Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH3:21])[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH:21]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(C)cc(=O)oc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-(3-methylbut-2-enyloxy)-8-acetylcoumarin (2.14 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.34 g of product m.p. 114-16° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H); 1.72 (s, 3H); 2.44 (d, 3H, J=1.22 Hz); 4.65 (d, 2H, J=6.5 Hz); 5.34-5.38 (m, 1H); 6.16 (d, 1H, J=1.2 Hz); 6.95 (d, 1H, J=8.8 Hz); 7.00 (d, 1H, J=18 Hz); 7.10 (d, 1H); 7.30-7.40 (m, 3H); 7.45-7.52 (m, 12H); 7.61 (d, 1H, J=8.9 Hz).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1>O.CC(C)=O>[S:1]([CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1)[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(CSC#N)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenyl-acetamido)penam-3carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with water and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5](C)=[C:6]([CH:9]=1)C#N.[CH3:14][C:15]([OH:17])=[O:16]>O.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:6])=[C:14]([CH:9]=1)[C:15]([OH:17])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Temperature: 120 °C
Yield: 84 %

Procedure:
A mixture of 5-chloro-2-methyl-4-nitrobenzonitrile (1 g, 5 mmol) in AcOH (10 mL), water (10 mL) and conc. sulphuric acid (10 mL) was heated to 120° C. for 5 h. Water (100 mL) was added and the solid was removed by filtration and dried to give 5-chloro-2-methyl-4-nitrobenzoic acid (905 mg, 84%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M−H]−=214 at 2.12 min. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.76 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:19][O:18]2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:19]=[O:18])=[CH:13][CH:12]=1
Reactant: Fc1ccc(C2(c3ccc(F)cc3)CO2)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=CC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
Under vigorous stirring 18.5 g of boron trifluoride etherate was added slowly to a solution of 60.6 g of 2,2-bis(4-fluorophenyl)oxirane in 450 ml of toluene. The mixture was washed twice with water, the solvent was evaporated and the residue was distilled to yield α-(4-fluorophenyl)-4-fluorobenzeneacetaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 5 °C
Yield: 96.8 %

Procedure:
To a 500 ml, 4-necked flask fitted with a stirrer, thermometer, addition funnel and reflux condenser is charged sulfuric acid (50 ml) and methyl m-fluorobenzoate (8.5 g, 0.055 mole). The reaction mixture is then cooled to 5° C. and a solution of potassium nitrate (reagent 5.57 g, 0.055 mole) is concentrated sulfuric acid (50 ml) is added dropwise over a 30 minute period. Ten minutes after completion of addition the reaction mixture is poured onto 500 g of cracked ice and the product extracted into benzene (3×100 ml). The combined benzene extracts are dried with anhydrous magnesium sulfate and the filtrate reduced in vacuo to give 10.6 g (96%) of product, which is a yellow liquid. Anal. Calcd. for C8H6FNO4 : C, 48.20; H, 3.04; F, 9.54; N, 7.02. Found: C, 50.15; H, 3.34; F, 9.17; N, 6.77.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:23]=[CH:22][C:10]([C:11](=[O:21])[CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14]2)=[CH:9][CH:8]=1.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+]>O1CCCC1.O>[C:26]([CH:25]([CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:13]([CH2:12][C:11]([C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[O:21])[CH2:14]1)[C:24]([O:30][CH2:31][CH3:32])=[O:29])(=[O:27])[CH3:28]
Reactant: O=C(CC1CCN(CCO)C1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCC(CC(=O)c2ccc(F)cc2)C1)C(C)=O
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A solution of 3.88 g of methanesulfonyl chloride is added at 0° C. to a suspension of 8.5 g of the product obtained in Stage A in 100 ml of tetrahydrofuran. The mixture is left stirring for 3 hours at 15° C., and this suspension is then added to a solution, cooled to 0° C., of 4.4 g of ethyl acetoacetate containing 1.63 g of sodium hydride in 100 ml of tetrahydrofuran. The mixture is then brought to reflux for 12 hours, hydrolyzed with 5 ml of water and concentrated, and the residue is take up in 150 ml of dichloromethane. The organic phase is washed with 50 ml of water, dried over anhydrous sodium sulfate and concentrated. The oil obtained is purified by chromatography on 600 g of 70-230 mesh silica, using a mixture of dichloromethane and methanol (99:1 V/V) as eluant.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH:20]=[CH:21][C:22]=1[Cl:23]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][C:26]2([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:27][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc(Cl)c(Cl)c2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 1.7 mL of methyl acetoacetate, 630 mg of NaH 60% dispersion in oil, 9.85 mL of 1.6M n-butyl lithium in hexane, 4.0 g of 3-(3,4-dichlorophenyl)propiophenone and 150 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 4 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 145°-147° C.). 1H NMR (CDCl3) δ 2.18-2.35 (m, 2 H), 2.39-2.50 (m, 1 H), 2.68-2.80 (m, 1 H), 2.96 (dd, 2 H), 3.36 (dd, 2 H), 6.90-7.50 (m, 8 H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[C:10]([C:7]1[S:8][CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1nc(CN=[N+]=[N-])cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc(CN)cs1
Temperature: 60 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (1.08 g, 6.13 mmol) in dry DMF (21 mL) and treated with NaN3 (1.20 g, 18.39 mmol) at 65° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(4-(azidomethyl)-thiazol-2-yl)-ethanone as a yellow oil. To a solution of the crude azide (200 mg, 1.10 mmol) in THF (6 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The org. layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH-Et3N). LC-MS-conditions 01: tR=0.26 min; [M+H]+=157.04.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCC(OC(C)=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To rac-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HF)(70 mg, 0.187 mmol) in 1,2-dichloroethane (3 ml) was added ethyl 7-oxoheptanoate (97 mg, 0.562 mmol). The reaction mixture was stirred at room temperature for 20 minutes and sodium triacetoxyborohydride (119 mg, 0.562 mmol) was added. The solution was stirred at room temperature overnight. Water (5 ml) was added and the reaction mixture was stirred vigorously for 15 minutes. The resulting mixture was extracted with DCM (×3). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (20 ml). The solvent was removed in vacuo and the resulting crude was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound LC-MS Rt=1.58 mins; [M+H]+ 530.4, Method 2minLC_v003.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[Br:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>>[Br:1][C:23]1[CH:24]=[C:19]([CH2:18][CH2:17][Br:16])[CH:20]=[CH:21][C:22]=1[NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CNc1ccc(CCBr)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCOC(=O)CNc1ccc(CCBr)cc1Br

Procedure:
Ethyl N-[2-bromo-4-(2-bromoethyl)phenyl]aminoacetate was prepared according to a similar manner to that described in Reference Example 6 using 1 molar equivalent of both N-bromosuccinimide and 0.4M aqueous sodium thiosulfate solution to ethyl N-[4-(2-bromo-ethyl)phenyl]aminoacetate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)(C)OC(=O)N1CCCC(ON2C(=O)c3ccccc3C2=O)C1
Yield: 57 %

Procedure:
Reaction of tert-butyl 3-hydroxypiperidine-1-carboxylate with N-hydroxyphthalimide following the procedure described for the preparation of Reference Example 9 gave tert-butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidine-1-carboxylate (2.3 g, 57%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 1.47-1.58 (1H, m), 1.74-1.76 (1H, m), 1.90-1.92 (1H, m), 2.08-2.11 (1H, m), 3.04-3.40 (2H, m), 3.66-3.68 (1H, m), 3.70-4.14 (1H, m) 4.24-4.27 (1H, m), 7.74-7.76 (2H, m), 7.82-7.86 (2H, m).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[O:4][CH2:3]1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]=[C:2]1[CH2:3][O:4][C@@H:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C@H:6]([N+:8]([O-:10])=[O:9])[CH2:7]1
Reactant: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: C=C1CO[C@@H](c2cc(F)c(F)cc2F)[C@H]([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran (798 mg, 2.94 mmol) in chloroform (42 mL) and isopropyl alcohol (7.8 mL) was added silica gel (5.1 g), and sodium borohydride (420 mg, 11.1 mmol), and the reaction mixture stirred for 30 minutes at room temperature. The reaction mixture was then quenched by dropwise addition of hydrochloric acid (6 mL, 2N) and filtered. The resulting solid residue was washed with ethyl acetate (100 mL). The combined filtrate was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The resultant amber oil (802 mg) was dissolved in tetrahydrofuran (15 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 40 μL) was added. The solution was stirred for 105 minutes and then transferred to a separatory funnel containing ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was washed with brine and the aqueous layer extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield a crude product which was purified by flash chromatography (silica, 8-10% ether in hexane) to yield trans-5-methylene-3-nitro-2-(2,4,5 trifluorophenyl)tetrahydro-2H-pyran. A portion of this product (388 mg) was resolved by HPLC (ChiralCel OD, 1.5% isopropyl alcohol in heptane) to yield the slower-moving enantiomer, (2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[N:13]1([C:20]2[C:25]([CH2:26][NH:27][C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[C:34]=4[Cl:41])[N:31]=[N:30][N:29]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[Cl:41][C:34]1[C:35]([Cl:40])=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[C:28]([NH:27][CH2:26][C:25]2[C:20]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH:2]([CH3:4])[CH3:1])[CH2:15][CH2:14]3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:29][N:30]=[N:31]1
Reactant: CC(C)=O
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2N2CCCNCC2)c(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CCCN(c2ncccc2CNc2nnnn2-c2ccc(F)c(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (0.5 mL) was added to a mixture of the product of Example 289 (80 mg, 0.183 mmol) and sodium triacetoxyborohydride (77 mg, 0.366 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by preparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min to provide the title compound. MS (ESI+) m/z 479.3 (M+H)+; Rt=1.63 min. 1H-NMR (400 MHz, DMSO-d6) δ 0.96 (d, J=6.6 Hz, 1H), 1.80 (m, 2H), 1.90 (s, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.38 (m, 4H), 4.44 (d, J=5.3 Hz, 1H), 5.75 (s, 1H), 6.84 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.58 (t, J=5.5 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.07 (dd, J=1.9 Hz, J=4.7 Hz, 1H).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])#[N:16]>>[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)=[O:21])#[N:16]
Reactant: Oc1ccc(CNn2cnnc2)cc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: N#Cc1cccc(C(=O)N(Cc2ccc(O)cc2)n2cnnc2)c1
Yield: 15.3 %

Procedure:
The procedure of Preparation Example 34 was repeated, except that 101 mg of 4-[N-(1,2,4-triazol-4-yl)aminomethyl]phenol was used in place of 4-methoxybenzylamine, and 105 mg of 3-cyanobenzoyl chloride was used in place of 4-cyanobenzoyl chloride. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 26 mg of 3-cyano-N-(4-hydroxybenzyl)-N-(1,2,4-triazol-4-yl)benzamide.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]([CH3:65])[C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][N:51]([CH3:65])[C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1
Reactant: CN(C)c1ccc(-c2cccc(N)c2)cn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(N(C)C)nc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 66.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-dimethylamino-pyridin-3-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 66% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].O.O.[Br-].[Ca+2].[Br-]>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Br-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 87.7 %

Procedure:
2 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 20 ml of 50% v/v aqueous methanol, and 20 g of calcium bromide dihydrate were added to the resulting solution. The mixture was then stirred at 70° C. for 50 minutes, after which it was treated as described in Example 2, to give 1.55 g of 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid, in the form of a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[CH3:9]O>>[CH3:9][O:7][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: CO
Product: COC(=O)c1ccco1
Temperature: 80 °C
Yield: 91 %

Procedure:
With reference to the chemical reaction formula 6, 2-furan carboxylic acid (20 g, 178 mmol) and 0.5M of HCI/methanol (400 mL) are put in one after another to be dissolved in an 1 L round-bottom flask and are refluxed at 80° C. for 2 hours to be reacted. After the solvent is removed by vacuum drying, the residue from which is diluted in EtOAc to be moved to a separatory funnel, and washed in turn with ice water and 5% of sodium bicarbonate (NaHCO3) aqueous solution, with pH checked at 7˜8 at the end. After moisture in the funnel is removed by MgSO4, the residue having been filtered and vacuum evaporated is separated by flash chromatography (hexanes: EtOAc=10:1) to obtain a 2-furan carboxylic acid methyl ester (20.53 g, 162 mmol, 91% of yield), in the form of light yellow oil. The data of1H and 13C-NMR referring to that is as below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](Cl)=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>C(#N)C>[S:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:19]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Cl)n2)CC1
Reactant: Nc1ccccc1S
Solvent: CC#N
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4s3)n2)CC1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carbonyl chloride (100 mg, 0.2996 mmol) and 2-aminobenzenethiol (112.5 mg, 96.98 μL, 0.8988 mmol) in acetonitrile was heated at 70° C. overnight. The reaction mixture was allowed to cool to RT, filtered and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were combined but still contained an impurity. The mixture was therefore purified on silica gel by flash column chromatography (50% EtOAc/Hexanes) to afford the title compound as a bright orange solid (23.2 mg, 20% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (3H, t), 3.12 (2H, q), 3.36 masked signal, 3.54 (4H, m), 7.39 (2H, br s), 7.44-7.48 (1H, d), 7.52-7.57 (1H, d), 8.06 (1H, m), 8.11 (1H, m), 8.24 (1H, s) ppm; MS (ES+) 405