Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:23])[C:13](=[O:22])[CH2:14][N:15]2[CH2:20][CH2:19]N(C)[CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].ClCC(N(C1C=CC([N+]([O-])=O)=C(OC)C=1)C)=[O:27].N1CCOCC1.CN1CCNCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:23])[C:13](=[O:22])[CH2:14][N:15]2[CH2:20][CH2:19][O:27][CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N(C)C(=O)CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: COc1cc(N(C)C(=O)CCl)ccc1[N+](=O)[O-]
Agent: CN1CCNCC1
Solvent: C1COCCN1
Product: COc1cc(N(C)C(=O)CN2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
N-(3-Methoxy-4-nitro-phenyl)-N-methyl-2-morpholin-4-yl-acetamide was prepared in an analogous fashion to N-(3-Methoxy-4-nitro-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-acetamide of Example 471a by treating the in situ generated 2-Chloro-N-(3-methoxy-4-nitro-phenyl)-N-methyl-acetamide with morpholine rather than 1-methyl piperazine. After workup the crude product was pumped under high vacuum to remove majority of morpholine, as some carried along in organic phase after extraction. Small residual amounts were separated after subsequent reduction via trituration with Et2O. (1.19 g, 73%). LC/MS (E/I+) 310.11 (M+H).
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH2:20]([O:24][C:25]1[N:26]=[CH:27][C:28]([C:31]([OH:33])=O)=[N:29][CH:30]=1)[C:21]#[C:22][CH3:23].[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([F:51])=[C:39]([C@:41]2([CH3:50])[C:46]([F:48])([F:47])[CH2:45][O:44][C:43]([NH2:49])=[N:42]2)[CH:40]=1.C(OCC)(=O)C>CO.C(OC(C)C)(C)C>[NH2:49][C:43]1[O:44][CH2:45][C:46]([F:47])([F:48])[C@:41]([C:39]2[CH:40]=[C:35]([NH:34][C:31]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH2:20][C:21]#[C:22][CH3:23])=[CH:30][N:29]=3)=[O:33])[CH:36]=[CH:37][C:38]=2[F:51])([CH3:50])[N:42]=1
Reactant: CC#CCOc1cnc(C(=O)O)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CC#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A solution of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM) (74 mg, 0.25 mmol) in methanol (5 ml) was cooled to 0° C. and treated with 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid (CAS[1221447-98-8]) (40.8 mg, 0.21 mmol). The suspension was stirred at 0° C. for 30 minutes, then a solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) (50 mg, 0.19 mmol) in methanol (1 ml) was added dropwise. The resulting yellow solution was stirred at 0° C. for 4 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue treated with a saturated solution of sodium carbonate (10 ml). Extraction with ethyl acetate, combination of the organic layers, drying over sodium sulphate, and evaporation at reduced pressure yielded the crude product. After chromatography on a silica-NH2 phase using ethyl acetate as the eluent, the product was obtained as a yellowish oil which, after trituration in isopropyl ether, yielded the 5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide (52 mg, 63% yield) as a white solid. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.O>[Cl:16][C:11]1[CH:10]=[C:9]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1Cl
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(cycloheptylidene)methyl]-2-chlorophenol (124) (0.32 g, 0.82 mmol), ethyl acrylate (0.90 mL, 8.17 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.08 mmol), triethylamine (0.60 mL, 4.08 mmol) and DMF (10 mL). The stirred reaction mixture was heated overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of water and EtOAc (100 mL). The layers were separated and the organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give reddish brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.23 g (69%) of compound 125 as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=7.1 Hz, 3H), 1.58 (br s, 8H), 2.30 (br s, 4H), 4.25 (q, J=7.1 Hz, 2H), 5.42 (s, 1H), 6.39 (d, J=15.9 Hz, 1H), 6.90-7.00 (m, 2H), 7.10 (d, J=1.8 Hz, 1H), 7.14 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H). LCMS (ESI): m/z, 433 (M+Na)+, 409 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])C#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NO.[OH:13][N:14]=[C:15]([NH2:22])C1C=CC=CC=1>CCO>[OH:13][N:14]=[C:15]([NH2:22])[CH2:10][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=NO)c1ccccc1
Reactant: CC(C#N)c1ccccc1
Agent: NO
Solvent: CCO
Product: NC(CCc1ccccc1)=NO
Yield: 70.5 %

Procedure:
Phenylpropionitrile (1 g, 7.6 mmol) was reacted with hydroxylamine (50% in water, 0.94 cm3, 15.2 mmol, 2 eq) in EtOH (7.6 cm3) in the same manner as in the preparation of N′-hydroxybenzimidamide (EtOAc used in extraction) to give the product N′-hydroxy-3-phenylpropanimidamide (0.88 g, 70.5%) as a white solid, mp 42-43° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:17])[N:6]([CH3:16])[C:7](=[O:15])[NH:8]2.[Cl:18]N1C(=O)CCC1=O>>[Cl:18][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[NH:8][C:7](=[O:15])[N:6]([CH3:16])[C:5]2=[O:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)n(C)c(=O)c2c1OC
Product: COc1cc(Cl)c2[nH]c(=O)n(C)c(=O)c2c1OC
Yield: 67 %

Procedure:
Following the procedure employed in Example 11, treatment of 5,6-dimethoxy-3-methylquinazolin-2,4(1H, 3H)-dione 1/4 hydrate with N-chlorosuccinimide gives the title compound after isopropanol crystallization in 67% yield, mp 224°-227° C.
Reaction SMILES: C([O:9][CH:10]1[CH2:13][N:12]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].Cl>CO.C(Cl)Cl.O1CCOCC1>[OH:9][CH:10]1[CH2:13][N:12]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH2:11]1
Reactant: COC(=O)c1coc(N2CC(OC(=O)c3ccccc3)C2)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1coc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 3-benzoyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (5.24 g, 17.3 mmol) (obtained as described in Reference Example 70(6)) in a mixture of methanol (260 ml) and methylene chloride (80 ml) was added a catalytic amount of sodium methoxide at room temperature and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was neutralized with 4 N hydrogen chloride gas in dioxane and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (95:5) as the eluant to afford 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (2.65 g, yield 77%) as pale brown crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[NH2:13][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1cccc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(F)c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl (3-fluoro-2-nitrophenyl)acetate (4.5 g, 21 mmol) in 100 mL of EtOAc was added 500 mg of Pd/C. The reaction was stirred at room temperature at 1 atm of H2 for 4 hours. Filtered off the catalyst and the filtration was concentrated to get methyl (2-amino-3-fluorophenyl)acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)C=Cc1cccc(O)c1
Product: COC(=O)C=Cc1cccc(O)c1

Procedure:
3-(3-Hydroxy-phenyl)-acrylic acid (2 g, 12.2 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]([NH2:38])=O)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:19]1[CH:18]=[C:17]([S:22]([NH:25][C:26]2[C:27]3[C:32](=[C:31]([C:36]#[N:38])[CH:30]=[CH:29][CH:28]=3)[CH:33]=[CH:34][CH:35]=2)(=[O:24])=[O:23])[CH:16]=[C:15]([Cl:14])[CH:20]=1
Reactant: NC(=O)c1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.49 ml trifluoroacetic anhydride are added dropwise to a mixture of 1.13 g 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid amide and 1.07 ml triethylamine in 50 ml methylene chloride while cooling with an ice bath. Then the ice bath is removed and the reaction mixture is stirred for one hour at ambient temperature. In all, another 1.00 ml triethylamine and 0.70 ml trifluoroacetic anhydride are added successively and the reaction mixture is stirred overnight at ambient temperature. For working up the mixture is combined with 50 ml of water. The organic phase is washed with 2 N citric acid solution and saturated sodium hydrogen carbonate solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (85:15 to 65:35).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:16][OH:17].[OH-].[K+].O>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][C:11]([CH3:13])([CH3:12])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)=CC(=O)c1ccc(C)c(Br)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=NOC(C)(C)C2)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(3-bromo-4-methylphenyl)-3-methylbut-2-en-1-one, (prepared herein before in step 2 of intermediate 1; 1.0 g, 3.95 mmol, 1.0 eq), and hydroxylamine hydrochloride (330 mg, 4.74 mmol, 1.2 eq) in ethanol (10 mL) at 0° C., was added an aqueous solution of potassium hydroxide (1N, 4 mL) until the pH of the reaction was basic. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (20 mL) followed by water (20 mL). The layers were separated and the organic layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc in hexane) to afford 250 mg of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.08 (s, 2H), 2.43 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 268, 270 [(MH)+, Br79,81].
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([NH:36][S:37]([C:40]2[C:41]3[N:42]=[CH:43][CH:44]=[N:45][C:46]=3[CH:47]=[CH:48][CH:49]=2)(=[O:39])=[O:38])[CH:27]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:35][C:34]1[C:26]([Cl:25])=[CH:27][C:28]([NH:36][S:37]([C:40]2[C:41]3[N:42]=[CH:43][CH:44]=[N:45][C:46]=3[CH:47]=[CH:48][CH:49]=2)(=[O:38])=[O:39])=[C:29]([C:30]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:32])[CH:33]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCOCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (EXAMPLE 5, Step D) and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C19H16Cl2N4O4S, 466.0; m/z found, 465/467 [M−H]−. HPLC (reverse phase): RT=8.84 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.06 (d, J=1.8 Hz, 1H), 9.03 (d, J=1.8 Hz, 1H), 8.51 (dd, J=7.0, 1.5 Hz, 1H), 8.38 (dd, J=8.4, 1.4 Hz, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.70 (s, 1H), 7.14 (s, 1H), 4.35-4.10 (br m, 4H), 3.65-3.48 (br m, 4H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21](Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(Cl)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCC1CCNCC1

Procedure:
In 200 ml of ethanol is dissolved 10 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 5 g of 10% palladium-carbon (50% in water) as a catalyst. After absorption of hydrogen stops, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give ethyl 6-(4-piperidyl)hexanoate. Water (100 ml) and 200 ml of ethyl acetate are added to this product, and 10 g of sodium hydrogencarbonate is added to the mixture, followed by stirring. Benzyloxycarbonyl chloride (7.2 ml) is added dropwise to the mixture at room temperature, followed by stirring overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica-gel column chromatography (hexane:ethyl acetate=4:1) to give 7.7 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate as a colorless oily material.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=[C:11]([C:22](O)=[O:23])[CH:10]=1.Cl.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@H:33]([NH2:35])[CH3:34])[CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=[C:11]([C:22]([NH:35][C@H:33]([CH3:34])[CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:23])[CH:10]=1
Reactant: C[C@@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cccc(F)c3F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cccc(F)c3F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′,3′-difluoro-5-(5-methylpyridin-2-yl)biphenyl-3-carboxylic acid (30 mg, 0.092 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (20 mg, 0.11 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (88 mg, 0.23 mmol), N,N-diisopropylethylamine (64 μL, 0.37 mmol), N,N-dimethylformamide (0.5 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to afford the title compound as a light orange solid.
Reaction SMILES: O=S(Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Neat SOCl2 (25.7 g, 216.7 mmol) was added dropwise to a −60° C. solution of MeOH (100 mL). Upon completion of the addition, 3-(4-chlorophenyl)propanoic acid (10.0 g, 54.1 mmol) was added in several portions. Upon completion of the addition, the cooling bath was removed, and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was then concentrated to dryness, and the resulting residue was dissolved in DCM (100 mL), washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated to give methyl 3-(4-chlorophenyl)propanoate as an oil (10.48 g, 97%).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.CN(C)C=O.[SH:37][C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1>ClCCl.C(N(CC)CC)C.O>[CH2:1]([S:37][C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1)[CH:2]=[CH2:3]
Reactant: Sc1cnccn1
Reactant: C=CCO
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCSc1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
0.58 g of allyl alcohol was dissolved in 50 ml of dichloromethan and 2.89 g of triphenylphosphine and 1.96 g of N-bromosuccinimide were added thereto. The mixture was stirred at room temperature for 30 minutes, and 5 ml of dimethylformamide solution in which 1.0 g of 2-mercaptopyrazine and 1 ml of triethylamine were dissolved was added to the above solution. The resulting mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. The organic layer was separated and concentrated to dryness. The residues were purified by silica gel chromatography using ethyl acetate:n-hexane=1:1 as an eluate to give 0.6 g of titled compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2nc(N3CCOCC3)sc2c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 2-chloro-6-methoxy-benzothiazole (9.96 g, 0.05 mol), morpholine (10.86 mL, 0.12 mol) and triethylamine (13.9 mL, 0.10 mol) in ethanol (75 mL) was refluxed for twenty-one hours before it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichoromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a light yellow solid (12.23 g): MS: (+) m/z 251 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 26a (11.44 g, 37.48 mmol) is suspended in ethanol (400 mL) and ammonium formate (11.80 g, 187.0 mmol) and 20% Pd(OH)2/C (10.00 g, 18.79 mmol) are added. The reaction mixture is stirred at 95° C. under N2 for 30 minutes. The reaction mixture is cooled to room temperature and then filtered through celite, rinsing with ethanol. The filtrate is concentrated under reduced pressure to give 9.63 g (93%) of the pure desired product as a purple/red solid. MS ESI (+) m/z 276 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11](OC)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:11][OH:12])[CH2:9][CH2:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)C1(c2cncc(Br)c2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(c2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 71 Step B (200 mg, 0.78 mmol) in tetrahydrofuran (3.9 mL) at 0° C. was added a solution of diisobutyl aluminum hydride in hexanes (1.0 M, 1.56 mL, 1.56 mmol). The reaction was warmed to room temperature and stirred overnight. Water and magnesium sulfate were then added, and the resulting suspension was stirred for 30 minutes, then filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (20-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 229.67 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 2H), 7.83 (s, 1H), 3.69 (s, 2H), 0.96-0.90 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7].[Cl:29][CH2:30][C:31](Cl)=[O:32].[OH-].[Na+].S(=O)(=O)(O)O>B([O-])([O-])[O-].[Na+].[Na+].[Na+].C(OCC)(=O)C.C(O)C>[Cl:29][CH2:30][C:31]([NH:1][CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7])=[O:32]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(N)C(=O)O)[C@H]2SC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(NC(=O)CCl)C(=O)O)[C@H]2SC1

Procedure:
Five hundred milligrams of 7-(5-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 milliliters of sodium borate buffer and 650 milligrams of chloroacetyl chloride was added at ~20° C., keeping the pH of 9.0-9.5 by addition of 40 percent sodium hydroxide solution. After addition of the chloroacetyl chloride was complete, the reaction mixture was stirred for thirty minutes. The pH was adjusted to about 6.5 by addition of 30 percent sulfuric acid; then 10 milliliters of ethyl acetate:ethanol (9:1) was added, and the pH adjusted to 2.0. The organic layer was separated, dried over anhydrous magnesium sulfate, and ether was added, resulting in the precipitation of the desired 7-(5-(chloroacetamido)-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. It was separated as a white powder, 195 milligrams, and characterized: titration (in 66 percent dimethylformamide): initial pH 3.9 pKa's at 4.8 and 6.1. Amino acid analysis: 0.12 μM./mg. of glycine and 1.9 μM./mg. of α-aminoadipic acid. NMR in dimethylsulfoxide-d6 showed bands at 6.36, 6.58 (2-CH2, q, J = 18); 5.08, 5.35 (3-CH2, q, J = 13); 4.89 (H-6, d, J= 5.0); 4.34 (H-7, q, J = 5.0, 8.0); 3.41 (CONH2, s); 5.87 (COCH2Cl, s); 1.17 τ (7-NH, d, J = 8.0 Hz).