Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][C:10]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[N:11][CH:12]=1)[CH3:2].[ClH:28]>O1CCOCC1.CO.C(OCC)(=O)C.O>[ClH:28].[ClH:28].[NH:16]1[CH2:17][CH2:18][CH2:19][C@@H:14]([NH:13][C:10]2[N:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:27])=[N:8][CH:9]=2)[CH2:15]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cn1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-piperidinecarboxylate (6.26 g) in a mixture of 1,4-dioxane (25 mL) and MeOH (5 mL) was added 4N hydrogen chloride solution in ethyl acetate (30 mL) in water bath. The mixture was stirred at same temperature for 3 hrs. After evaporation of solvent, the residue was triturated with isopropylether to give ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (5.8 g) as an amorphous powder. 1H-NMR (300 MHz, DMSO-d6) δ 1.25 (3H, t, J=7 Hz), 1.46-1.65 (1H, m), 1.65-1.85 (1H, m), 1.85-2.06 (3H, m), 2.66-3.00 (2H, m), 3.05-3.25 (1H, m), 3.25-3.41 (1H, m), 4.18 (2H, q, J=7 Hz), 6.54 (1H, d, J=15 Hz), 7.57 (1H, d, J=15 Hz), 7.95-8.19 (2H, m), 8.28 (1H, s), 9.14 (2H, br peak)
Reaction SMILES: C(C1OC1)Cl.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=CC1=O>CCOCC.C(Cl)Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:11]([O:12][C:13]1[CH:14]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N+:28]=1[CH3:27])[CH3:10]
Reactant: Cn1c(=O)ccc2ccccc21
Reactant: CCOCC
Agent: CC[O+](CC)CC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClCC1CO1
Product: CCOc1ccc2ccccc2[n+]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Triethyloxonium fluoroborate is prepared from 3.70 g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58 g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The resulting solid triethyloxonium fluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 6.47 g (0.040 mole) of N-methyl-2-quinolone in 15 ml of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight. The solid is filtered to give 9.2 g (83.5%) of 2-ethoxy-1-methylquinolinium fluoroborate.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28]>CN(C=O)C.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>[CH3:30][Si:29]([C:27]#[C:28][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.65 g, 4.40 mmol) and Cu(I)I (168 mg, 0.880 mmol) in triethylamine (3.07 mL, 22.0 mmol) and DMF (40 mL) for 20 min. Then, ethynyltrimethylsilane (2.16 g, 22.0 mmol) and Pd(PPh3)4 (254 mg, 0.220 mmol) were added, the reaction was flushed with nitrogen, sealed and stirred at rt for 24 h. The reaction was concentrated to a brown oil, and purified by BIOTAGE® Horizon (160 g SiO2, 20-40% EtOAc/hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (980 mg) as a yellow solid. LC-MS retention time 3.230 min; m/z 346.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) d ppm 7.18 (s, 1 H), 4.77 (dd, J=9.2, 5.1 Hz, 1 H), 3.20 (br. s., 1 H), 3.14-3.39 (m, 1 H), 2.33 (dd, J=13.2, 9.4 Hz, 1 H), 1.69-1.78 (m, 1 H), 1.34-1.56 (m, 1 H), 1.49 (s, 9 H), 0.85 (dt, J=8.5, 5.7 Hz, 1 H), 0.41-0.47 (m, 1 H), 0.22-0.24 (m, 9 H).
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[C:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)[CH2:19][CH2:18]1)=[O:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.Cl.C(OCC)(=O)C.C(N(CC)CC)C.[C:52](Cl)(=O)[C:53](C)([CH3:55])[CH3:54].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[CH:33]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:23](=[C:20]3[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][CH:9]([NH:8][C:6](=[O:5])[C:53]([CH3:55])([CH3:54])[CH3:52])[C:10]([O:12][CH3:13])=[O:11])[CH2:22][CH2:21]3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)C(CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
600 mg (1.19 mmol) of methyl 2-[(t-butoxycarbonyl)amino]-4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoate was dissolved in 5 ml of ethyl acetate. 0.5 ml of 4 N hydrochloric acid/ethyl acetate solution was added to the obtained solution, and they were stirred at 0° C. for 3 hours. After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane. 602 mg (5.95 mmol) of triethylamine and 158 mg (1.31 mmol) of pivaloyl chloride were added to the obtained solution, and they were stirred for 10 minutes. Saturated aqueous sodium hydrogencarbonate solution and water were added to the reaction mixture. After extracting with ethyl acetate 3 times followed by the drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane:ethyl acetate=89:11 to 65:35) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([N:37]4[CH2:38][CH2:43][CH2:42][CH2:41]4)=[O:24])[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])([CH3:2])([CH3:4])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(C(=O)O)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(C(=O)N4CCCC4)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing 55 mg (0.12 mmol) of the product from Step C with 24 mg (0.18 mmol) of 1-hydroxybenzotriazole, 0.015 mL (0.18 mmol) of pyrrolidine, and 0.031 mL (0.18 mmol) of N,N-diisopropylethylamine in 1.0 mL of DMF was added 35 mg (0.18 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. The resulting mixture was stirred at ambient temperature for 16 h, then concentrated and purified directly by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 80% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 515.2 (M+1).
Reaction SMILES: [NH:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[S:3]1.SC1C=C(OC)C=CC=1C(C1C=CC=C(OC)C=1)=O.C(#N)C[C:45]#[N:46].N1CCCCC1>C(O)C>[NH:1]=[C:2]1[C:11]([C:45]#[N:46])([C:12]#[N:13])[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[S:3]1
Reactant: N#CCC#N
Reactant: COc1cccc(-c2c(C#N)c(=N)sc3cc(OC)ccc23)c1
Agent: COc1cccc(C(=O)c2ccc(OC)cc2S)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(C2c3ccc(OC)cc3SC(=N)C2(C#N)C#N)c1
Yield: 75 %

Procedure:
2-Imino-3-cyano-7-methoxy-4-(3-methoxy-phenyl)-2H-thiochromene: To a mixture of (2-mercapto-4-methoxyphenyl)-(3′-methoxyphenyl)-methanone (35 mg, 0.13 mmol) and malononitrile (8.5 mg, 0.13 mmol) in approximately 200 μL of dry ethanol was added piperidine (7.0 μL, 0.06 mmol) at approximately 0° C. The resultant mixture was stirred at approximately 0° C. for approximately 2.5 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, EtOAc:hexanes, 1:4) to yield 31 mg (75%) of 2-imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene-3-carbonitrile as an orange waxy oil. 1H NMR (CDCl3): 9.31 (brs, 1H), 7.42-7.46 (m, 1H), 7.03-7.11 (m, 2H), 6.91 (d,J=7.8 Hz, 1H), 6.85-6.86 (m, 1H), 6.80 (bs, 1H), 6.68 (dd, J=9.1, 2.6 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1>N1C=CC=CC=1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:11]([F:16])[CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)cc1F
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Pivaloyl chloride (72 mL, 580 mmol) was added slowly (caution—exothermic reaction) to an ice cold solution of 4-bromo-2-fluoroaniline (100 g, 526 mmol) in pyridine (200 mL). After the addition, the ice bath was removed and the hot reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into cold water (500 mL) and the precipitated product was collected by filtration and washed with 1N HCl. The solid was dissolved in EtOAc (1 L), dried over MgSO4, filtered, and concentrated under vacuum to provide N-(4-bromo-2-fluorophenyl)-2,2-dimethylpropanamide (125 g).
Reaction SMILES: CC[O-].[Na+].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][CH:13](Br)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[F:12][CH:13]([S:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C(F)Br
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)Sc1ccccc1
Yield: 89.6 %

Procedure:
To 150 ml of tetrahydrofuran (THF) were added 6.5 g (0.1 mole) of pulverized EtONa and 11.1 g (0.1 mole) of thiophenol and the mixture was refluxed for 10 minutes. Thereto was added 18.5 g (0.1 mole) of ethyl fluorobromoacetate and the mixture was refluxed for one hour with stirring. THF was removed by an evaporator and the precipitated NaBr was filtered. The organic layer was washed with water, dried and distilled to obtain 19.2 g (90%) of ethyl fluoro(phenylthio)acetate.
Reaction SMILES: [CH2:1]([CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][CH:9]1[C@H:20]([N:24]1[CH:28]=[C:27]([CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[N:26]=[C:25]1[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:30][CH2:29][C:27]1[N:26]=[C:25]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:24]([C@@H:20]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:18])[C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=[C:13]([Cl:19])[CH:12]=3)[CH:21]([CH3:23])[CH3:22])[CH:28]=1
Reactant: Cc1ccc(-c2nc(CN3C(=O)c4ccccc4C3=O)cn2[C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
To N-{1-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-chromen-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-ylmethyl}-phthalimide (0.50 g, 0.78 mMol) in EtOH (15 mL) was added hydrazine monohydrate (0.12 mL, 2.5 mMol). The reaction was stirred at RT for 72 h, filtered through a pad of Celite® to remove the insoluble precipitate, rinsed with EtOH and evaporated to dryness. Purification by flash chromatography on silica gel [5-10% (5% NH4OH in MeOH)/CH2Cl7] gave the title compound (364 mg, 91%) as a white solid foam: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1 H), 7.63 (d. J=1.8 Hz, 1 H), 7.37 (m, 6 H), 7.15 (m, 3 H), 6.71 (d, J=1.7 Hz, 1 H). 6.69 (s. 1 H), 5.00 (d, J=10.9 Hz, 1 H). 4.07 (d. J=15.5 Hz. 1 H). 3.92 (d. 1 H). 3.88 (d. 1 H), 2.72 (br s. 2 H). 2.65 (m. 1 H). 2.49 (s, 3 H). 2.48 (d. J=15.5 Hz. 1 H). 0.93 (d. J=6.6 Hz. 3 H). 0.30 (d. J=6.7 Hz. 3 H): MS (ES) m/e 512.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][CH3:27])[C:21]([OH:23])=O)[N:19]=1.Cl.[NH2:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])=[C:34]([Cl:37])[CH2:35][S:36][C@H:31]12.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O1CCCC1.O.CN(C)C=O>[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][CH3:27])[C:21]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=4)=[O:39])=[C:34]([Cl:37])[CH2:35][S:36][C@H:31]23)=[O:23])[N:19]=1
Reactant: CCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Phosphoryl chloride (1.76 g.) and trimethylsilylacetamide (0.4 g.) were added to a stirred suspension of 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 1.0 g) in tetrahydrofuran (10 ml.) below 5° C., and stirred at the same temperature for 30 minutes. N,N-Dimethylformamide (0.4 g.) was added to the solution and stirred below 5° C. for 20 minutes [Solution A]. Trimethylsilylacetamide (4.8 g.) was added to a stirred suspension of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (1.9 g.) in tetrahydrofuran (15 ml.), and the solution was stirred at room temperature for an hour. To the solution was added the above Solution A all at once at -20° C., and the solution was stirred at 0° C. for an hour. Water (50 ml.) was added to the resultant solution at -20° C., and adjusted to pH 8.0 with an aqueous solution of sodium bicarbonate. Tetrahydrofuran (50 ml.) and a saturated aqueous solution of sodium chloride (50 ml.) were added to the solution. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After concentrating the solution under reduced pressure, the residue was triturated with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.0 g.).
Reaction SMILES: [OH-].[Na+].Cl[O-].[Na+].[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14](Br)=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10].[C-]#N.[Na+].[CH3:22][NH:23]CCNC>[Cu]I>[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]([C:22]#[N:23])=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNCCNC
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
A 500-mL four-necked flask equipped with a mechanical stirrer, thermocouple, condenser and sodium hydroxide/sodium hypochlorite scrubber was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Example 1) (99.1% purity, 24.1 g, 0.10 mol) and xylenes (100 g) while maintaining an atmosphere of argon through a gas inlet line connected to the condenser. The mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (6.2 g, 0.121 mol, assuming 95% purity), copper(I) iodide (2.9 g, 0.015 mol) and N,N′-dimethylethylenediamine (7.6 g, 0.085 mol) were added. Stirring was continued for an additional 15 to 20 minutes while the mixture was purged with argon, after which time the mixture was maintained under an argon atmosphere. The mixture was heated at reflux (about 140° C.), while venting through the scrubber. After 4.5 h the mixture was cooled to 25° C., water (100 mL) was added over 5 minutes, and stirring was continued for an additional 30 minutes. The mixture was filtered and the solid collected was washed with water (2×50 mL) and xylenes (50 mL), and then dried to a constant weight in a vacuum-oven at 55° C. to give the title compound (18.2 g) as an off-white solid melting at 203-204° C.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:26]2[CH:47]=[CH:46][C:29]([C:30]([N:32]3[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[O:31])=[CH:28][C:27]=2[C:48]#[N:49])=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[N:18][N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(#N)C.CO>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:26]2[CH:47]=[CH:46][C:29]([C:30]([N:32]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][C:27]=2[C:48]#[N:49])=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[N:18][N:19]=1
Reactant: Cc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)cc3C#N)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: Cc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N4CCCNCC4)cc3C#N)cnc2N)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43.8 %

Procedure:
tert-Butyl 4-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3-cyano-benzoyl]-1,4-diazepane-1-carboxylate (9.9 g, 11.32 mmol) was dissolved in anhydrous CH2Cl2 (100 mL) at room temperature and TFA (10 mL, 129.8 mmol) added. Additional TFA (10 mL, 129.8 mmol) was added and the reaction mixture stirred at room temperature for 3.5 h and then concentrated in vacuo. The material was dissolved in a mixture of acetonitrile and methanol (10; 1 mixture) and PS—HCO3 (5 eq) added. The mixture was stirred for 1 h at room temperature and then the resin removed by filtration and washed with acetonitrile and methanol. The filtrate was concentrated in vacuo and the residue recrystallised from acetonitrile. The isolated solid was washed with ether and dried to give the product as a yellow solid (2.41 g, 35% yield); 1H NMR (400 MHz, DMSO) d 1.76-1.84 (m, 2H), 2.67 (s, 3H), 2.88-2.93 (m, 4H), 3.42-3.44 (m, 2H), 3.67-3.74 (m, 2H), 7.2 (d, 1H), 7.84-7.87 (m, 1H), 7.89-7.99 (m, 1H), 8.04-8.09 (m, 2H) and 8.85 (s, 1H) ppm; MS (ES+) 487.26
Reaction SMILES: Cl.CN[O:4][CH3:5].[CH3:6][CH:7]([CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[C:8]([N:10]1[C@@H:14](CC2C=CC=CC=2)COC1=[Se])=[O:9]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:27][CH:23]([CH:24]([CH3:25])[CH3:26])[CH:7]([CH3:6])[C:8]([N:10]([O:4][CH3:5])[CH3:14])=[O:9]
Reactant: CNOC
Reactant: CC(C)C(O)C(C)C(=O)N1C(=[Se])OC[C@@H]1Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C(C)C(O)C(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 55.5 %

Procedure:
N,O-Dimethylhydroxyl-amine hydrochloride (380 mg, 3.90 mmol) and 4-dimethylaminopyridine (244 mg, 2.00 mmol) was added to a solution of (4S)-3-(2,4-dimethyl-3-hydroxyl-1-oxopentyl)-4-(phenylmethyl)-2-oxazolidineselone (616 mg, 2.00 mmol) in CH2Cl2 (10 mL). The resulting solution was stirred at room temperature for 4 days. The solvent was removed under reduced pressure. Purification of the residue by silica gel column chromatography (CH2Cl2/ether; 95/5; v/v) afforded 210 mg (55%) of 3-hydroxy-N-methoxy-N,2,4-trimethyl-pentanamide. 1H NMR δ 3.94 (br s, 1H), 3.72 (s, 3H), 3.45 (dd, 1H, J=8.4 Hz, J=2.1 Hz), 3.21 (s, 3H), 3.10 (br m, 1H), 1.73 (m, 1H), 1.16 (d, 3H, J=7.1 Hz), 1.04 (d, 3H, J=6.6 Hz), 0.88 (d, 3H, J=6.8 Hz); 13C NMR δ 178.48, 76.90, 61.48, 35.72, 31.88, 30.20, 19.16, 18.90, 9.90
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16]Br.C(OCC)(=O)C>ClCCl.CCCCCC>[Br:16][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:9]
Reactant: COc1ccc(N)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
To a solution of p-anisidine (10 g, 0.08 mol) and sodium carbonate (17.2 g, 0.16 mol) in dichloromethane (400 ml) was added a solution of bromine (3.8 ml), 0.072 mol) in dichloromethane (200 ml) dropwise. The reaction was stirred at ambient temperature for 45 minutes, diluted with dichloromethane (200 ml) and washed with water (2×200 ml). The organic layer was dried over magnesium sulphate, and the solvent was removed in vacuo to yield a dark brown oil. Chromatography on silica eluting with a gradient of ethyl acetate in hexane (10%, 15% and 20%) afforded the title compound as a dark red oil (4 g, 25%), m/z (ES+) 202 (M30 +H, 100%). 1H NMR (250 MHz, CDCl3) δ 3.73 (3H, s), 3.78 (2H, broad s), 6.72 (2H, t, J 1.2 Hz), 7.00 (1H, q, J 1.26 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[F:25])[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
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: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1F
Yield: 65.5 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol), 1-(2,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (97.4 mg, 0.367 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.40 mmol) and in the same manner as in Example 65, the title compound (115 mg, 66%) was obtained as a white solid.