Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([N:35]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][N:44]=3)[C:36]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C>Cl.O1CCOCC1.CO>[NH:8]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([N:35]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][N:44]=3)[C:36]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH2:31][CH2:30]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C:9]([NH2:18])=[NH:10]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)CCCCC3)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNC(=N)N)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.1 %

Procedure:
N-[1-[2-[1-[2-(1,2-Di-tert-butoxycarbonylguanidino)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (synthesized in Example 44) (105 mg) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution (12 mL) and methanol (5 mL). The solution was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure and the resulting residue was crystallized (from methanol-ethyl acetate) to give the title compound (69 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: OCC1CCNCC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(CO)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-yl-methanol according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 1.05-1.14 (m, 2 H), 1.61-1.70 (m, 9 H), 2.74 (t, J=12.0 Hz, 2 H), 3.26 (t, J=5.5 Hz, 4 H), 3.45 (d, J=5.8 Hz, 2 H), 5.92 (d, J=5.5 Hz, 1 H), 6.74-6.77 (m, 1 H), 6.97 (d, J=7.6 Hz, 1 H), 7.25-7.29 (m, 2 H), 7.46-7.56 (m, 2 H), 7.87-7.89 (m, 2 H), 7.98 (d, J=7.7 Hz, 1 H), 8.22 (s, 2 H).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10]Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:12].[Na+]>CC(C)=O>[N:1]1([C:7]([O:9][CH2:10][Br:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [Br-]
Reactant: O=C(OCCl)N1CCOCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCBr)N1CCOCC1
Temperature: 60 °C
Yield: 80.2 %

Procedure:
Chloromethyl morpholine-4-carboxylate [285] (0.3 g, 1.67 mmol, 1.0 eq) and sodium bromide (0.86 g, 8.3 mmol, 5.0 eq) was taken in acetone (10 ml). The reaction was refluxed at 60° C. for 24 h. Reaction progress was monitored by TLC/1H NMR. The reaction was filtered off and filtrate was evaporated to dryness under reduced pressure to yield light brown gel, bromomethyl morpholine-4-carboxylate [286] (0.30 g, 80%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)[O:27][C@@H:26]([CH2:28][N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)[CH2:25][O:24]1.C(=O)([O-])[O-].[K+].[K+].[ClH:50]>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.O1CCOCC1>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][C@H:26]([OH:27])[CH2:25][OH:24])[CH:33]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12].[ClH:50]
Reactant: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C[C@H](O)CO)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (45.0 mg, 0.116 mmol), 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (71.5 mg, 0.232 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), potassium carbonate (48.1 mg, 0.348 mmol) and 4:1 Dioxane:water (7 mL) was heated to 90° C. for 2 h. The solution was allowed to cool to rt. 2 M of HCl in water (4 mL) was added until pH 2, and the mixture was stirred at rt overnight. The solution was passed through a SCX cartridge that was washed with MeOH, and the product was eluted with 2M NH3 in MeOH. The material was dry-loaded onto silica gel for column chromatography, eluting with 5% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in DCM, and 2.0 M of HCl in Et2O (0.4 mL) was added. The solution was stirred at rt for 20 min and concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.1 Hz, 3 H), 3.52 (dd, J=5.3, 1.3 Hz, 2 H), 3.95-4.02 (m, 1H), 4.13 (dd, J=14.1, 7.6 Hz, 1 H), 4.31 (dd, J=14.0, 4.2 Hz, 1H), 5.27 (q, J=7.1 Hz, 1 H), 7.17 (dd, J=8.6, 8.6 Hz, 1H), 7.35 (d, J=1.3 Hz, 1 H), 7.37 (d, J=2.0 Hz, 1 H), 7.41 (br. s., 1 H), 7.59 (s, 1 H), 7.82 (s, 1 H), 8.31 (d, J=2.0 Hz, 1 H). MS (ES+): m/z=448.99/451.01 (100/68) [MH+]. HPLC: tR=3.05 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]=[N+]=[N-])[C@H:13]([O:20][CH3:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1CO>[Zn]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([O:20][CH3:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: OCC1CCCO1
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A mixture of 0.123 g (0.42 mmole) of (rac)-(3R,4R)-4-azido-3-methoxy-piperidine-1-carboxylic acid benzyl ester, 0.105 g (0.39 mg-atom) of zinc, 0.20 g of ammonium chloride and 4 mL of tetrahydrofuran-methanol (1:1) was stirred at room temperature for 2 hours and then filtered through a Celite pad, washing with 25 mL of water and 25 mL of tetrahydrofuran. The combined filtrates were made strongly acidic with hydrochloric acid and extracted twice with 25 mL of ethyl acetate. The aqueous layer was made basic with potassium carbonate and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.069 g of (rac)-(3R,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.C1OCCOCCOCCOCCOCCOC1.[F-].[K+].F[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45].S([O-])(O)(=O)=O.[K+]>C(#N)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45]
Reactant: COC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 85 %

Procedure:
Glycine methyl ester hydrochloride (2.2 g, 18 mmol), diisopropylethylamine (2.9 g, 29 mmol), 18-crown-6 (370 mg, 1.4 mmol) and potassium fluoride (1.6 g, 28 mmol) were added to a solution of 1-fluoro-2-nitrobenzene (2 g, 14 mmol) in acetonitrile (150 ml). The mixture was heated at 80° C. for 48 h and cooled. 0.3N potassium hydrogen sulphate and ethyl acetate were added and the mixture separated. The organic phase was washed with water and brine, filtered through phase separation paper and reduced. Chromatography (15% EtOAc/85% 6080 petroleum ether) afforded N-(2-nitrophenyl)glycine methyl ester as a yellow solid (2.5 g, 85%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=S)[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N)(=O)=[O:18])C=CC=CC=1.C1(N=C=S)CCCCC1.OO>C(=O)([O-])[O-].[K+].[K+].CO.[OH-].[Na+]>[CH:1]1([NH:7][C:8](=[O:18])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: NC(=S)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: OO
Agent: S=C=NC1CCCCC1
Solvent: CO
Product: NC(=O)NC1CCCCC1

Procedure:
5 Grams N-[4-(β-<N'-methyl-N'-pyridyl-ureido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl-thio-urea (prepared by reaction of 4-(β-<N'-methyl-N'-2-pyridyl-ureido>-ethyl)-benzenesulfonamide and cyclohexylisothiocyanate in an acetonic solution in the presence of potassium carbonate, melting point 143°-145° C. from methanol) were dissolved in 50 ml of 1N sodium hydroxide solution. 5 Milliliters of 30% H2O2 were added and the mixture was heated for 15 minutes on the steam bath. After cooling the solution was acidified. The precipitate was suction-filtered and recrystallized from ethanol/dimethylformamide. The N'-[4-(β-<N'-methyl-N'-2-pyridyl-ureido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea obtained melted at 167°-169° C.
Reaction SMILES: [OH-:1].[NH4+].[NH4+].[NH4+].[OH:5][P:6]([O-:9])([O-:8])=[O:7].O.O.O.O.[N+:14]([O-:17])([O-:16])=[O:15].[Ca+2:18].[N+:19]([O-:22])([O-:21])=[O:20]>O>[OH2:5].[OH2:15].[OH2:20].[OH2:1].[N+:14]([O-:17])([O-:16])=[O:15].[Ca+2:18].[N+:19]([O-:22])([O-:21])=[O:20].[P:6]([O-:9])([O-:8])([O-:7])=[O:5].[Ca+2:18].[Ca+2:18].[Ca+2:18].[P:6]([O-:9])([O-:8])([O-:7])=[O:5]
Reactant: O=P([O-])([O-])O
Reactant: [OH-]
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Agent: [NH4+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 8 h

Procedure:
Tricalcium phosphate (β-whitlockite crystalline form) was prepared by the following technique. A solution of 141.7 grams of calcium nitrate tetrahydrate in 400 ml of water was prepared and the pH adjusted to about pH 11 with concentrated ammonium hydroxide. This solution was then diluted to about 900 ml with water and placed in a three liter flask fitted with a dropping funnel and mechanical stirring apparatus. Separately, 66.1 grams of ammonium phosphate dibasic was added to 750 ml of water. The pH of the resulting solution was adjusted to about pH 11 with concentrated ammonium hydroxide resulting in the formation of a precipitate which was subsequently dissolved by the addition of water (about 2000 ml total volume of the solution). The ammonium phosphate dibasic solution was then slowly added to the reaction flask containing the calcium nitrate tetrahydrate solution and the resulting mixture was stirred overnight. A precipitate formed which was collected by centrifugation, washed with water and again collected by centrifugation. The precipitate was then suspended in a 2 percent aqueous ammonium sulfate solution and filtered leaving a residue which was subsequently dried in vacuo at 90° C. leaving 63.7 g of tricalcium phosphate. The tricalcium phosphate was then sintered at 1150° C. for one hour, and then ground to a fine powder.
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>N1C=CC=CC=1.CCOC(C)=O>[OH:22][CH2:21][CH2:20][O:23][C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
K-t-BuO (1.24 g, 11 mmol) was added to a mixture of the product obtained in Step 1 (1.98 g, 6.5 mmol) and ethylene glycol (2.54 ml, 45.5 mmol) in pyridine (15 ml). The reaction mixture was stirred at 100° C. for 6 h and at room temperature overnight. The solution was then poured into ice-water and diluted with EtOAc. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by chromatography on silica gel eluting hexane/EtOAc (1:1) to give 1.71 g (65%) of title product as an orange oil. MS m/z 331 (M+H)+. Step 3: tert-Butyl 4-(4-{2-[(2-oxo-2H-chromen-7-yl)oxy]ethoxy}-1,2,5-thiadiazol-3-yl)-1-piperazinecarboxylate.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)[C:17]([CH3:34])([CH3:33])[CH2:16][C:15]=2[C:14]([C:35](O)=[O:36])=[CH:13][CH:12]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)[C:17]([CH3:33])([CH3:34])[CH2:16][C:15]=2[C:14]([C:35]([NH:9][S:6]([CH:3]2[CH2:5][CH2:4]2)(=[O:8])=[O:7])=[O:36])=[CH:13][CH:12]=1
Reactant: CC1(C)Cc2c(C(=O)O)ccc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(C(=O)NS(=O)(=O)C3CC3)ccc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (50 mg, 1.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (151 mg, 1.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (50 mg, 0.13 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.25 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid-[8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (13 mg, 20%) as a white solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 505.05, observed: 504.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][N:10](C)C=O.[Cu](C#N)C#N.C(N(CC)CC)C>C(OCC)(=O)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(Cl)cn1
Reaction time: 4 h
Yield: 27 %

Procedure:
The compound (10.0g) obtained in (1) above, dimethylformamide (50 ml), copper cyanide (6.98 g), triethylamine (10.9 ml) and molecular sieves 4A (2 g, heat-treated) were placed in an autoclave. The outer temperature was set for 200° C. and the mixture was stirred for 4 hours. Water and ethyl acetate were added to the reaction mixture, and, after filtering off insoluble matters, extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give 1.92 g of a white solid (yield 27%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([B-](F)(F)F)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[K+].Cl[C:21]1[C:26]2[O:27][CH:28]([CH3:32])[C:29](=[O:31])[NH:30][C:25]=2[CH:24]=[C:23]([CH:33]=[O:34])[CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH3:32][CH:28]1[O:27][C:26]2[C:21]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][C:23]([CH:33]=[O:34])=[CH:24][C:25]=2[NH:30][C:29]1=[O:31]
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Reactant: F[B-](F)(F)c1ccccc1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Temperature: 115 °C
Reaction time: 42 h
Yield: 19.4 %

Procedure:
To a solution of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium phenyltrifluoroborate (0.245 g, 1.330 mmol), and 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 4.00, 16 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 42 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation. The impure material was reconstituted in DMSO (1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 45-70% ACN:0.05% TFA (aq). The early fractions were combined and the solvent was removed via rotary evaporation. The purified product was dried in vacuo to provide the title compound as an off-white solid (0.0459 g, 0.172 mmol, 19.37% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.82 Hz, 3H) 4.85-4.92 (m, 1H) 7.38-7.43 (m, 2H) 7.46-7.51 (m, 2H) 7.57-7.62 (m, 2H) 7.64 (d, J=2.02 Hz, 1H) 9.91 (s, 1H) 11.04 (s, 1H). ESI-MS: m/z 268.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.CO.[Li+].[OH-]>C1COCC1.O>[C:5]1([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[O:10][N:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)no2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2nc(-c3ccccc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of methyl 4-(3-(4-fluorophenyl) 1,2,4-oxadiazol-5-yl)benzoate (600 mg, 2.14 mmol) in THF (12 mL) was added MeOH (3 mL) and a solution of LiOH (351 mg, 8.57 mmol) in H2O (3 mL). The reaction was stirred at room temperature for 2 h. The reaction was quenched upon the addition of 1N HCl (30 mL) and extracted with EtOAc (2×30 mL). The organic extracts were dried over MgSO4, and concentrated under vacuum to afford 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoic acid (550 mg, 87%) as a white solid. 1H-nmr (400 MHz, CDCl3) δ 8.37 (d, J=8 Hz, 2H), 8.30 (d, J=8 Hz, 2H), 8.26-8.19 (m, 2H), 7.62-7.52 (m, 3H); MS (ESI) m/z 266.8
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](CC(N)=O)(C)C.[NH2:26][CH:27]1[C:48](=[O:49])[N:29]2[C:30]([C:45]([OH:47])=[O:46])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH2:41][C:42]([OH:44])=[O:43])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([NH:26][CH:27]1[C:48](=[O:49])[N:29]2[C:30]([C:45]([OH:47])=[O:46])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH2:41][C:42]([OH:44])=[O:43])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12)=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csnn1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csnn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Phosphorus oxychloride (0.65 g.) was added under ice-cooling to dry dimethylformamide (0.31 g.) and the mixture was stirred for 30 minutes at 40° C. Dry ethyl acetate (15 ml.) was added thereto and to the suspension was added under ice-cooling 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)-acetic acid (syn isomer) (0.65 g.), after which the resulting mixture was vigorously stirred for 30 minutes at the same temperature to give a solution. On the other hand, trimethylsilylacetamide (4.20 g.) was added to a suspension of 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.20 g.) in dry ethyl acetate (50 ml.), and the mixture was stirred for 2.5 hours at ambient temperature. To this suspension was at a time added at -20° C. the above-obtained ethyl acetate solution, and the resulting mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was extracted after addition of ethyl acetate (70 ml.) and water (35 ml.). The organic layer was extracted with a sodium bicarbonate aqueous solution (35 ml.). To the aqueous extract was added ethyl acetate (70 ml.), and the mixture was adjusted. to pH 2.0 with conc. hydrochloric acid with stirring and then the ethyl acetate layer was separated. The ethyl acetate layer was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give white powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.36 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].C[Mg+].[Br-].[CH2:20](OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][C:4]=1[CH3:16])[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=[C:10]2[CH3:20]
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
General Procedure A CeCl3 7 H2O (1.28 g, 3.4 mmol) was heated in an oil bath to 140-150° C. under high vacuum without stirring for 2 h, and then with stirring for 2 h. Argon was then introduced, and the flask was cooled to room temperature. Tetrahydrofuran (10 mL) was added, and the resulting slurry solution was stirred at room temperature under the argon atmosphere for 3 h. A solution of 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 0.53 g, 2.3 mmol) and 5 mL of tetrahydrofuran was added, and the reaction mixture was stirred for 1 h, then cooled to 0° C. A solution of 3 M MeMgBr in diethyl ether (1.2 mL, 3.4 mmol) was added, and the ice bath was removed. After 1 h, the reaction was poured into concentrated sulfuric acid in ice, extracted with ethyl acetate, washed with IN NaHCO3, brine, dried over MgSO4, and filtered. The solvent was removed to give 0.42 g (80%) of the title compound as an orange oil.