Reactant: COc1ccc(C(F)(F)F)cc1-c1cc(Cl)nnc1C
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1-c1ccnnc1C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
6-Chloro-4-[2-methoxy-5-(trifluoromethyl)phenyl]-3-methylpyridazine (Preparation 42, 800 mg, 2.6 mmol) was dissolved in methanol (32 mL), the solution was degassed with argon for 15 minutes then palladium on charcoal (160 mg) was added and placed under a balloon of hydrogen gas for 4 hours. The reaction mixture was filtered through diatomaceous earth, washed with methanol (20 mL) and the combined filtrate concentrated in vacuo to afford the title compound as a solid (700 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=1.C1COCC1.CO>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1OC
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline (0.46 g, 1.41 mmol, 1.0 eq.), and THF (10 mL), MeOH (4 mL), DMF (2 mL), and TEA (2 mL). The 6,7-Dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline was dissolved completely in the above solution mixture, and was flushed with nitrogen for at least 5 minutes. The Pd/C (10% by weight) (0.090 g, 20% by weight) was then added. A balloon filled with H2 was connected to the flask after the nitrogen was vacuumed out. The reaction mixture was stirred at room temperature for 4 hours. The palladium was filtered out through Celite, and the filtrated was collected and concentrated via rotary evaporation. The resulting oil-like product was taken up into 5 mL of water and 1 mL of acetonitrile and lyophilized to yield 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine as a light brown solid (0.411 g, 98.1%). 1H NMR (400 MHz, CDCl3): 8.54 (d, 1H), 7.85 (d, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.18 (dd, 1H), 6.96 (d, 1H), 6.61 (d; 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.73 (s, 2H); MS (EI) for C16H15N3O3: 298 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][C:11]3=O)[C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][C:11]3=[S:31])[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Solvent: Cc1ccccc1
Product: S=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Temperature: 160 °C

Procedure:
A suspension of 172 mg (0.55 mmol) of 3-(5-chloro-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-one and 110 mg (0.27 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide in 20 mL of toluene is heated at 160° C. for 90 min under microwave condition. The resulting mixture is concentrated in vacuo and the residue is purified by flash chromatography to give the desired compound.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[OH-].[Na+:28]>O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[Na+:28]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.8 g.) in water (48 ml.) was added dropwise 1 N aqueous sodium hydroxide solution at the rate that the pH value of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as sodium 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (4.8 g.), mp>250° C. This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3° to 5° C., and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (1.44 g.), mp 165° to 170° C. (dec.).