Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][N:13]1[C:36](=[O:37])[C:35]([C:30]2[NH:29][C:28]3[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=3[S:32](=[O:34])(=[O:33])[N:31]=2)=[C:3]([OH:4])[CH:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]12
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1NCCC(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCCC21
Temperature: 25 °C
Yield: 47.8 %

Procedure:
cis-2-(3,3-Dimethyl-butylamino)-cyclooctanecarboxylic acid methyl ester (0.18 g, 0.67 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.23 g, 0.67 mmol) was added followed by N-methylmorpholine (0.15 mL, 1.40 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.70 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.28 mL, 2.00 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (50 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,9,10,10a-decahydro-cycloocta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.18 g, 0.32 mmol, 48%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.02 (9H, s), 1.42-2.21 (14H, m), 2.80-2.86 (1H, m), 3.06 (3H, s), 3.11-3.15 (1H, m), 3.66-3.70 (1H, m), 3.99-4.04 (1H, m), 6.57 (1H, s), 7.22-7.26 (1H, m), 7.60-7.66 (2H, m). LC-MS (ESI) calcd for C25H36N4O6S2 552.71, found 553.3 [M+H+].
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)C(C)C)(C)C.Cl>ClCCl.N1C=CC=CC=1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][N:23]1[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]2[C:27]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC(F)(F)F
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1OCC(F)(F)F
Reaction time: 22 h

Procedure:
A dichloromethane (21 mL) solution of 3.9 mL of 2,2,2-trifluoroethanol and 4.3 mL of pyridine was added dropwise to a dichloromethane (83 mL) solution of 9.0 mL of trifluoromethanesulfonic anhydride under cooling with ice over a period of 25 minutes. Thereto was dropwise added a dichloromethane (60 mL) solution of 8.50 g of N-hydroxyphthalimide and 18.5 mL of N,N-diisopropylethylamine at the same temperature over a period of 45 minutes, which was then stirred for 22 hours. To the reaction mixture was added 100 mL of 1 mol/L hydrochloric acid. The organic layer was separated, washed sequentially with 1 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) and washed with hexane to provide 4.43 g of N-(2,2,2-trifluoroethoxy)phthalimide as white solid form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([CH2:18][NH2:19])=[N:15][N:14]=2)=[CH:9][CH:8]=1.[OH:23][CH:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C)C=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17][C:16]([CH2:18][NH:19][C:25](=[O:26])[CH:24]([OH:23])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)C(O)CCCCCCc1ccccc1
Reactant: NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1)C(O)CCCCCCc1ccccc1

Procedure:
A solution of (5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methanamine (0.85 mmol), 2-hydroxy-8-phenyloctanoic acid (0.85 mmol), 1-hydroxybenzotriazole hydrate (1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.0 mmol), and DIPEA (3.4 mmol) in dimethylformamide (4 mL) was stirred at room temperature for 22 h. The resulting mixture was diluted with NaHCO3 (saturated) and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (MeOH—CH2Cl2) to yield N-((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)-2-hydroxy-8-phenyloctanamide. A solution of N-((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)-2-hydroxy-8-phenyloctanamide (0.22 mmol) in CH2Cl2 (5 mL) was treated with the Dess-Martin periodinane (0.34 mmol) and stirred overnight. The resulting mixture was quenched with a solution of sodium thiosulfate dissolved in saturated aqueous NaHCO3, and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[CH:26]([CH3:28])[CH3:27].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH:26]([C:3]1[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:5][N:6]([S:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:9])[C:2]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])[CH3:28]
Reactant: CC(C)c1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccccc1
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: [Na+]
Product: CC(C)c1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 36.8 %

Procedure:
Using tert-butyl {[5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (596 mg), phenylboronic acid (307 mg), tetrakis(triphenylphosphine)palladium (218 mg) and sodium carbonate (401 mg), a procedure as in Reference Example 56 was performed to give the title compound as a pale-red oil (yield 218 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:13]=[C:14]([N:21]4[CH2:26][CH2:25][C:24]5[N:27]=[CH:28][N:29](S(C6C=CC(C)=CC=6)(=O)=O)[C:23]=5[CH2:22]4)[C:15]4[O:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.ClC1N=C(Cl)C2OC=CC=2N=1.[OH-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.O1CCOCC1>[N:27]1[C:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:15]4[O:20][CH:19]=[CH:18][C:16]=4[N:17]=[C:12]([NH:11][C:7]4[CH:6]=[C:5]5[C:10]([C:2]([CH3:1])=[N:3][NH:4]5)=[CH:9][CH:8]=4)[N:13]=3)[CH2:22][C:23]=2[NH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc3c2CN(c2nc(Nc4ccc5c(C)nn(C(=O)OC(C)(C)C)c5c4)nc4ccoc24)CC3)cc1
Agent: Clc1nc(Cl)c2occc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1n[nH]c2cc(Nc3nc(N4CCc5nc[nH]c5C4)c4occc4n3)ccc12
Temperature: 65 °C
Yield: 33 %

Procedure:
A flask was charged with tert-butyl 3-methyl-6-(4-(3-tosyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5 (4H)-yl)furo[3,2-d]pyrimidin-2-ylamino)-1H-indazole-1-carboxylate (0.040 g, 0.062 mmol, prepared using C from Preparation #AJ.1, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with Example #3, Step B) and 1,4-dioxane (1.0 mL). To the mixture was added 2 N aqueous NaOH, (0.094 mL, 0.19 mmol) and the mixture was heated to about 65° C. for about 4.5 h. The mixture was cooled to rt and DCM (10 mL) and saturated aqueous NH4Cl (3 mL) were added. The layers were separated and a solid remained in the aqueous layer. The solid was collected by vacuum filtration and dried overnight at about 60° C. in a vacuum oven to give 4-(6,7-dihydro-3H-imidazo[4,5-c]pyridin-5 (4H)-yl)-N-(3-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidin-2-amine (0.008 g, 33%): LC/MS (Table 2, Method c) Rt=1.60 min; MS m/z: 387 (M+H)+. Syk IC50=A
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1>C1(C)C=CC=CC=1.CCOCC>[CH2:11]1[C:12]2[N:8]([C:7]([C:1]([Cl:4])=[O:2])=[CH:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: c1cc2n(c1)CCC2
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2n1CCC2
Temperature: 25 °C

Procedure:
To a stirred, ice-bath cooled portion (30 ml) of 12.5% phosgene in toluene was added a solution of 2,3-dihydro-1H-pyrrolizine (0.80 g, 0.0074 m) in ether (30 ml) dropwise over ca two minutes. After stirring cold for ca 2.5 hr, the reaction mixture is allowed to warm to room temperature, the volatiles are removed in vacuo, and the resultant crystalline 2,3-dihydro-1H-pyrrolizine-5-carbonyl chloride used as is in the next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[N:42][CH:43]=[C:44]([C:46]#[N:47])[CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[N:42][CH:43]=[C:44]([CH:45]=5)[C:46]#[N:47])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: N#Cc1cncc(Br)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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cncc(C#N)c5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A solution of the compound (508 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-5-cyanopyridine (274 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (238 mg, 45%) as a brown oily substance.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.CCOC(C)=O>CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH2:11])=[S:10])=[CH:17][CH:16]=1
Reactant: NC(=S)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: NC(=S)N(Cc1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In Example 107, reduction of the nitro group in compound 342 by reaction with stannous chloride in methanol proceeded selectively and resulted in the formation of amino derivative 343 in high yield, as follows: A mixture of thiourea 342 (0.287 g, 1 mmol) and SnCl2.2H2O (0.5 g, 2.2 mmol) in MeOH (25 mL) was refluxed for 4 hours, cooled to room temperature, then poured into EtOAc (150 mL. The mixture was sequentially washed with saturated NaHCO3 (5×20 mL) and H2O (3×20 mL), dried over MgSO4, then evaporated. The residue was chromatographed over silica gel (2×15 cm, eluant: 1% MeOH in CHCl3) to produce (4-aminophenyl)-benzyl thiourea 343 (0.192 g, 75% yield) as a white powder. Relevant data: mp 153°-155° C. (from EtOAc); 1H NMR (DMSO-d6): δ4.65 (d, 2H, J=5.7 Hz), 5.05 (br.s., 2H, NH2), 6.50 (d, 2H, J=9 Hz), 6.85 (d, 2H, J=9Hz), 7.25 (m, 5H), 7.61 (br.s., 1H, NH), 9.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ47.50, 114.72, 126.96, 127.23, 127.51, 128.66, 139.57, 146.88, 181.305; MS m/e (1%): 257 (M+, 42), 256 (17), 182 (25), 165 (6), 150 (100), 108 (75), 107 (37), 106 (47), 91 (92).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:5].C(C1C=CC(N)=CC=1)(C)(C)C.[Si]([O:39][CH2:40][CH2:41][O:42][C:43]1[C:50]([CH3:51])=[CH:49][C:46]([CH:47]=O)=[CH:45][C:44]=1[CH3:52])(C(C)(C)C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:47]2[C:46]2[CH:49]=[C:50]([CH3:51])[C:43]([O:42][CH2:41][CH2:40][OH:39])=[C:44]([CH3:52])[CH:45]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(C(C)(C)C)cc2)cc(C)c1OCCO
Temperature: 140 °C
Yield: 99 %

Procedure:
Following the method described for in Example 21, compound 2-amino-N-(4-tert-butylphenyl)benzamide was made from 4-tert-butylaniline, in 99% yield, and was isolated as a brown solid. 2-Amino-N-(4-tert-butylphenyl)benzamide (1.14 g, 4.25 mmol) and 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.31 g, 4.25 mmol) were combined in DMA (20 mL) and p-TsOH (0.164 g, 0.86 mmol) was added, followed by NaHSO3 (0.488 g, 4.69 mmol). The mixture was heated to 140° C. for 24 hours, before concentrating, diluting with ethyl acetate (250 mL), washing with water (200 mL), and then brine (200 mL), before drying over Na2SO4, filtering, and concentrating. Purification by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/hexanes to 100% ethyl acetate to 10% methanol/ethyl acetate, afforded the title compound as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ 8.19 (d, J=7.2 Hz, 1H), 7.87-7.92 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.56-7.61 (m, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 6.96 (s, 2H), 4.83 (t, J=5.4 Hz, 1H), 3.62-3.67 (m, 4H), 2.06 (s, 6H), 1.25 (s, 9H). MS (APCI) m/z: 443 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:22][CH:23]2[C:50](=[O:51])[N:25]3[C:26]([C:34]([O:36][CH:37]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:35])=[C:27]([CH:30]=[C:31]([Br:33])[Br:32])[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.COCCO>C(Cl)Cl.O>[NH2:22][CH:23]1[C:50](=[O:51])[N:25]2[C:26]([C:34]([O:36][CH:37]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:27]([CH:30]=[C:31]([Br:33])[Br:32])[CH2:28][S:29][C@H:24]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Br)Br)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: COCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Br)Br)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Pyridine (0.39 ml) was added to a suspension of phosphorus pentachloride (1.01 ml) in dry methylene chloride (25 ml) at 5° C., and the mixture was stirred at ambient temperature for 30 minutes. Benzhydryl 7-phenylacetamido-3-(2,2-dibromovinyl)-3-cephem-4-carboxylate (2.5 g) was added to the above mixture at -10° C. and stirred for two-hours. Then, methylcellosolve (2.3 ml) was added to the reaction mixture at -30° C. and the resulting solution was stirred for an hour. To the above solution was added 5 ml of water and the separated organic layer was washed in turn with a saturated aqueous solution of sodium bicarbonate and brine, dried. The solvent was evaporated to give benzhydryl 7-amino-3-(2,2-dibromovinyl)-3-cephem-4-carboxylate (1.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([O-])=O.[OH-].[Na+]>Cl.CO.[Zn]>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:5]=[C:4]([CH:16]=[CH:15][CH:14]=2)[NH2:1])[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Oc2cccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc(Oc2cccnc2)c1
Reaction time: 1 h
Yield: 39.9 %

Procedure:
Compound 4 (1.613 g, 7.461 mmol, 1.000 eq) was dissolved in 1N HCl in MeOH (75 mL) and zinc (1.46 g, 22.3 mmol, 3.00 eq) was added. The reaction was stirred for 1 hour and additional zinc (975 mg, 14.9 mmol, 2 eq) was added to drive the reaction to completion as determined by TLC. The reaction was neutralized with 1N NaOH (75 mL), filtered and extracted (3×) with CH2Cl2. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 555 mg (85%) of the title compound as a brown oil: 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.31 (m, 2H), 7.39-7.38 (m, 2H), 7.01 (t, J=8.0 Hz, 1H), 6.35 (dd, J=8.0, 1.6 Hz, 1H), 6.19 (t, J=2.2 Hz, 1H), 6.14 (dd, J=7.9, 2.0 Hz, 1H), 5.27 (s, 2H); ES-MS [M+1]+: 187.2.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O.[NH2:16][NH2:17].C(O)(=O)C>CS(C)=O>[NH:16]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[NH2:17]
Reactant: NN
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: NNc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
7.5 g (36 mmol) of 4-fluoro-3-trifluoromethylbenzoic acid is dissolved in 12 mL dimethylsulfoxide and, after the addition of 15 mL (0.24 mol) of hydrazine hydrate (80%), stirred for 5 hours at 100° C. After cooling, it is combined with ice and acidified with glacial acetic acid. The precipitated product is suction filtered and dried. Yield: 5.3 g (66%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.O1CCCC1.CO.[OH-].[Li+]>O>[F:20][CH:18]([F:19])[O:17][C:10]1[C:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:8]([CH3:29])[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:11]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccc(F)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of [2-difluoromethoxy-8-fluoro-3-(4-fluorobenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), tetrahydrofuran (4.0 mL), methanol (4.0 mL), water (3.0 mL) and lithium hydroxide (0.020 g) was stirred at room temperature for 40 minutes. The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a white solid, 0.10 g.
Reaction SMILES: [CH3:1][C:2]1[N:38]=[C:5]2[N:6]([CH:33]([CH3:37])[C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:40][O:41][CH2:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH2:42]([O:41]/[N:40]=[C:34](\[CH3:35])/[CH:33]([N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:18][CH:19]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:38]=[C:5]12)[CH3:37])[CH3:43]
Reactant: CCON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)C(C)=O)c2nc(C)nn12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)/C(C)=N/OCC)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
A mixture of 2-methyl-4-(1-methyl-2-oxopropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)ethane hydrochloride (0.76 g) and pyridine (5 mL) was stirred at 100° C. for 48 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.14 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[C:7]([F:17])[C:8]([F:16])=[C:9]([F:15])[CH:10]=2)[N:5]=1)[CH3:2].P(Cl)(Cl)([Cl:20])=O>O>[Cl:20][C:12]1[C:11]2[C:6](=[C:7]([F:17])[C:8]([F:16])=[C:9]([F:15])[CH:10]=2)[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1
Reactant: CCOc1cc(O)c2cc(F)c(F)c(F)c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOc1cc(Cl)c2cc(F)c(F)c(F)c2n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-ethoxy-6,7,8-trifluoro-4-hydroxyquinoline (69.5 g) is phosphoryl chloride (430 cc) is heated with stirring to a temperature in the region of 100° C. for 30 minutes. The solution obtained is concentrated under reduced pressure (20 kPa) at approximately 60° C. to a volume of 100 cc. The residue is taken up with ethyl acetate (750 cc); the solution obtained is poured with stirring in the course of 10 minutes into a mixture of water (400 cc) and ice (200 g), and left stirring under these conditions for 30 minutes. After separation of the organic extract, the aqueous phase is again extracted with ethyl acetate (2×250 cc). The combined organic extracts are washed with water (3×250 cc), dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at approximately 40° C. The oily residue obtained is taken up with petroleum ether (40-60) (370 cc). After filtration through diatomaceous silica, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at approximately 30° C. 4-Chloro-2-ethoxy-6,7,8-trifluoroquinoline (70.7 g) is obtained in the form of a beige solid, m.p. 45° C., which is used without further purification for the subsequent steps.