Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].[CH:16]1(O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]#[CH:12])[C:13]([O:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: OC1CCCC1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of Boc-L-propargyl glycine (5 g, 23.45 mmol) in DCM (100 ml) was added cyclopentanol (3.03 g, 35.2 mmol), EDC (4.93 g, 25.8 mmol) and DMAP (0.286 g, 2.345 mmol). The mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the residue was subjected to column chromatography eluting with 7 to 12% EtOAc in hexanes. Yield=5.5 g, 19.55 mmol, 83% yield.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[CH:6]=[CH:5]2.C(N(CC)CC)C.C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:57]=[O:58]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:57]=[O:58])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc2cc(I)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Solvent: CCN(CC)CC
Product: Nc1ccc2cc(C=O)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
A mixture of 6-iodo-quinolin-2-ylamine (200 mg, 0.74 mmol), triethylamine (0.26 mL, 1.85 mmol), diphenylpropylphosphine (dpp, 17 uL, 0.074 mmol) and palladium(II) acetate (17 mg, 0.074 mmol) in dry N,N-dimethylformamide (4 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (0.53 mL, 1.5 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 4 h. The reaction was allowed to cool to 25[ ]C and then extracted with methylene chloride (2×50 mL). The combined organic layers were successively washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, ethyl acetate) afforded 2-amino-quinoline-6-carbaldehyde (30 mg, 24%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[NH3:10]>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:9])[CH:3]=1)[NH2:10]
Reactant: Fc1cc(F)cc(F)c1
Reactant: N
Product: Nc1cc(F)cc(F)c1

Procedure:
In a further embodiment, the present invention relates to a method for the two step preparation of 3,5-difluoroaniline from 1,3,5-trichlorobenzene. First, an amount of 1,3,5-trichlorobenzene is reacted with a fluoride-containing compound to obtain 1,3,5-trifluorobenzene. Second, the 1,3,5-trifluorobenzene is reacted with aqueous ammonia and a metal oxide or metal hydroxide to obtain the product 3,5-difluoroaniline.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[N:8]([C:11]1[C:16]([F:17])=[C:15]([F:18])[C:14]([CH:19]=[CH:20][C:21]2[C:25]([CH3:27])([CH3:26])[O:24][C:23](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[C:22]=2[C:33]#[N:34])=[C:13]([F:35])[C:12]=1[F:36])=[N+]=[N-].N1C=CNN1.N1CC1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[CH:2]2[N:8]1[C:11]1[C:12]([F:36])=[C:13]([F:35])[C:14]([CH:19]=[CH:20][C:21]2[C:25]([CH3:27])([CH3:26])[O:24][C:23](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[C:22]=2[C:33]#[N:34])=[C:15]([F:18])[C:16]=1[F:17]
Reactant: C1=CC2CCC1C2
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1c(F)c(F)c(N=[N+]=[N-])c(F)c1F
Agent: C1=CNNN1
Agent: C1CN1
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Reaction time: 0.08 h

Procedure:
Norbornene (excess amount) and 2-{4-[2-(4-azido-2,3,5,6-tetrafluoro-phenyl)-vinyl]-3-cyano-5,5-dimethyl-5H-furan-2-ylidene}-malononitrile (SM) were mixed together in an NMR tube with CDCl3. The NMR tube was spinning in the NMR instrument and the reaction began instantly. After 5 minutes, some starting material was converted to the dihydrotriazole compound (its structure was identified from its NMR data), which is quite unstable and converted only to the rearrangement product, an aziridine compound at these reaction conditions (the aziridine compound formed here has the same NMR spectrum as the aziridine compound prepared independently). After about 2 h, the starting material was almost gone and the aziridine compound was the main component. After 4 h, the aziridine compound is the only component with some minor byproducts.
Reaction SMILES: C1(S(C2C=CC(CC[C@@H](O)CO)=C(Br)C=2)(=O)=O)C=CC=CC=1.[C:23]1([S:29]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][C@H:38]([CH2:42][NH:43][CH3:44])[O:39]3)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([S:29]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][C@@H:38]([CH2:42][NH:43][CH3:44])[O:39]3)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Agent: O=S(=O)(c1ccccc1)c1ccc(CC[C@@H](O)CO)c(Br)c1
Product: CNC[C@@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1

Procedure:
((S)-7-Benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine was prepared as a hydrochloride salt following the procedure described for the corresponding (R) enantiomer in step 10 of Example 6, but substituting ((S)-7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine for ((R)-7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine: Mp 270.0-270.4° C.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH:17]([CH2:28][CH3:29])[CH2:16]1)C1C=CC=CC=1>ClCCl>[Cl:27][C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]2[CH2:28][CH3:29])[CH:26]=[N:25][CH:24]=1
Reactant: CCC1CN(Cc2ccccc2)CCN1c1cncc(Cl)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCC1CNCCN1c1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-Choroethyl chloroformate (4.16 g, 29.1 mmol) was added dropwise under 2 h to a stirred solution of the product obtained in step 2 above (6.15 g, 19.4 mmol) in dry dichloromethane (75 mL) at 0° C. After being stirred at room temperature for 15 h, the reaction mixture was concentrated in vacuo and methanol was added. The mixture was heated at reflux for 2 h and concentrated. The residue was dissolved in CHCl3 and passed through a short (4 cm) plug of silica gel using CHCl3/MeOH (8:2) as eluent. Solvents were evaporated off and the residue was purified by chromatography on silica gel (12×5 cm) using CHCl3/MeOH/Et3N (95:5:0.2) as eluent. This provided 1.9 g (43%) of the title compound as an oil. MS m/z 226/228 (M)+(35Cl/ 37Cl-isotope pattern). HRMS m/z calcd for C10H15ClN4(M)+ 226.0985, found 226.0986.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: Cc1ccc(Br)nc1
Reactant: N#CCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)c2ccc(F)cc2)nc1
Yield: 66.1 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-5-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. and the mixture was heated to reflux for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 2-(α-cyano-4-fluorobenzyl)-5-methylpyridine (4.35 g) as yellow oil.
Reaction SMILES: C(NCCC1C=CC(S([NH:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([Cl:26])[CH2:22][CH2:21]2)=[O:18])(=O)=O)=CC=1)(=O)C.[OH-].[Na+].O.COC1C=CC(Cl)=CC=1C(Cl)=O>CC(C)=O>[Cl:26][CH:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[NH2:16])[CH2:25][CH2:24]1
Reactant: CC(=O)NCCc1ccc(S(=O)(=O)NC(=O)NC2CCC(Cl)CC2)cc1
Agent: COc1ccc(Cl)cc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)NC1CCC(Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 g of N-[4-(β-acetoamido-ethyl)-benzenesulfonyl]-N'-(4-chlorocyclohexyl)-urea (melting point 151° -153°C) are heated under reflux for 2 hours with 1.6 g of sodium hydroxide and 30 ml of water. Then the whole is cooled to room temperature, 20 ml of acetone are added and 1.2 g of glacial acetic -chlorobenzamido>-ethyl)-benzenesulfonyl] acid, and 4.1 g of 2-methoxy-5-chlorobenzoylchloride are added in portions and stirring is continued for 1 hour. The precipitate if filtered off with suction, stirred with bicarbonate solution and recrystallized from methanol/dimethylformamide. The N-[4-(β-<-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4-chlorocyclohexyl)-urea obtained melts at 178°-179°C.
Reaction SMILES: OC1N=C2C=C(/C=C/C3SC=C(C(C)C)N=3)C=CN2C(=O)C=1.OC1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=CN3C(=O)C=2)C1.[CH:51]([O:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[N:61]=[C:62]3[CH:79]=[C:78](/[CH:80]=[CH:81]/[C:82]4[S:83][CH:84]=[C:85]([CH:87]([CH3:89])[CH3:88])[N:86]=4)[CH:77]=[CH:76][N:63]3[C:64](=[O:75])[C:65]=2/[CH:66]=[CH:67]/[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:55]1)=[O:52]>>[CH:51]([O:53][C@@H:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[N:61]=[C:62]3[CH:79]=[C:78](/[CH:80]=[CH:81]/[C:82]4[S:83][CH:84]=[C:85]([CH:87]([CH3:89])[CH3:88])[N:86]=4)[CH:77]=[CH:76][N:63]3[C:64](=[O:75])[C:65]=2/[CH:66]=[CH:67]/[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:55]1)=[O:52]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(OC=O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(N4CCCC(O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@@H](OC=O)C4)nc3c2)n1
Yield: 56 %

Procedure:
2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (500 mg, 1.60 mmol) was treated in the same manner as in Example 102, (F) and (G) to obtain the title compound (488 mg, 56%).
Reaction SMILES: [C:1]([C:20]1[NH:24][N:23]=[C:22]([S:25][CH2:26]Cl)[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28].[Na+]>CC(C)=O.O>[C:1]([C:20]1[NH:24][N:23]=[C:22]([S:25][CH2:26][I:28])[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCSc1n[nH]c(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: ICSc1n[nH]c(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of trityl-3-chloromethylthio-1,2,4-triazole (11.5 g: 30.0 mMol.) in acetone (150 ml) is added sodium iodide (9.00 g: 60.0 mMol.), and the mixture is stirred t 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodiumsulfate, and concentrated to give trityl-3-iodomethylthio-1,2,4-triazole as yellow crystals [NMR δ (CDCl3) ppm: 4.70(s, 2H), 7.1 to 7.2(m, 6H), 7.3 to 7.4(m, 9H), 7.96(s, 1H) : 13 g]. To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl) -2-trityloxyiminoacetylamino-3-argentiothio-3-cephem- 4-carboxylic acid diphenylmethyl ester 1-oxide (16.8 g : 15 mMol.) in hexamethylphosphoramide (90 ml) is added trityl-3-iodomethylthio -1,2,4-triazole (13 g). and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate mixed with saturated brine, and filtered through Celite. The organic layer is taken, washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=5:1-3:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(trityl-1,2,4-triazol-3-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester 1- oxide (11.29 g) as Pale brown foam. Yield: 59%. NMR δ (CDCl3) ppm: 1.49(s, 9H), 3.19, 3.82(ABq, J=18.5Hz, 2H), 4.19(d, J=4.6Hz, 1H), 4.16, 4.22(ABq, J=13.7Hz, 2H), 6.19(dd, J=4.6Hz, J=10.1Hz, 1H), 6.97(s, 1H), 7.05-7.5(m, 41H), 7.90(s, 1H), 8.04(d, J=10.1Hz, 1H), 8.30(brs, 1H). IR ν (CHCl3) cm-1 : 3400, 1804, 1725, 1689, 1543, 1496, 1449, 1371, 1040. 2) Acyl=(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl: Het=1-methyl-1.2.4-triazol-3-yl (4E3-2)
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][O:18][C@@H:17]1[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])C1C=CC=CC=1.[OH-].[Li+].OO.S([O-])([O-])=[O:35].[Na+].[Na+].Cl>O>[CH:22]([C@@H:17]1[C@H:16]([C:14]([OH:15])=[O:35])[CH2:21][CH2:20][CH2:19][O:18]1)=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S([O-])[O-]
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCCO[C@@H]1C=Cc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Product: O=C(O)[C@@H]1CCCO[C@@H]1C=Cc1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirring solution of (4R)-4-benzyl-3-[(2R,3R)-2-styryl-tetrahydro-pyran-3-carbonyl]-oxazolidin-2-one (177 mg, 0.453 mmol) in 4:1 tetrohydrofuran:water (2.27 mL) at 0° C. was added lithium hydroxide (17.3 mg, 0.724 mmol) dissolved in 900 μL of water. To the resulting solution was added 30 wt % aqueous hydrogen peroxide (205 μL) dropwise, and the now pale yellow solution was stirred for 30 min. The solution was then poured into water (50 mL) containing a 1.5 mL-aliquot of 1.3 M sodium sulfite, and the resulting aqeuous layer was acidified with 6N aqueous hydrogen chloride (10 mL). The aqueous layer was washed with ethyl acetate (3×50 mL), and the combined organic layers were washed with brine (15 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 33% ethyl acetate in hexanes) to yield the desired product 100 mg (95%) as a pale yellow oil. MS (ESI), m+/z: (M+H)+=233.2.
Reaction SMILES: Cl.[C:2]1([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C1(C)C=CC=CC=1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])[CH2:12][CH2:13]2)=[N:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 110 °C
Yield: 43.8 %

Procedure:
A 350 ml, pressure vessel was charged with 4-(phenylsulfonyl)piperazine hydrochloride (1.50 g, 5.71 mmol, Example 15, step 1), 2,5-dibromopyridine (1.76 g, 7.42 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of toluene, sodium tert-butoxide (1.37 g, 14.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.105 g, 0.114 mmol, Strem Chemical Inc, Newburyport, Mass.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (0.198 g, 0.343 mmol, Strem Chemical Inc, Newburyport, Mass.). The tube was sealed and heated at 110° C. for 3 h. After that time, the reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried (MgSO4) and concentrated to give a yellow solid. This solid was slurried with cold (0° C.) MeOH (25 mL) to give 1-(5-bromo-2-pyridinyl)-4-(phenylsulfonyl)piperazine (0.957 g) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C[Si]([C:16]#[N:17])(C)C.Cl.C(OCC)C>ClCCl.[I-].[Zn+2].[I-]>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:16]#[N:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Product: N#CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To a stirred solution of 3-nitrobenzaldehyde (5.0 g, 33.1 mmol) in dichloromethane (30 ml) at 0 ° C. was added trimethylsilyl cyanide (4.63 ml, 34.7 mmol). After stirring for 6 h at room temperature, zinc iodide (210 mg, 0.66 mmol) was added which caused the reaction mixture to warm and gently reflux. After 30 min, the reaction mixture was treated with hydrochloric acid (2M, 100 ml) and diethyl ether (150 ml) and stirred vigorously for 16 h. The phases were separated and the aqueous phase was further extracted with diethyl ether (3×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 and then 1:1). This gave the title compound as a clear oil (5.0 g, 85%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3Br)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1.C[Sn](C)(C)[Sn](C)(C)C>O1CCOCC1.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(Br)n1
Reactant: Brc1ncoc1-c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: C1COCCO1
Product: Cc1cccc(-c2ncoc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A solution of 5-benzo[1,3]dioxol-5-yl-4-bromo-oxazole (156 mg, 0.58 mmol), 2-bromo-6-methyl-pyridine (100 mg, 0.58 mmol, 1 equiv), 1,1,1,2,2,2-hexamethyl-distannane (190 mg, 0.58 mmol, 1 equiv) and tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol, 0.1 equiv) in 1,4-dioxane (6 mL) was heated to reflux overnight. The resulting reaction mixture was cooled to ambient temperature and concentrated in vacuo. Silica gel chromatography (gradient from hexane to 30% ethyl acetate in hexane) provided 2-(5-Benzo[1,3]dioxol-5-yl-oxazol4-yl)-6-methyl-pyridine (114 mg, 70%).[LCMS: Rt=1.79 min, M+H=281.2]
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]#[N:31])=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClC1C=CC=CC=1Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([Cl:12])=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:11])[N:31]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(Cl)cccc2Cl)cc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1Cc1ccc(Cl)cc1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a solution of 1.0 g of N-methyl-N-(p-toluenesulfonyl)-2,6-dichlorobenzohydrazonoyl chloride in 10 ml of o-dichlorobenzene at room temperature, were added 0.46 g of p-chlorobenzyl cyanide and 0.41 g of anhydrous aluminum chloride. The reaction mixture was heated at 120° C. for 30 minutes. Aster cooling, the section mixture was poured into iced-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.7 g of 5-(4-chlorobenzyl)-3 (2,6-dichlorophenyl)-1-methyl-1H-1,2,4-triazole. m.p.112°-115° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CO.[CH2:14]([OH:16])C.C(Cl)(Cl)Cl>O.C(Cl)(Cl)Cl>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[CH:14]=[O:16]
Reactant: CCO
Reactant: Oc1ccc2ccccc2c1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1c(O)ccc2ccccc12

Procedure:
In step (a), β-naphthol is preferably first added to an aqueous alcoholic alkaline medium, for instance a solution of an alkali metal hydroxide in a mixture of water and a C1-C4 aliphatic alcohol, especially methanol or ethanol, at an elevated temperature preferably at a temperature within the range of 70°-100° C. To the resulting pale brown emulsion, the chloroform reactant is then added slowly -- preferably dropwise -- at an elevated temperature, preferably 70°-100° C. After the addition of a few drops of chloroform, the reaction mixture assumes a blue colouration which is allowed to change to green before any further chloroform is added. Subsequently, chloroform is added slowly and at such a rate that the green colouration is maintained. After completion of the addition of chloroform, the alkali metal salt of 2-hydroxy-1-naphthaldehyde may be isolated e.g. by filtration, and washed, preferably with brine.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]([C:28](F)(F)F)=O.[CH2:32]([O:39][N:40]1[C:46](=[O:47])[N:45]2[CH2:48][C@H:41]1[CH2:42][CH2:43][C@H:44]2[C:49]([NH:51][NH2:52])=[O:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:51]([C:49]([C@@H:44]1[CH2:43][CH2:42][C@@H:41]2[CH2:48][N:45]1[C:46](=[O:47])[N:40]2[O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:50])[NH2:52])(=[O:25])[CH3:28]
Reactant: O=C(O)C(F)(F)F
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(N)C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
HATU (0.90 g, 2.48 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (1.0 g, 2.48 mmol), acetic acid (0.12 g, 2.07 mmol) and DIPEA (1.1 μg, 8.3 mmol) in dry DMF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The mixture was then quenched with saturated sodium chloride (50 mL) and exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 1:10 petroleum ether/EtOAc) to afford (2S,5R)—N-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.6 g, 73%). ESI-MS (EI+, m/z): 333 [M+H]+.