Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27]([CH2:30]Br)=[N:28][CH:29]=1.CCCCCC>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([CH2:30][N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:28][CH:29]=1
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: BrCc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(Cc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of ethyl 4-methylpiperidine-4-carboxylate hydrochloride (0.08 g, 0.48 mmol) in EtOH (5.0 mL) was added DIPEA (0.22 mL, 1.20 mmol) at rt and the mixture stirred at rt for 10 minutes followed by addition of 5-bromo-2-(bromomethyl)pyrimidine (0.10 g, 0.40 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 20% EtOAc:hexane to obtain the desired product as a yellow solid (0.10 g, 73% yield). 1H NMR (DMSO-d6): δ 1.09 (s, 3H), 1.13 (t, J=7.20 Hz, 3H), 1.45 (m, 2H), 2.00 (m, 2H), 3.12 (m, 2H), 3.32 (m, 2H), 3.62 (q, J=7.20 Hz, 2H), 4.08 (m, 2H) and 8.94 (s, 2H).
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]2[C:9]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:12][CH:13]=2)=[N:5][N:4]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>ClCCl>[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([CH2:2][C:3]2[O:7][C:6]([C:8]3[C:9]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:12][CH:13]=3)=[N:5][N:4]=2)[CH2:54][CH2:53]1
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)CCOc1nc(NCCc2ccncc2)ncc1-c1nnc(CO)o1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2nnc(-c3cnc(NCCc4ccncc4)nc3OCC[Si](C)(C)C)o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 mL of dichloromethane, 5-(5-hydroxymethyl[1,3,4]oxadiazol-2-yl)-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine (0.76 g, 1.83 mmol) obtained in Step 2 was dissolved, then methanesulfonic anhydride (0.48 g, 2.75 mmol) and triethylamine (0.37 g, 3.66 mmol) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, saturated aqueous sodium hydrogen carbonate solution was added and the reaction mixture was separated. Further, an aqueous layer was extracted with dichloromethane and those organic layers were combined. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), then 1-methylpiperazine (403 mg, 4.03 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, the mixture was treated as described above. The residue was purified by silica gel chromatography (chloroform/methanol) to give 5-[5-(4-methylpiperazinyl)methyl[1,3,4]oxadiazol-2-yl]-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine [Compound (IH) in which R2B is 2-(4-pyridyl)ethylamino and —X—Y—Z— is
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])(CC)C.[CH2:17]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)[CH2:18][CH3:19].O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:35]=[CH:34][CH2:33][CH2:32][C@H:29]2[CH2:30][CH2:31][C@H:26]([C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24]3)[CH2:27][CH2:28]2)=[C:6]([F:10])[C:5]=1[F:11])[CH3:2]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Reactant: CCOc1cccc(F)c1F
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=Cc3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
Under nitrogen gas stream, a solution of 30.7 g (194 mmol) of 1-ethoxy-2,3-difluorobenzene in 300 ml of THF was cooled down to −70° C., 194 ml of sec-butyl lithium (1.0M cyclohexane solution) was added by drops thereto while being maintained at the same temperature, and they were stirred at the same temperature for 2 hours. To this reaction mixture was added by drops a solution of 45.1 g (162 mmol) of the crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal obtained by the reaction in the fifth step in 450 ml of THF while being maintained at the same temperature, and stirred for 2 hours. Subsequently, they were raised up to −50° C. and stirred for 2 hours. The reaction mixture was added to 200 ml of water to terminate the reaction, the solvent was distilled off under a reduced pressure, the residue was extracted with 500 ml of toluene, and the organic layer was washed with 100 ml of water thrice, and then dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was removed by filtration, 2.83 g of p-toluenesulfonic acid monohydrate was added to the filtrate, and heated to reflux for 4 hours. The organic layer was washed with 200 ml of water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: mixed solvent of heptane/toluene=7/3) to obtain 50.2 g of a crude 1-ethoxy-2,3-difluoro-4-(4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butenyl)benzene.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O)=CC=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCC#C[Si](C)(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CCCN=[N+]=[N-]
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 4-(trimethylsilyl)but-3-ynyl 4-methylbenzenesulfonate (1.38 g; 4.65 mmol) and sodium azide (0.908 g; 13.96 mmol) in DMF (5 mL) was heated at 60° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with an aqueous solution of saturated ammonium chloride, dried and concentrated under reduced pressure to yield 0.700 g (90%) of (4-azidobut-1-ynyl)trimethylsilane which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.CC(O)=O.Cl.CCO>O.[Pt](=O)=O.O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1
Reactant: OCCCc1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: OCCCC1CCCNC1
Reaction time: 72 h

Procedure:
A 500 mL Parr hydrogenation bottle was charged with 3-Pyridinepropanol (10.0 g, 72.9 mmol), platinum(IV)oxide hydrate (Adam's Catalyst) (500 mg), AcOH (30 mL), and HCl, 37% (1 mL). Contents of the bottle were hydrogenated at 47 psi for three days. EtOH and water were added, and the reaction mixture was filtered through CELITE. NaOH (10 N) was added and the mixture was extracted with methylene chloride, dried with anhydrous MgSO4, filtered and concentrated. The product was concentrated from PhMe and used without further purification. 1H NMR (CD3OD): δ 3.55 (t, J=5 Hz, 2H), 3.0{tilde over (5)} 2.95 (m, 2H), 2.5{tilde over (5)} 2.45 (m, 1H), 2.23 (t, J=10 Hz, 1H), 1.8 9 1.86 (m, 1H), 1.7{tilde over (0)} 1.66 (m, 1H), 1.6 0 1.44 (m, 4H), 1.2{tilde over (8)} 1.22 (m, 2H), 1.0 6 1.00 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([C:15]([NH2:17])=[O:16])=[C:6]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:28].[BH4-].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>CO.O1CCCC1.O>[OH:28][CH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][C:7]=3[C:15]([NH2:17])=[O:16])[CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22]1
Reactant: COc1cc2ncc(C(N)=O)c(Nc3cccc4c3CCC4=O)c2cc1OC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc4c3CCC4O)c2cc1OC

Procedure:
6,7-Dimethoxy-4-[(1-oxo-2,3-dihydro-1H-inden-4-yl)amino]-3-quinolinecarboxamide (0.062 g, 16.4 mmol) was dissolved in a mixture of methanol (7 ml), tetrahydrofuran (4 ml) and water (3 ml). Sodium borohydride was added in portions (3×5 mg) and during 5 min. After 20 min the reaction mixture was acidified with acetic acid and then made alkaline with saturated aqueous sodium hydrogencarbonate and evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed twice with water and evaporated. The residue was dissolved in methanol and water was added. The title compound, which slowly precipitated, was filtered off and dried to give 40 mg (64%). 1H NMR (DMSO-d6): δ 10.68 (1H, s); 8.82 (1H, s); 8.20 (1H, bs); 7.55 (1H, bs); 7.22 (1H, s); 7.07 (1H, t, J 7.5 Hz); 7.04 (1H, t, J 7.4 Hz); 6.75 (1H, s); 6.63 (1H, d, J 7.5 Hz); 5.20 (1H, d, J 5.7 Hz); 5.01 (1H, q, J 6.2 Hz); 3.85 (3H, s); 3.26 (s, moisture signal overlapping); 2.72–2.63 (1H, m); 2.50–2.36 (m, solvent signal overlapping); 2.30–2.20 (1H, m) and 1.76–1.65 (1H, m).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O>[C:1]1([CH2:7][CH2:8][CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of diethyl 2-phenylethylmalonate (3.61 g) and potassium hydroxide (1.69 g, 2.5 eq) in water (15 ml) was refluxed for 2 h and cooled to room temperature. The solution was washed with diethyl ether (2×10 ml) and then acidified to pH 2 (5M hydrochloric acid). The aqueous phase was extracted with diethyl ether (2×20 ml). The combined extracts were washed with water (2×20 ml), saturated brine (20 ml), dried (MgSO4) and evaporated to give the title compound as a white solid (1.85 g, 65%); νmax (KBr) 3080(br), 1705 cm-1 ; δH [(CD3)2CO], 2.18 (2H, m, CH2), 2.70 (2H, m, CH2), 3.40 (1H, t, J 7.4 Hz, CH), 7.25 (5H, m, Ph). DCIMS MNH4+ 226.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[NH:6][CH3:7])#[CH:2].Br[C:12]#[C:13][C:14]([OH:17])([CH3:16])[CH3:15]>C(N)(C)C.CO.[Cu]Cl>[OH:17][C:14]([CH3:16])([CH3:15])[C:13]#[C:12][C:2]#[C:1][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([NH:6][CH3:7])[CH:4]=1
Reactant: C#Cc1cccc(NC)c1
Reactant: CC(C)(O)C#CBr
Agent: Cl[Cu]
Solvent: CO
Solvent: CC(C)N
Product: CNc1cccc(C#CC#CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
100 mg of copper (I) chloride were dissolved in a mixture of 20 ml of isopropylamine and 10 ml of methanol in an atmosphere of argon, and 1350 mg of 3-ethynyl-N-methylaniline were then added to the reaction mixture, followed by stirring at room temperature for 10 minutes. 3300 mg of 1-bromo-3-hydroxy-3-methyl-1-butyne were then dropwisely added to the solution over a time of about 3 hours, followed by stirring at room temperature for 2 hours. After the solvent had been evaporated from the reaction mixture, the residue was neutralized and diluted by 1N hydrochloric acid and subjected to extraction with 50 ml of ether three times. The organic layer was dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel chromatography using benzene as an eluent to obtain 1600 mg of 5-hydroxy-5-methyl-1-[3-(N-methylamino)phenyl] hexa-1,3-diyne.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C:15]2[C:16](Cl)=[N:17][C:18]([Cl:22])=[CH:19][C:20]=2[CH3:21])=[O:13])[C:5]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH:9]3[CH2:11][CH2:10]3)[C:16]3[N:17]=[C:18]([Cl:22])[CH:19]=[C:20]([CH3:21])[C:15]=3[NH:14][C:12](=[O:13])[C:4]=2[CH:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1NC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(Cl)nc2c1NC(=O)c1cc(Br)cnc1N2C1CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
A solution of 5-bromo-2-(cyclopropylamino)-N-(2,6-dichloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (105 mg, 0.254 mmol) in pyridine (3.0 mL) was heated to 50° C. while a 1 M solution of NaHMDS in THF (0.53 mL, 0.53 mmol) was added. The resulting solution was stirred at 50° C. for 3 h. The reaction was quenched with aqueous saturated NH4Cl, diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (hexane:EtOAc, 7:3) to give the title compound (32 mg, 33% yield).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][O:11][NH3+:12].[Cl-]>N1C=CC=CC=1>[CH3:10][O:11][N:12]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: CO[NH3+]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: CON=C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
53 ml of anhydrous pyridine were added to a mixture of 3.34 g of 4-piperidone hydrochloride monohydrate and 2.0 g of o-methylhydroxylamine hydrochloride, and the mixture was kept stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, and the crystalline residue was washed with ethyl acetate and collected by filtration. The crystals were washed with saturated aqueous sodium bicarbonate solution until basic and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was stripped off, giving 2.5 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=[C:21]([C:23](=[O:30])[NH:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:46][C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH:20]=[C:21]([C:23](=[O:30])[NH:24][C:25]2[CH:29]=[N:28][N:27]([CH2:46][C:47]3[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=3[CH3:49])[CH:26]=2)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cn[nH]c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1cc(NC(=O)c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c2)cn1

Procedure:
Intermediate (2d), 2-[2-oxo-5-(1H-pyrazol-4-ylcarbamoyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (50 mg, 0.091 mmol), Cs2CO3 (45 mg, 0.136 mmol) and 2-methylbenzyl bromide (21 mg, 15 ul, 0.11 mmol) were stirred in N,N-dimethylformamide (5 mL) at ambient temperature for 48 hours. The inorganics were separated via filtration and the filtrate was concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane (gradient) to afford the desired title compound as a solid, 55 mg, 93%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:41]1[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 75.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(3-acetyl-6-bromoquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (60 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (48 mg, 0.166 mmol) to afford the desired product (52 mg, 76%) as an brown solid: ESI MS m/z 622, [C32H33Cl2N5O4+H]+
Reaction SMILES: [H-].[Na+:2].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([O-:16])(=[O:15])=[O:14].[Na+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([O-:16])(=[O:15])=[O:14].[Na+:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]

Procedure:
To a solution of sodium 2-methoxy-ethylate prepared by adding 7.3 g of sodium hydride (14.6 g as a state of 50% liquid paraffin dispersion) to 300 ml of methyl cellosolve, 55 g of sodium 2-chloro-5-nitrobenzenesulfonate was added with stirring. The reaction mixture was heated to a temperature from about 80° to 85° C. in a hot water bath with stirring for 30 minutes. After carried out filtration with heating, 1.5 liters of isopropyl alcohol were added to the filtrate. The crystals thus-formed were separated by filtration and washed with 100 ml of isopropyl alcohol. Yield: 59 g. m.p.: 238°-239° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH4+].[OH-]>CO>[Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2Br)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Brc1cccnc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((3-bromopyridin-2-yl)oxy)piperidine-1-carboxylate in MeOH (10 mL) was added HCl (2 mL, 1 N). The reaction mixture was stirred at rt for 2 h before adjusting the pH to ˜9 with NH4OH. The mixture was then concentrated to dryness and the crude product purified by FCC to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (dd, J=4.8, 1.7, 1H), 8.06 (dd, J=7.7, 1.7, 1H), 6.98 (dd, J=7.7, 4.9, 1H), 5.31 (m, 1H), 3.18-3.07 (m, 4H), 2.22-2.05 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([N:7]([CH3:20])[C:8]1[N:9]=[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16]=1[C:17](O)=[O:18])=[O:6].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[CH2:45]([NH2:55])[C:46]1[CH:54]=[CH:53][C:52]2[O:51][CH2:50][O:49][C:48]=2[CH:47]=1>C(Cl)Cl>[O:51]1[C:52]2[CH:53]=[CH:54][C:46]([CH2:45][NH:55][C:17]([C:16]3[N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C:10]4=[N:9][C:8]=3[N:7]([C:5](=[O:6])[C:4]3[CH:21]=[CH:22][CH:23]=[C:2]([Cl:1])[CH:3]=3)[CH3:20])=[O:18])=[CH:47][C:48]=2[O:49][CH2:50]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)O)CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)NCc1ccc3c(c1)OCO3)CCCC2
Yield: 35.7 %

Procedure:
2-[(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid (232 mg, 0.70 mmol), EDCI (146.6 mg, 0.76 mmol, 1.1 eq.) and HOAt (9.5 mg, 0.07 mmol, 0.1 eq.) were dissolved in DCM (10 mL). Piperonylamine (96 μL, 0.77 mmol, 1.1 eq.) was then added thereto. The reaction mixture was stirred over night and the solvent was then removed. EtOAc (70 mL) was added thereto and the reaction mixture was washed in succession with 0.5 M KHSO4 in water (70 mL) and saturated aqueous NaHCO3 solution (70 mL). The aqueous phases were extracted with EtOAc (30 mL). The combined organic phases were washed with saturated aqueous NaCl solution (70 mL), dried over sodium sulphate, and the solvent was removed under vacuum. The untreated product was purified by column chromatography (SiO2, DCM→DCM/2% MeOH). 116.8 mg (36%) of the desired product 2-[(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid(benzo[1,3]dioxol-5-ylmethyl)-amide were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:19]1([CH2:25][C:26]([NH:28][CH:29]2[C:41](=[O:42])[N:31]3[CH:32]([C:38]([OH:40])=[O:39])[CH:33]([CH2:36][OH:37])[CH2:34][S:35][C@H:30]23)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O.C(OCC)(=O)C>[C:19]1([CH2:25][C:26]([NH:28][CH:29]2[C:41](=[O:42])[N:31]3[CH:32]([C:38]([O:40][CH2:8][C:7]4[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[O:39])[CH:33]([CH2:36][OH:37])[CH2:34][S:35][C@H:30]23)=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(CO)CS[C@H]12
Temperature: 25 °C
Yield: 75.8 %

Procedure:
4-Nitrobenzyl bromide (1.64 g.) and triethylamine (0.73 g.) were added to a solution of 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (2.0 g.) in dimethylsulfoxide (20 ml.) and stirred at room temperature for an hour. The resultant solution was poured into a solution of water (200 ml.) and ethyl acetate (200 ml.), and the organic layer was separated. Water (200 ml.) was added to the organic layer and then adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give 4-nitrobenzyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (2.1 g.).