Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:3]1([OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9])#[CH:2].Br[C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][N:18]3[C:22]([CH2:28][N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[C:30]4[CH3:38])=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]3[C:16]=2[CH:39]=1>CS(C)=O.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>[OH:10][C@@:3]1([C:1]#[C:2][C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[C:22]([CH2:28][N:29]5[C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=6[N:31]=[C:30]5[CH3:38])=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]4[C:16]=3[CH:39]=2)[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 19 %

Procedure:
Similar to as described in General Procedure E with the exceptions of using Pd(PPh3)4 in DMSO, 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to yield the titled compound as a yellow solid (21 mg, 19%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([NH:14][C:15]1[C:16]2[C:21]([C:22]3[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][C:27]=3[CH:28]=1)=[CH:20][C:19]([CH3:33])=[CH:18][CH:17]=2)(=O)[CH3:12].[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:11]([NH:14][C:15]1[C:16]2[C:21]([C:22]3[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][C:27]=3[CH:28]=1)=[CH:20][C:19]([CH3:33])=[CH:18][CH:17]=2)[CH3:12]
Reactant: COc1ccc2cc(NC(C)=O)c3ccc(C)cc3c2c1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNc1cc2ccc(OC)c(OC)c2c2cc(C)ccc12
Reaction time: 2 h

Procedure:
1700 ml (2.05M) of a 20% solution of diisobutylaluminium hydride in toluene are added at room temperature over a period of 45 minutes to a suspension of 105.7 g (0.342M) of 9-acetylamino-3,4-dimethoxy-6-methyl-phenanthrene in 1500 ml anhydrous tetrahydrofuran. The mixture is then warmed with stirring under a nitrogen atmosphere for 2 hours at 80°. The reaction mixture is then cooled at 0° and under nitrogen atmosphere and a mixture of 2500 ml 2N hydrochloric acid/ice, cooled at -10°, is added by portions at such a rate that the gas evolution is maintained. The acid solution is made alkaline to pH 10 by addition at 0° of 3 liters 2N sodium hydroxide and the mixture is extracted three times with methylene chloride/2-propanol 7:3. The organic phases are combined, washed, dried and evaporated to give the title compound. M.pt. 100°-102° after crystallisation from acetone/ether.
Reaction SMILES: [H-].[Na+].Cl.[NH:4]1[C:8]([C:9](=[O:11])[CH3:10])=[CH:7][CH:6]=[N:5]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl>C1COCC1>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:4]1[C:8]([C:9](=[O:11])[CH3:10])=[CH:7][CH:6]=[N:5]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)c1ccn[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccnn1COCC[Si](C)(C)C
Temperature: 0 °C

Procedure:
To a suspension of sodium hydride (3.07 g, 76.75 mmol) in 100 mL of anhydrous THF cooled to 0° C. under N2 (g) inlet was added 1-(1H-pyrazole-5-yl)ethan-1-one hydrochloride (3.09 g, 21.08 mmol). After warming to rt over 1 h, a solution of 2-(trimethylsilyl)ethoxymethyl chloride (4.5 mL, 25.43 mmol) in 100 mL of anhydrous THF was added to the reaction flask via cannulation. The reaction was quenched with water and extracted with EtOAc after 2 h. The organic phase was collected, dried with sodium sulfate, filtered and concentrated under reduced pressure followed by purification by flash chromatography (silica, 50:50 EtOAc/hexane) to give 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)ethanone. LCMS; 241.1 m/z (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1(C)[C:36](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:32]([CH3:36])=[CH2:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #75, Step A, 0.05 g, 0.104 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.035 g, 0.209 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride dichloromethane complex (0.017 g, 0.021 mmol) and K2CO3 (0.029 g, 0.209 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC (eluting with 50% EtOAc in petroleum ether) to give 4-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 76%) as a pale-white solid. LC/MS (Table 1, Method 5) Rt=3.653 min.; MS m/z: 441 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([O:17]CC)=[O:16].[OH-].[Na+].C(OCC)(=O)C>CO>[O:1]=[C:2]1[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CN1CCCC(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 91C (2.7 g, 10.33 mmol) in methanol (10 mL) was added sodium hydroxide (2.0 M) (10.33 ml, 20.66 mmol). After stirring for 30 minutes, thin layer chromatography (100% ethyl acetate) showed complete consumption of the starting material. The reaction was diluted with ethyl acetate (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to supply the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.15 (m, 5H), 4.35 (d, J=16.9, 1H), 4.01 (d, J=16.9, 1H), 3.80-3.69 (m, 1H), 3.68-3.51 (m, 1H), 3.44 (dt, J=5.6, 11.3, 2H), 2.31-2.12 (m, 1H), 2.09-1.77 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH:13](Br)([CH3:15])[CH3:14].CCOCC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:7]#[N:8])[CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)C(C#N)c1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
469 g (3.1 mol) of 4-chlorobenzyl cyanide, 30 g of tetrabutylammonium bromide, 1500 g of 50% strength sodium hydroxide solution and 438 g (3.56 mol) of isopropyl bromide are initially introduced into a 4 l multineck apparatus with reflux condenser and internal thermometer. The temperature rises after the stirrer is switched on. It is maintained at 40° C. for 4 h, initially by cooling and later by heating. The reaction mixture is cooled to room temperature, poured into a mixture of 500 ml of ether and 500 ml of water, the aqueous phase is separated off, and the organic phase is washed successively with 5% strength hydrochloric acid, sodium bicarbonate solution and water. After having been dried with sodium sufate, the solvent is removed by distillation. The residue remaining is 585.3 g of 97% pure 4-α-isopropylbenzyl cyanide. The product is pure enough for the subsequent hydrogenation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH:14]([CH2:17][NH2:18])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:20]=[CH:19][C:12]3[O:13][CH:14]([CH2:17][NH:18][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[CH:28][C:29]5[CH:30]=[CH:31][C:32](=[O:36])[O:33][C:34]=5[CH:35]=4)[CH2:15][O:16][C:11]=3[CH:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1COc2cc(OCc3ccccc3)ccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNCC3COc4cc(OCc5ccccc5)ccc4O3)cc2o1
Temperature: 108 °C

Procedure:
2,3-Dihydro-6-benzyloxy-1,4-benzodioxin-2-methanamine (2.4 g, 8.85 mmole), 7-(3-chloropropoxy)coumarin (2.15 g, 9.0 mmole), diisopropylethylamine (7.0 ml, 40.2 mmole) and sodium iodide (1.35 g, 9.0 mmole) were combined in 200 ml of DMF and heated at 108° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of water dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using 1% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.27 on silica gel tlc with 2.5% methanol/dichloromethane) were combined and concentrated in vacuum and the residue redissolved in dichloromethane and boiled on a hot plate, the solvent gradually being replaced with isopropanol. Upon addition of 6 ml of 4N HCl/isopropanol and cooling, 1.22 g of the title compound, m.p. 184°-187° C., precipitated as a beige solid, monohydrochloride.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.P(Br)(Br)([Br:17])=O>>[Br:17][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1nc(-c2ccccc2)ncc1I
Product: Brc1nc(-c2ccccc2)ncc1I
Temperature: 100 °C
Yield: 62.3 %

Procedure:
A mixture of 5-iodo-2-phenylpyrimidin-4-ol (1.97 g, 6.67 mmol, 1.0 eq) and POBr3 (100 g) was heated to 100° C. for 8 hours. The solution was cooled down to 55° C. and poured into ice-water while stirring vigorously. The mixture was maintained below 25° C. during the quench. The reaction mixture was extracted with CH2Cl2. The organic layer was washed (cold water), dried (Na2SO4), evaporated and purified by silica gel chromatography (hexane as eluent) to afford 4-bromo-5-iodo-2-phenylpyrimidine (1.5 g, 62.5%). LC-MS (m/z): 360.8 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.47-7.50 (m, 3H), 8.37-8.40 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: [N:1]1([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH3:8])[CH2:3][CH2:2]1.[Br:13]Br>CO>[C:10]([N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH2:8][Br:13])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)C1CCN(C(C)=O)CC1
Reactant: BrBr
Solvent: CO
Product: CC(=O)N1CCC(C(=O)CBr)CC1
Reaction time: 3 h
Yield: 80.2 %

Procedure:
1,1′-(Piperidine-1,4-diyl)diethanone (38.00 g, 224.6 mmol) was dissolved in methanol (700 mL) and bromine (12.11 mL, 235.8 mmol) was added in portions. The resulting mixture was agitated 3 hours and the solvent was removed in vacuo. The resulting solid was triturated with ethyl acetate and partitioned between ethyl acetate and sodium carbonate solution. The organic phase was separated, washed with brine, dried and evaporated to give the desired product (44.70 g, 80.23% yield) as yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.CC([O-])(C)C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:36])([F:38])[F:37])[C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](COCc2ccccc2)C1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](COCc2ccccc2)C1
Temperature: 100 °C
Yield: 83.6 %

Procedure:
A 20 mL vial was charged with tert-butyl (3R)-3-((benzyloxy)methyl)-1-piperazinecarboxylate (1.19 g, 3.88 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.39 g, 4.31 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), RuPhos Palladacycle (0.047 g, 0.039 mmol, Strem Chemical Inc, Newburyport, Mass.), NaOtBu (0.938 g, 9.76 mmol, Sigma-Aldrich, St. Louis, Mo.) and toluene (12 mL). The mixture was degassed by bubbling Ar through the solution for 10 min. The vial was sealed and the mixture was heated at 100° C. for 3 h. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (100 g of silica, 0-30% EtOAc in hexanes) to afford tert-butyl (3R)-3-((benzyloxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (1.78 g) as an off-white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH2:23][C:20]3[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=3)[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cccc(C)c42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([Br:17])[C:15]=1[CH3:16])[NH2:12].C(=O)([O-])[O-].[Li+].[Li+]>CN1CCCC1=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:12][C:11]1[CH:10]=[C:9]([Br:8])[C:15]([CH3:16])=[C:14]([Br:17])[CH:13]=1)[CH3:7]
Reactant: Cc1c(Br)cc(N)cc1Br
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNc1cc(Br)c(C)c(Br)c1
Yield: 33 %

Procedure:
The DNA ligase inhibitor L67 (10) was synthesized by incubation of ethyl chloroacetate with 3,5-dibromo-4-methylaniline in the presence of lithium carbonate in N-methyl-2-pyrrolidinone as the solvent at 100° C. for 16 hours to produce N-(3,5-dibromo-4-methylphenyl)glycine ethyl ester in 33% yield after recrystallization from ethanol.
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1Cl)=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:13])[CH3:10].[N:26]1([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1[N:29]1[CH2:30][CH2:31][N:26]([C:32]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:33])[CH2:27][CH2:28]1)=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cnccc2[nH]c1=O
Agent: C1CN2CCN1CC2
Solvent: O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Temperature: 110 °C
Yield: 92.1 %

Procedure:
DABCO (0.7 g, 6.3 mmol) was added to a solution of 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester (120) (0.8 g, 3.16 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (0.93 g, 4.74 mmol) DMA at room temperature. The solution was heated at 110° C. for 2 h. The solution was cooled and poured into ice cold 10% ammonium chloride solution in water. The solids formed were filtered, washed by water, and dried to yield 1.2 g (92%) of 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) as white solids. MP: 231° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.18 (m, 4H), 3.89 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 7.14 (dd, J=3.6, 4.8 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.91 (s, 1H); EIMS m/z 413 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[N:8]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]=1[CH3:18])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[N:8]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]=1[CH2:18][Br:19])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(Cl)c(Cl)n(CCC(C)C)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)c1c(Cl)c(Cl)n(CCC(C)C)c1CBr
Yield: 99.7 %

Procedure:
4,5-Dichloro-2-methyl-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester (14.3 g, 48.9 mmol), N-bromosuccinimide (8.93 g, 50.2 mmol), and benzoyl peroxide (1.18 g, 4.89 mmol) were suspended in 123 mL of benzene and heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated to afford 18.1 g of the crude 4,5-dichloro-2-bromomethyl-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a brown oil.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])=[C:16](OS(C)(=O)=O)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])=[C:16]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N3CCCCC3)CS[C@H]12

Procedure:
In a further example, p-nitrobenzyl 7-phenoxyacetamido-3-methylsulfonyloxy-3-cephem-4-carboxylate is reacted in DMF at 0° C. with 2-molar equivalents of piperidine to provide after isolation, p-nitrobenzyl 7-phenoxyacetamido-3-piperidino-3-cephem-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1.Cl[CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>>[OH:34][CH:31]([CH2:32][OH:33])[CH2:30][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1
Reactant: OCC(O)CCl
Reactant: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Product: COc1cccc(OCC(O)CO)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available 3-chloropropane-1,2-diol. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 470.28 g/mol.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][N:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:24][CH2:25]O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:25][CH2:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:17]1[CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CCN2CCCCCC2CCO)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCN2CCCCCC2CCBr)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4 ml of phosphorus tribromide are added dropwize to 2.9 g (9.4 mmol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-(2-hydroxyethyl)-hexahydro-azepine in 100 ml of carbon tetrachloride, whilst cooling with ice, and the mixture is stirred for 15 hours at ambient temperature. Then water is added, whilst cooling with ice water is continued, and the mixture is made slightly alkaline with 2 molar sodium hydroxide solution. The aqueous/alkaline solution is separated off and extracted twice with methylene chloride. The combined organic solutions are dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 3.6 g (100% of theory).
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:11]([CH2:19]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:44]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:2]([O:9][C:10]1[C:11]([CH:19]=[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COc2cc3c(cc2C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)OCC3)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=C(c1ccccc1)c1ccccc1)c1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
A mixture of (5-benzyloxy-2,3-dihydro-benzofuran-6-yl)methyl triphenylphosphine iodide (2.0 g, 0.0033 mol) in tetrahydrofuran (20 ml) was cooled to an internal temperature of 5° C. under nitrogen and a solution of n-butyllithium (1.55M in hexane, 1.9 ml, 0.0030 mol) was added dropwise. The resulting mixture was stirred for 10 minutes then benzophenone (0.47 g, 0.0030 mol) was added portionwise. The ice bath was removed and the reaction was allowed to stir for 18 hours, then heated to reflux for 4 hours. The reaction mixture was concentrated to a dark oil which was dissolved in ethyl acetate (20 ml), washed with water (10 ml), saturated sodium chloride (10 ml). The combined organic layers were dried (MgSO), concentrated then chromatographed over silica gel (hexane/ethyl acetate, 90/10, an eluent) to afford 1-(5-benzyloxy-2,3-dihydrobenzofuran-6-yl)-2,2-diphenyl-ethene (0.27 g, 22%).