Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:43]1([C:49]2[C:53]([C:54](O)=[O:55])=[CH:52][O:51][N:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[C:43]1([C:49]2[C:53]([C:54]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:55])=[CH:52][O:51][N:50]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1conc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1conc1-c1ccccc1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (8 mg, 0.06 mmol), TBTU (22 mg, 0.12 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (10 μL, 0.06 mmol) in DMF (0.6 mL) was added to 3-phenylisoxazole-4-carboxylic acid (11 mg, 0.06 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C19H17N3O2: 319.1321, found 319.1326.
Reaction SMILES: O[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:9])=[C:6]([S:18][CH3:19])[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:9])=[C:6]([S:18][CH3:19])[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc(-c2nc(O)c(C(=O)Nc3ccc(C)cc3)c(SC)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ccc(-c2nc(Cl)c(C(=O)Nc3ccc(C)cc3)c(SC)n2)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
4-Hydroxy-N-(4-methylphenyl)-6-(methylthio)-2-[4-(methylthio)phenyl] pyrimidine-5-carboxamide (0.5 g, 1.25 mmol) was refluxed in phosphorus oxychloride (10 ml) for 3 hours and subsequently cooled to room temperature. The reaction mixture was poured onto ice-water mixture, neutralised with saturated sodium bicarbonate solution and the solid thus separated was extracted with ethylacetate. The organic layer was washed with water; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound, 0.3 g, yield 57%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11]CC)=O.O.[NH2:15][NH2:16]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH:15][NH2:16])=[O:11]
Reactant: NN
Reactant: CCOC(=O)CCc1ccccn1
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1ccccn1

Procedure:
To a stirring 5 mL EtOH solution of 0.58 g (3.2 mmol) of ethyl 3-(2-pyridinyl)propanoate (4), prepared as described above in Example 4, was added 0.32 g (6.5 mmol) of hydrazine hydrate. The reaction was heated at reflux for three weeks. Although the reaction was still incomplete, the solvent was removed under vacuum. The resulting gum was triturated with diethyl ether (Et2O). The product remained a gum. The yield of 3-(2-pyridyl)propanoic acid, hydrazide (5) was 0.22 g (42%). This product was used immediately in the manner described in Example 6 below.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20].[CH3:30][N:31]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[C:32]1[C:39](Cl)=[O:40]>CO.C(Cl)Cl.[Pd]>[CH3:30][N:31]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[C:32]1[C:39]([NH:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][C:5]2[CH:4]=[C:3]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:20])[N:2]([CH3:1])[CH:6]=2)=[O:9])[N:11]([CH3:18])[CH:12]=1)=[O:40]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide (0.343 g, 0.85 mmol; see Preparation 1(iv) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (200 mg) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (160 g, 0.85 mmol) in DCM (10 mL) was then added and allowed to stir for 1 h at RT, the solvent was removed under reduced pressure, the crude product obtained was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound.
Reaction SMILES: O=[C:2]([CH2:25][CH3:26])[CH:3]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])[C:4](=[O:15])[NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:9]1([C@@H:6]([NH:5][C:4]([C:3]2[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:2]=2[CH2:25][CH3:26])=[O:15])[CH2:7][CH3:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: CCC(=O)C(C(=O)N[C@@H](CC)c1ccccc1)c1ccccc1C(=O)O
Solvent: CC#N
Product: CCc1c(C(=O)N[C@@H](CC)c2ccccc2)c2ccccc2c(=O)n1-c1ccccc1
Yield: 39 %

Procedure:
A sealed mixture of 2-[2-oxo-1-((S)-1-phenyl-propylcarbamoyl)-butyl]-benzoic acid (82 mg, 0.2 mmol) and aniline (0.3 ml, 3.3 mmol) in acetonitrile (0.3 ml) was heated under microwave irradiation at +160° C. for 10 min. The mixture was partitioned between ethyl acetate (20 ml) and 3M aq. HCl (2×8 ml), sat. aq. NaHCO3 (2×10 ml and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (SiO2, gradient heptane-ethyl acetate) to give 32 mg of the title compound. LC-MS (m/z) 411.5 (MH+); tR=1.48. 1H NMR (500 MHz, DMSO-d6): a mixture of two atropisomers.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:42]2[CH2:43][CH2:44][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:40][CH2:41]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2,4-dihydroxybenzoate (5.1 g, 30.33 mmol) and triphenylphosphine (9.52 g, 36.3 mmol) were stirred in THF (200 ml) under nitrogen. The mixture was cooled in an ice bath and treated with a solution of 1-Boc-4-hydroxypiperidine (6.8 g, 33.8 mmol) and diethyl azodicarboxylate (5.73 ml, 6.34 g, 36.4 mmol) in THF (100 ml) added dropwise over 30 min. The mixture was stirred at ambient temperature for 18 hours, then diluted with ethyl acetate and washed with 1M NaOH, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 10% ethyl acetate in hexane, and the product fractions were evaporated to dryness in vacuo to give methyl 2-hydroxy-4-(1-Boc-4-piperidyloxy)benzoate.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:22][O:23][CH2:24][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([OH:12])=[O:11]
Reactant: COCCl
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(=O)O)ccc1OC
Yield: 76.5 %

Procedure:
In a similar manner to Step 1 of Example 347, isovanillic acid (5.00 g, 29.7 mmol) was suspended in dichloromethane (100 mL), and the suspension was treated with diisopropylethylamine (22.8 mL, 131 mmol) and chloromethyl methyl ether (4.96 mL, 65.4 mmol). The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL) and treated with 4 mol/L aqueous potassium hydroxide solution (50 mL). The solvent was evaporated under reduced pressure. The residue was added with 4 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-methoxymethoxy-4-methoxybenzoic acid (4.82 g, yield 76%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.Br.[CH2:27]([N:30]=[C:31]=[O:32])[CH:28]=[CH2:29]>COCCO>[CH2:27]([NH:30][C:31]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)=[O:32])[CH:28]=[CH2:29]
Reactant: C=CCN=C=O
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Agent: Br
Solvent: COCCO
Solvent: CCN(CC)CC
Product: C=CCNC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
Triethylamine (1.05 g) was added to 40 ml of a suspension containing 2.70 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide suspended in 2-methoxyethanol, and the mixture was stirred at room temperature for 10 minutes. To the mixture was added 1.10 g of allyl isocyanate, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The crystals obtained were washed with water, dried and then recrystallized from methanol to obtain 2.35 g of 2-[(ALLYLCARBAMOYL) amino]methyl-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:3]1.[H-].[Na+].I[CH2:24][C:25]#[N:26]>CN(C=O)C>[C:25]([CH2:24][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)#[N:26]
Reactant: Cc1cc(O)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC#N)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of tert-butyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 1.80 mmol) in DMF (10 mL) was added 60% NaH (215.8 mg, 5.40 mmol) in DMF (5 mL) at 0° C. The reaction mixture was stirred for 30 min, followed by addition of 2-iodoacetonitrile (450.5 mg, 2.70 mmol). The reaction mixture was stirred for an additional 5 h at room temperature, quenched by water (15 mL) at 0° C., and acidified by 1N HCl to pH=7. The resulting mixture was extracted by EtOAc (3×10 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as a white solid (120 mg, yield: 21%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:54]1[CH:55]=[CH:56][C:57]2[N:79]([CH:80]=1)[C:60]1[N:61]([C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)[C:62](=[O:69])[C:63]3[C:68]([C:59]=1[N:58]=2)=[CH:67][CH:66]=[CH:65][CH:64]=3.[N:81]1([CH2:86][CH2:87][NH2:88])[CH2:85][CH2:84][CH2:83][CH2:82]1>O1CCOCC1>[N+:76]([C:73]1[CH:72]=[CH:71][C:70]([N:61]2[C:60]3[N:79]4[CH:80]=[C:54]([NH:88][CH2:87][CH2:86][N:81]5[CH2:85][CH2:84][CH2:83][CH2:82]5)[CH:55]=[CH:56][C:57]4=[N:58][C:59]=3[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]2=[O:69])=[CH:75][CH:74]=1)([O-:78])=[O:77]
Reactant: O=c1c2ccccc2c2nc3ccc(Br)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: NCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: O=c1c2ccccc2c2nc3ccc(NCCN4CCCC4)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 25.5 %

Procedure:
An oven-dried pyrex screw-tube was charged with rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ((rac)-BINAP) (0.3 equiv., 0.138 mmol, 0.086 g), Pd2(dibenzylidene-acetone)3 (Pd2 dba3) (0.1 equiv., 0.046 mmol, 0.042 g) and Cs2CO3 (1.4 equiv., 0.643 mmol, 0.210 g). Dry dioxane (1 ml) was added and the screw-tube was purged with Ar. The reaction mixture was heated at 80° C. for 30 min, after which it was allowed to cool to room temperature. 9-Bromo-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-5(6H)-one (18) (1.0 equiv., 0.460 mmol, 0.200 g) and pyrrolidineethanamine (1.0 equiv., 0.460 mmol, 0.052 g) were added and the reaction mixture was stirred at 100° C. until no starting materials were left. The progress of the reaction was monitored by LCMS. Removal of the solvent under reduced pressure, followed by column chromatography (gradient elution: dichloromethane→dichloromethane/methanol 9:1) of the resulting residue gave 6-(4-nitrophenyl)-9-(2-pyrrolidin-1-yl-ethylamino)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (67) (0.055 g, yield=26%, purity (LC)=97%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:13]=[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][N:11]3[CH:15]=2)=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3cc(-c4ccccc4)ccc3n2)cc1
Yield: 49 %

Procedure:
Dissolving crude 5-phenyl-2-amino-pyridine obtained and 8.0 g (29 mmol) of 2,4′-dibromo acetophenone into 100 milliliter of ethanol, adding 3.7 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 3 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 5.4 g of 2-(4-bromo-phenyl)-6-phenyl-imidazo [1,2-a] pyridine (yield: 49%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>CS(C)=O.CCOC(C)=O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][O:17][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: COCCOCOc1cccc(CO)c1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOCOc1cccc(COc2ccc3ccccc3n2)c1
Reaction time: 0.33 h

Procedure:
To a suspension of 60% NaH (44 mg, 1.1 mmol) in DMSO (2 mL) is added dropwise a solution of [3-(2-methoxy-ethoxymethoxy)-phenyl]-methanol (212 mg, 1.0 mmol, example 72) in DMSO (1 mL). Let stir 20 min. then added 2-chloroquinoline (180 mg, 1.1 mmol) and heated to 100° C. for 1 hr. Cooled reaction mixture to room temp. and diluted with EtOAc. The organic layer is washed with sat. NH4Cl soln., brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 25% ethyl acetate in hexanes) to give the title compound as a colorless oil. MS (ESI) 340 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1CCN2C(=NCCC2)CC1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU (27.6 mmol, 4.13 mL) was injected followed by cyclohexylmethyl bromide (23.0 mmol, 3.21 mL) and the reaction was warmed to 55° C. After stirring for 15 hours, the reaction was cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was removed under vacuum, and the crude product was triturated with hexanes providing 3.05 g (64%) of an off-white colored solid. H1-NMR (CDCl3): δ7.80 (2H,m), 7.73 (2H,m), 3.98 (2H,d), 2.03-1.65 20 (5H,m), 1.31-1.03 (6H,m).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>>[CH3:3][CH:2]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: Oc1ccccc1Br
Reactant: CC(C)CCCC(C)Br
Product: CC(C)CCCC(C)Oc1ccccc1Br

Procedure:
In the same manner as Example 1: 2-bromo- 6-methyl-heptane was reacted with o-bromo-phenol to obtain o-bromo-phenyl 1,5-dimethyl-hexyl ether (boiling point = 190°-193°C/17 mmHg);
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][N:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][N:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccno2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccno2)cc1

Procedure:
Bisbenzoyl peroxide (560 mg, 0.232 mmol) is added to a solution of 2.17 g (13.65 mmol) of 5-(4-methyl-phenyl)-isoxazole (Lin, Y.-i.; Lang, Jr., S. A. J. Org. Chem. 1980, 45, 4857) and N-bromosuccinimide (2.43 g, 13.65 mmol) in 64 mL of CCl4, and the reaction mixture is heated at reflux overnight. The reaction mixture is then concentrated in vacuo, and the product is purified by chromatography on silica gel (20% EtOAC/hexane, Rf=0.6) to yield 5-(4-bromomethyl-phenyl)-isoxazole. 1H NMR (250 MHz., CDCl3) δ8.30 (d, 1 H), 7.73 (d, 2 H), 7.45 (d, 2 H), 6.51 (d, 1 H), 4.50 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:13][NH2:14])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cccc(Br)c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Methyl 3-bromobenzoate (2 g, 9.3 mmol) was dissolved in 25 ml ethanol. Hydrazine hydrate (4.5 ml, 92.9 mmol) was added and the reaction was stirred at 80° C. overnight. The reaction mixture was evaporated under reduced pressure and a white solid was formed. This solid was washed with water and diethyl ether and dried in the vacuum oven to afford 1.8 g (90% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:12](CC)CC)C>C(#N)C>[C:1]([NH2:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To 3,3′-(3-amino-2,6-pyridinediylbistoxy)]bis(benzonitrile) (1.0g, 2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirring for 3 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3) as eluent gave N-[2,6-bist3-cyanophenoxy)-pyridin-3-yl]benzamide; NMR (CDCl3) 8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[N:14]=[C:15](F)[CH:16]=[CH:17][C:11]=2[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH2:1]([N:8]1[CH2:13][C:12]2[N:14]=[C:15]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=3[O:27][CH3:26])[CH:16]=[CH:17][C:11]=2[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C1N(Cc2ccccc2)Cc2nc(F)ccc2N1c1ccccc1
Product: COc1ccc(CNc2ccc3c(n2)CN(Cc2ccccc2)C(=O)N3c2ccccc2)c(OC)c1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
A mixture of 3-benzyl-6-fluoro-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (112 mg, 0.34 mmol, 1.0 equiv) and 2,4-dimethoxybenzyl-amine (1.0 mL, 6.7 mmol, 20 equiv) was heated in the microwave reactor at 150° C. for 2 h. The crude reaction mixture was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-50%) to afford 3-benzyl-6-(2,4-dimethoxy-benzylamino)-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (66 mg). MS: [M+H]+=481.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([CH2:60][C:61]([N:63]2[CH2:67][CH2:66][C@H:65]([NH:68][C:69]([O:71][CH2:72][C:73]3[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=3)=[O:70])[CH2:64]2)=[O:62])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:57]([C:54]1[CH:55]=[CH:56][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])[CH2:43][C@H:44]2[CH2:60][C:61]([N:63]2[CH2:67][CH2:66][C@H:65]([NH:68][C:69]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=3)=[O:70])[CH2:64]2)=[O:62])=[O:48])=[CH:52][CH:53]=1)([O-:59])=[O:58]
Reactant: O=C(N[C@H]1CCN(C(=O)C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CC(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@@H]12
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (478 mg) in anhydrous acetonitrile (5.5 ml), a solution of (2R,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonylmethyl]pyrrolidine (450 mg) in anhydrous acetonitrile (5.5 ml) and diisopropylethylamine (0.140 ml) were added under ice cooling. The resulting mixture was allowed to stand for one day at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water and saline, dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography on a silica gel column. From the fraction eluted with ethyl acetate-methanol (20:1), 4-nitrobenzyl (1R,5R,6S)-2-[(2R,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonylmethyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (675 mg) was obtained as a powder.