Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:29]([Cl:40])[CH:28]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:19]=[CH:18]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:55]=1[N:61]=[C:62]=[O:63]>O.O1CCCC1>[ClH:40].[Cl:40][C:29]1[CH:28]=[C:27]([NH:26][C:24]2[C:25]3[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11])[CH:18]=[CH:19][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]1[CH2:35][CH2:36][N:37]([C:62]([NH:61][C:55]2[C:56]([F:60])=[CH:57][CH:58]=[CH:59][C:54]=2[F:53])=[O:63])[CH2:38][CH2:39]1
Reactant: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(Cl)c3)c21)c1ccccc1
Reactant: O=C=Nc1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1c(F)cccc1F)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.4 %

Procedure:
To a mixture of 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was added 2,6-difluorophenyl isocyanate (93 mg) with vigorous stirring. The mixture was stirred at room temperature for 2 hrs, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:85). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (202 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pt].CO.C1COCC1>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:3][C:2]=1[Cl:1]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 95 %

Procedure:
A solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.500 g, 0.870 mmol) in 3:1 MeOH/THF (30 mL) was subjected to hydrogenation at 45 psi in the presence of 5% sulfided platinum on carbon (50 mg). After 18 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite and the filtrate concentrated to dryness at reduced pressure. The residue was recrystallized from hexane/EtOAc to afford the title compound (0.45 g, 95%) as an off-white solid. LCMS (m/z, ES+)=544 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CC(=O)O
Product: O=C(O)c1cccnc1Nc1cc(Cl)cc(Cl)c1
Yield: 97.9 %

Procedure:
2-Chloronicotinic acid (10 g) was combined with 3,5-dichloroaniline (15 g) in 150 mL acetic acid and heated at reflux for 4 hr. Upon cooling, a white solid formed which was collected by filtration, washed with acetic acid, water, and dried to give 17.6 g of 2-(3,5-dichlorophenylamino)nicotinic acid.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:4]([Cl:26])[CH:3]=1.[N-:27]=[N+]=[N-].[Na+].CNCCNC.CS(C)=O>O>[NH2:27][C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:4]([Cl:26])[CH:3]=1
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Reactant: [N-]=[N+]=[N-]
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 110 °C
Yield: 53.7 %

Procedure:
N-[3-(4-Bromo-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.5 g, 1.1 mmol) was taken in a reaction vial, followed by addition of sodium azide (0.286 g, 4.4 mmol), cuprous iodide (0.063 g, 0.3 mmol), N,N′-dimethylethane-1,2-diamine (0.058 g, 0.6 mmol) and dimethylsulfoxide (12 mL). The vial was sealed properly and heated at 110° C. for overnight. The reaction mixture was cooled to room temperature and water (100 mL) was added, extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) column chromatography using 2% methanol in dichloromethane to afford pure N-[3-(4-amino-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.23 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O.[C:27]([OH:30])(=O)[CH3:28]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])/[CH:5]=[CH:15]/[S:16]([CH2:19][S:20](/[CH:23]=[CH:24]/[C:4]1[CH:3]=[CH:2][C:9]([O:10][CH3:11])=[C:27]([OH:30])[CH:28]=1)(=[O:21])=[O:22])(=[O:17])=[O:18]
Reactant: COc1ccc(C=O)cc1N
Reactant: CC(=O)O
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Product: COc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(OC)c(O)c2)cc1N
Yield: 62 %

Procedure:
A solution of 3-amino-4-methoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 148-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[S:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]4[S:27][CH:28]=[C:24]([CH3:23])[CH:25]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K2CO3 (162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh3)4 (22 mg, 0.019 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(4-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.78 (d, 1H), 7.6 (m, 2H), 7.3-7.38 (m, 3H), 7.17 (d, 1H), 7.02 (d, 1H), 7.0 (s, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (s, 4H), 3.1 (m, 1H), 2.41 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[S:8][C:9](Cl)=[C:10]([Cl:13])[C:11]=1[Cl:12].C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:18]([C:9]1[S:8][C:7]([Cl:6])=[C:11]([Cl:12])[C:10]=1[Cl:13])=[O:17]
Reactant: Clc1sc(Cl)c(Cl)c1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1sc(Cl)c(Cl)c1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Add a solution of n-BuLi (21.6 mL, 2.5 M in hexane, 54.0 mmol) to a solution of 2,3,4,5-tetrachloro-thiophene (10 g, 45.0 mmol) in dry THF (160 mL) at −78° C. and stir the mixture for 2 hours. Add a solution of trifluoro-acetic acid ethyl ester (9.59 g, 67.6 mmol) in THF (15 mL) and stir at −78° C. for additional 2.5 hours. Quench the reaction with saturated NH4Cl solution (100 mL). Extract the aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and evaporate under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (10:1 to 5:1) to afford 2,2,2-trifluoro-1-(3,4,5-trichloro-thiophen-2-yl)-ethanone as a brown oil (10.4 g, 81.9%). 13F NMR (400 MHz, CDCl3) δ −73.38 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1>[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][C:11]=1[C:26]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)=[O:27]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Cc1cccc(N)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)n1
Yield: 81 %

Procedure:
A solution of 5.49 g of 2-amino-6-methylpyridine and 10 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 500 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. The solution was filtered and evaporated. The residue was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent) to afford 9.8 g of 1,2-dihydro-4-hydroxy-N-(6-methyl-2-pyridyl)-1-phenyl-3-quinolinecarboxamide which was dissolved in chloroform, treated with 35 g of activated manganese dioxide and stirred for three hours at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.C(N(CC)CC)C.C1(CC(Cl)=O)CC1.[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:30]([CH:29]2[CH2:27][CH2:28]2)=[O:26])[CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: O=C(Cl)CC1CC1
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)C2CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
An ice-cooled mixture of 4-methyl-5-nitropyridin-2-amine (1 g, 6.5 mmol), triethylamine (1.31 g, 13 mmol) in tetrahydrofuran (20 mL) was treated with cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) drop wise. After complete addition the reaction mixture was stirred at room temperature for 1 hour, cooled to 0° C. and added cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) followed by stirring at room temperature for 1 hour. The solvent was evaporated under vacuum and water (100 mL) was poured into the reaction mixture and extracted with ethyl acetate (2×150 mL). The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue (1.5 g) was taken-up in methanol and water (4:1, 40 mL). Potassium carbonate was added to it and stirred at room temperature for 20 hours. The mixture was concentrated under vacuum. Residue was taken up in water (100 mL) and extracted with ethyl acetate (2×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude compound, which upon purification by silica gel column chromatography using methanol in dichloromethane (1%) as eluent afforded N-(4-methyl-5-nitropyridin-2-yl)cyclopropanecarboxamide (0.6 g, 52%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[CH:12]=[CH:11][N:10]=1.O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[OH:16][CH2:15][C:14]1[C:9]([CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[N:10][CH:11]=[CH:12][C:13]=1[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccnc(CN)c1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccnc(CNC(=O)C(C)C)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isobutyryl chloride (29 μL, 0.276 mmol) in DCM (0.20 mL) was added to a vigorously stirred mixture of (2-aminomethyl-4-methyl-pyridin-3-yl)-methanol (30 mg, 0.20 mmol) in DCM (1.0 mL) and aqueous Na2CO3 (1 M, 1 mL) at 0° C. After stirring for 30 min at 0° C., DCM (10 mL) and water (1 mL) was added, and the aqueous layer was extracted with DCM (1×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with MeOH/DCM 1:20) to give the title compound. MS (m/z): 223.0 [M+H+].
Reaction SMILES: C[O:2]C1C=CC(C(O)=O)=CC=1[N+]([O-])=O.ON1C(=O)CCC1=O.[CH:23]1([N:29]=[C:30]=[N:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:32]1([NH:31][C:30]([NH:29][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:2])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1.97 g (10 mmoles) of 4-methoxy-3-nitrobenzoic acid was dissolved in 50 ml of acetonitrile. 1.15 g (10 mmoles) N-hydroxysuccinimide was added with agitation. Finally 2.063 g (10 mmoles) of N,N′-dicyclohexylcarbodiimide were added and the mixture agitated. After 2 hours at approx. 20° C. a precipitate of dicyclohexyl-urea had formed. The solution was filtered through a Gooch 3G funnel. The formation of ester was determined by t.l.c. of the filtrate (CHCl3/MeOH=9:1, v/v). Observation under U.V. revealed the ester as a dark spot of Rf approx. 0.9. After evaporation of the acetonitrile a whitish-yellow powder remained in the flask. The powder was redissolved in 50 ml of hot isopropanol. Approximately 2 spatula-tips activated charcoal were added and the solution was boiled in a boiling water-bath for about 5 minutes. The boiling solution was quickly poured through a sintered glass filter (G4, previously heated by a passage of hot isopropanol) into a hot flask. The solution was allowed to cool down overnight. White, needle-like crystals were formed (m.p. approx. 145-152° C.) having the expected t.l.c. properties.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:24]=[CH:25][C:18]=12>C1COCC1.C(OCC)(=O)C>[Cl:32][C:31]1[C:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]3[CH:25]=[N:24]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
Sodium hydride (62.4 mg, 1.56 mmol) was to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (200 mg, 1.04 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (360 mg, 1.35 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (245 mg, 55.8%). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, 3H), 3.33-3.48 (m, 5H), 3.74-3.82 (m, 4H), 4.13-4.18 (m, 2H), 5.81-5.86 (m, 1H), 7.43-7.48 (m, 1H), 7.98-8.02 (m, 1H), 8.39-8.41 (m, 1H), 8.58 (s, 1H), 8.60-8.63 (m, 1H); m/z (ESI+) (M+H)+=422.36; HPLC tR=1.93 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=S)[NH:3]1.CI.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.[Na].[N:20](=[C:22]([C:28]#[N:29])[C:23](OCC)=[O:24])[OH:21]>CCO>[NH2:29][C:28]1[N:16]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:4]2[N:5]([CH2:6][CH:2]([CH3:1])[N:3]=2)[C:23](=[O:24])[C:22]=1[N:20]=[O:21]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CC1CNC(=S)N1
Agent: [Na]
Solvent: CCO
Solvent: CI
Product: CC1CN2C(=O)C(N=O)=C(N)N(Cc3ccc(Cl)cc3)C2=N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 4-methylimidazoline-2-thione (45.0 g., 0.387 mole; purified by water recrystallization) in ethanol (200 ml., dried over 4A molecular sieve), methyl iodide (54.9 g., 0.387 mole) was added dropwise. The reaction was stirred at room temperature for 4 hr. during which time the solid dissolved. To this solution 4-chlorobenzylamine (54.8 g., 0.387 mole) was added and the solution was heated at reflux for 16 hrs. This solution was added while hot to a solution of sodium (35.6 g., 1.55 gram atom) in ethanol (900 ml., dried over 4A molecular sieve), and ethyl oximinocyanoacetate (5.50 g., 0.387 mole) was added in portions. The mixture was refluxed for 3 hrs. and concentrated in vacuo. Water (600 ml.) was added to the residue and the solution neutralized with HOAc. The orange precipitate was collected, washed with CH3CN and Et2O to give 95.6 g. (77%) orange solid, m.p. 222°-223° (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19]CCI)=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].C(O)(=O)C.CN(C)C=O>C(OCC)(=O)C.[Zn]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])[C:14]([C:17]([OH:19])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCI)=CS[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)O)=CS[C@H]12

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-(2-iodoethoxycarbonyl)-2-cephem-4-carboxylate (2.79 g., 4.05 mmol.) was dissolved in a mixture of 8 ml. glacial acetic acid and 48 ml. dimethylformamide and 0° and was reacted with 2.79 g. zinc dust (10.5 eq.) for 1.5 hours. The reaction mixture was diluted with ethyl acetate and filtered through a celite filter. The filtrate was washed successively with sodium bicarbonate solution (3×), water, 1N.HCl, and brine and then dried (Na2SO4). Evaporation to dryness in vacuo gave 1.92 (89%) of benzhydryl 7-(2-thienylacetamido)-3-carboxy-2-cephem-4-carboxylate: nmr (CDCl3 ) δ3.84 (s, side chain CH2), 4.99 (d, 1, J = 4.0 Hz, C6 --H), 5.45 (m, C4 --H and C7 --H) and 7.80 (s, C2 --H).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[CH:32]1([C:35]([N:37]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43]([NH:45][NH2:46])=[O:44])[CH2:38]2)=[O:36])[CH2:34][CH2:33]1>ClCCl>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][C:12]([NH:46][NH:45][C:43](=[O:44])[CH2:42][C@@H:39]2[CH2:40][CH2:41][N:37]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH2:38]2)=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1cc(F)c(Br)cc1F
Temperature: -78 °C

Procedure:
To a round bottom flask, 4-bromo-2,5-difluoroaniline (2 g, 9.62 mmol) and triphosgene (0.999 g, 3.37 mmol) were added under nitrogen and the mixture was cooled to −78° C. Dichloromethane (40 mL) was added followed by the slow addition of Hunig's base (3.36 mL, 19.23 mmol). The reaction was allowed to room temperature. Analysis by LCMS indicated desired intermediate formation. The solution was re-cooled to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1.219 g, 5.77 mmol) in dichloromethane (10 mL) was added. The solution was allowed to warm to room temperature, and analysis by LCMS indicated desired product formation. After 2 h of stirring at room temperature the desired product began to precipitate out of solution and was collected by filtration and dried via vacuum filtration to afford the title product as a white solid (1340 mg, 62%). MS(ES)+ m/e 445.1, 446.9 M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:17]([NH2:19])=[S:18].[OH-].[Na+].ClC1[S:24][C:25]2[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:26]=2N=1.Cl>C(O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][S:18][C:17]1[S:24][C:25]2[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:26]=2[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc(Cl)sc21
Reactant: NC(N)=S
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of 3-phenoxybenzyl chloride (2.84 g, 13.0 mmol), thiourea (1.22 g, 16 mmol) and ethanol (30 mL) was heated under reflux for 1 hr. 1 M aqueous sodium hydroxide solution (20 mL) was added to the reaction mixture and the mixture was further heated under reflux for 1 hr. The reaction mixture was cooled, and 2-chloro-5,6-dihydro-1,3-benzothiazol-7(4H)-one (1.55 g, 7.99 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (AcOEt:hexane=1:19-1:1) to give the title compound (2.67 g, yield 91%) as a pale-yellow oil.