Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][C:9]([O-:11])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([NH:17][C:9](=[O:11])[CH2:8][C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C([O-])Cc1ncccc1F
Reactant: Cc1c(N)cccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)Cc1ncccc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.6 %

Procedure:
A mixture of sodium 2-(3-fluoropyridin-2-yl)acetate (1.847 g, 10.37 mmol), 3-bromo-2-methylaniline (1.41 mL, 11.4 mmol), DIEA (5.4 mL, 31.1 mmol) and HATU (4.73 g, 12.4 mmol) in DMF (30 mL) was stirred at room temperature for 1.25 h. The mixture was diluted with EtOAc and washed twice with 10% aqueous LiCl, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was dissolved in hot EtOAc, allowed to cool, and the resulting white solid collected by filtration and washed with 60% EtOAc-hexanes. The combined filtrates were concentrated and the residue was recrystallized twice using the same procedure. The residue from concentration of the final filtrate was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide a solid which was combined with the recrystallized batches to provide N-(3-bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide as a white solid (2.03 g, 61% yield). Mass spectrum m/z 323, 325 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(=O)=O.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:21]1([CH2:20][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC3CCCC3)c2)OC1(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), cyclopentylmethyl methanesulfonate (0.10 g, 0.58 mmol), and sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 2 h. After cooling it was diluted with ethyl acetate, washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.11 g of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C@H:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[C:13]([OH:31])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C@H:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)=[C:13]([OH:31])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(NC[C@H]4CCCN4C(=O)OC(C)(C)C)c(O)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(NC[C@H]4CCCN4)c(O)c3)nc12
Reaction time: 3 h

Procedure:
tert-Butyl (2R)-2-([{4-(6-chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-hydroxyphenyl]amino}methyl)pyrrolidine-1-carboxylate (Example 250a) (0.017 g, 0.037 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml). After 3 h, the reaction mixture was evaporated and the residue was purified by HPLC-C18, giving the title product as a bis(trifluoroacetate) (0.012 g, 55%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[NH:14]C(=O)OC(C)(C)C.Cl>O1CCOCC1>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1CO
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(OC(F)(F)F)cc1CO
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of tert-butyl 2-(hydroxymethyl)-4-(trifluoromethoxy)phenylcarbamate (19.3 g, 62.9 mmol) in dioxane (100 mL) was treated with a 4 N solution of HCl in dioxane (126 mL, 504 mmol HCl), and the mixture was stirred overnight. The solution was concentrated in-vacuo, the residue was partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate (200 mL), and the mixture was stirred until gas evolution had ceased. The layers were separated, the organic phase was washed with saturated sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo to yield 12.3 g of a pale yellow oil, which was used as-is in the next step. 1H NMR (400 MHz, DMSO) δ ppm 4.36 (m, 2 H) 5.14 (m, 3 H) 6.64 (d, J=8.79 Hz3, 1 H) 6.92 (dd, J=8.79, 2.64 Hz, 1 H) 7.06 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:16]=O)[C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:21][N:20]=[CH:16][C:7]=3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1
Reactant: NN
Reactant: CC(C)n1c(=O)c(C=O)c(Cl)c2ccc(Br)cc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c2cn[nH]c2c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
As described in Step 1.3., to a solution of 7-bromo-4-chloro-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carbaldehyde (1.0 g, 3.08 mmol) in 30 mL of DMF at 0° C. is added hydrazine hydrate (0.19 mL, 3.70 mmol). After stirring for 8 hours at room temperature, the reaction mixture is poured into water. The orange-coloured precipitate formed is filtered off and washed with water and then dried under vacuum to give 859 mg of an orange-coloured solid (yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](Cl)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C-]#[Si+].[C:17]([O-])([O-])=[O:18].[K+].[K+]>>[CH3:17][O:18][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1OC
Reactant: O=C([O-])[O-]
Agent: [C-]#[Si+]
Agent: [K+]
Product: COc1cc(OC)c([N+](=O)[O-])cc1OC

Procedure:
Into a two liter flask, provided with a cooling device, were introduced successively a solution of methanolic potash (100 g of KOH and 500 cm3 of methanol), then 100 g (0.46 mole) of 4,5-dimethoxy 2-nitro chlorobenzene and carborundum. The mixture was brought to boiling under reflux for 6 h. After cooling, the reaction medium was filtered; the precipitate obtained was washed with methanol.
Reaction SMILES: CNN.[O:4]1[CH2:10][CH:9]([N:11]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][CH2:6][CH2:5]1>C1COCC1>[O:4]1[CH2:10][CH:9]([N:11]([C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[NH2:19])[CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N(C1COCCOC1)N1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(N)C1COCCOC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
Methylhydrazine (0.21 mL) was added dropwise to a solution of t-butyl 1,4-dioxepan-6-yl(1,3-dioxoisoindolin-2-yl)carbamate (710 mg) in THF (7 mL) over 1 minute. The reaction mixture was stirred at room temperature for 3 days and further stirred at 50° C. for 11 hours. After the reaction mixture was returned to room temperature, the insoluble matter was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure. After toluene was added to the residue, precipitated solid was removed by filtration, The filtrate was purified by silica gel column chromatography (ethyl acetate/n-heptane, 15% to 25%) to give the title compound (393 mg).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:32])[CH2:24][C:23](=O)[C:22]2[C:17](=[CH:18][C:19]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:20][CH:21]=2)[O:16]1>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:23]2[C:22]3[C:17](=[CH:18][C:19]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:20][CH:21]=3)[O:16][C:15]([CH3:32])([CH3:14])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Reactant: Fc1ccc([Mg]Br)c2ccccc12
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc(F)c2ccccc12
Yield: 14 %

Procedure:
Reaction of 4-fluoro-1-naphthylmagnesium bromide with an equivalent amount of 2,2-dimethyl-7-(2-dimethylaminoethoxy)-4-chromanone in dry tetrahydrofuran, by an analogous method to that described in Example 1 gave the title compound (14%). The hydrochloride salt had m.p. 224.5°-226° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[C:8]([CH3:14])[CH:9]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(O)ccc1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-cyclohexyl-3-methyl-phenol (65 mg, 0.34 mmol, 1 eq.), 4-(4-Hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.34 mmol, 1 eq.) and PPh3 (134 mg, 0.51 mmol, 1.5 eq.) in dry DCM (3 mL) is added 1,1′-(azodicarbonyl)-dipipperidine (129 mg, 0.51 mmol, 1.5 eq.) in DCM (1 mL). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by silica gel chromatography (10% EtOAc in hexanes) to give 4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=3[F:34])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].NCl>C1COCC1.O.[Zn]>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:19]([NH2:20])=[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=3[F:34])[N:17]=[CH:16][N:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2[N+](=O)[O-])CC1
Agent: NCl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2N)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71.3 %

Procedure:
Mixture of 4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (197 mg, 0.3 mmole), Zn Dust (2.4 mmole, 8 eq) and 1 mL of Sat NH2Cl solution in 2 mL THF and 2 mL H2O was stirred at room temperature for 25 minutes. Zn Dust was filtered off by celite and washed with ethyl acetate. Crude was purified by column chromatography (Hexane/Ethyl Acetate=1/2, Rf=0.44) to give compound A120 as a yellow oil (100 mg, 71%). 1H NMR (DMSO-d6, 400 MHz) δ 1.19 (d, 6H), 1.62-1.68 (m, 2H), 1.88-1.93 (m, 2H), 3.23 (s, 3H), 3.33-3.39 (m, 2H), 3.64-3.70 (m, 2H), 4.77 (sep, 1H), 5.28-5.29 (m, 1H), 7.68 (d, 1H), 7.77 (d, 1H), 7.88 (s, 1H), 8.06 (t, 1H), 8.41 (sb, NH). Exact mass calculated for C20H26FN5O5S 467.2, found 468.5 (MH+).
Reaction SMILES: BrC1C=CC=C2C=1C=CC(S(NC1C=CN=CN=1)(=O)=O)=C2.[CH3:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[CH:26][CH:25]=1.[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[C:48]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52]([S:58](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:60])=[O:59])=[CH:53]2>>[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[C:48]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52]([S:58]([N:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:36][CH:35]=1)[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)(=[O:59])=[O:60])=[CH:53]2
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Agent: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cccc2c1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cccc3c2)cc1

Procedure:
The title compound was prepared in an analogous manner to that of intermediate W, except that N-(4-methoxybenzyl)thiazol-2-amine was used in place of 4-aminopyrimidine and perfluorophenyl 5-(2-chloro-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (intermediate Z) was used instead of perfluorophenyl 5-bromonaphthalene-2-sulfonate. MS (ESI, positive) m/z: 588.9.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17]O)=[CH:12]2)=[O:5].C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:25][CH2:17][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Nc1cccc2cc(CO)cnc12)c1c(Cl)cccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2cc(CBr)cnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethylquinoline (300 mg) in tetrahydrofuran were added carbon tetrabromide (573 mg) and triphenylphosphine (453 mg), and the mixture was stirred for 30 minutes at ambient temperature. Insoluble material was filtered off, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane) to give 3-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline (253.4 mg).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH:3](SC1C=CC=CC=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:41]C(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:41])=[O:5]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)C(Sc3ccccc3)C(=O)OC)cc2)cc1)c1ccccc1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 37.5 %

Procedure:
To a solution of methyl 3-hydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}-2-(phenylsulfanyl)propanoate (0.05 g, 0.09 mmol) in benzene was added AIBN (catalytic amount) and tributyl tin hydride, the resulting mass was refluxed at 80° C. for 4 h. RM quenched with water extracted with ethyl acetate, Organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to yellow oil which was further purified by Preparative TLC using 10% ethyl acetate in chloroform to get the titled compound as yellow oil (0.015 g, Yield: 37.5%) 1H NMR (300 MHz, CDCl3): δ 7.63-7.65 (m, 2H), 7.32-740 (m, 5H), 7.23-7.26 (d, 2H), 6.9-6.93 (m, 4H), 5.37-5.38 (d, 1H), 5.22 (s, 2H), 4.98 (s, 2H), 4.85-4.92 (t, 1H), 3.99 (s, 3H), 3.57 (s, 3H), 3.15-3.17 (d, 1H), 2.57-2.59 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][C:9]=1[F:11])[NH:6][CH2:5][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cc(F)c2c(c1)NCC2
Solvent: CC#N
Product: Fc1cc2c(c(F)c1Br)CCN2
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4,6-difluoroindoline (4.6 g, 29.8 mmol) in acetonitrile (50 mL) was added a solution of N-bromosuccinimide (3.68 g, 20.6 mmol) acetonitrile (30 mL) at 0° C. dropwise. The reaction was stirred for 30 minutes and quenched with saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated and the organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound (4.0 g, 58% yield) as colorless oil
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:37](Cl)(=[O:39])[CH3:38]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][N:29]([C:37](=[O:39])[CH3:38])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCNCc4ccccc4)cc3)cc2)CC1
Reactant: CC(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN(Cc4ccccc4)C(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(2-benzylamino-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and acetyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[C:11]([F:18])([F:17])C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:17][CH:11]([F:18])[O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1cc(F)ccc1Br
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Br)c(OC(F)F)c1

Procedure:
This compound is obtained in the form of an oil (unpurified) by refluxing a mixture of 2-bromo-5-fluorophenol and ethyl bromodifluoroacetate in acetone overnight in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[S:23][C:22]([N:24](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[S:23][C:22]([NH2:24])=[N:21][CH:20]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N)s2)n1
Yield: 93.3 %

Procedure:
A solution of tert-butyl N-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1,3-thiazol-2-yl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.7 g, 2.9 mmol) and TFA (8 mL) in DCM (15 mL) was stirred at RT for 16 hours. The solvent was removed under reduced pressure and the residue made basic with aqueous ammonia solution. The product was extracted with ethyl acetate, the organics dried over sodium sulphate, filtered and evaporated to give the desired material as a white solid (1 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:35].[C:36]([CH2:39][S:40][C:41]1[C:45]([C:46]#[N:47])=[C:44]([SH:48])[S:43][N:42]=1)(=[NH:38])[NH2:37]>CN(C=O)C>[C:36]([CH2:39][S:40][C:41]1[C:45]([C:46]#[N:47])=[C:44]([S:48][CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[C@H:11]([NH:10][C:8](=[O:9])/[C:7](/[C:5]4[N:6]=[C:2]([NH2:1])[S:3][CH:4]=4)=[N:25]\[O:26][CH2:27][C:28]([OH:30])=[O:29])[C:23](=[O:24])[N:13]3[C:14]=2[C:20]([O-:22])=[O:21])[S:43][N:42]=1)(=[NH:37])[NH2:38].[Na+:35]
Reactant: N#Cc1c(SCC(=N)N)nsc1S
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(SCC(=N)N)nsc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: -20 °C
Yield: 50.7 %

Procedure:
To a solution of sodium 7β-[2-(2-aminothiazol-4-yl) -(Z)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (554 mg) and 3-amidinomethylthio-4-cyano-5-mercaptoisothiazole (345 mg) in 7 ml of DMF was added 1.2 g of ethyl o-phenylenephosphate under stirring at -20° C. After stirring under ice-cooling for 2 hours, the reaction mixture was subjected to a column chromatography on silica gel (150 g), being washed with acetonitrile and eluted with acetonitrile/water (6:1). The eluate was concentrated. The resultant precipitate was collected by filtration and dissolved in 40 ml of trifluoroacetic acid under ice-cooling. The mixture was stirred at room temperature for an hour and distilled to remove the solvent. The residue was dissolved in a mixture of water and THF and then adjusted to pH 6 with an aqueous sodium hydrogencarbonate solution. The solution was washed with ethyl acetate, concentrated under reduced pressure and subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and lyophilized to give 363 mg of the title compound as a pale yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][O:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:6]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:5]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([O-])=O.O.NN>CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][O:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:6]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(SOSc2ccc([N+](=O)[O-])c(-c3ccccc3)c2C(=O)OCC)ccc([N+](=O)[O-])c1-c1ccccc1
Agent: NN
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(SOSc2ccc(N)c(-c3ccccc3)c2C(=O)OCC)ccc(N)c1-c1ccccc1
Temperature: 62.5 °C
Reaction time: 0.33 h

Procedure:
To 500 parts of methanol, 115 parts of para-nitrophenyl-o-carbethoxyphenylthio ether, 10 parts of activated carbon and 1 part of ferric chloride hexahydrate were added, and the mixture was stirred at a liquid temperature of 60 to 65° C. for 20 minutes. To this reaction liquid, a mixture of 68 parts of 80% hydrazine monohydrate and 100 parts of methanol were added dropwise over 1 hour while maintaining the liquid temperature at 65° C. or less, and reaction was further carried out at the same temperature for 3 hours. The mother liquid obtained by filtration of the reaction liquid was concentrated and the precipitated solid was washed with water and dried to obtain 95.4 parts of para-aminophenyl-o-carbethoxyphenylthio ether which is the title compound.