Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:9](=[O:12])[CH2:8][CH2:7][CH2:6][C:5]=2[NH:4][C:3]1=[O:13].[CH3:14]I>CC(C)=O>[CH3:14][N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH2:11][CH:2]([CH3:1])[C:3]1=[O:13]
Reactant: CI
Reactant: CC1CC2=C(CCCC2=O)NC1=O
Solvent: CC(C)=O
Product: CC1CC2=C(CCCC2=O)N(C)C1=O

Procedure:
Prepared analogously to Example 29 from 3-methyl- 3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione and methyl iodide in boiling acetone.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:34])[N:28]2[CH2:31][CH:32]=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:32][CH2:31][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:34])[CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (840 mg, 3.35 mmol) and [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (663 mg, 3.05 mmol) were combined in anhydrous DCM (10 ml) and anhydrous MeOH (2 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (2.03 g, 9.12 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (1 g, 71%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:18])[NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7].[CH3:19][C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1>C1COCC1>[CH3:18][N:4]([CH3:3])[N:5]([CH2:25][C:22]1[S:23][CH:24]=[C:20]([CH3:19])[N:21]=1)[C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7]
Reactant: COC(=O)c1cccc(C(=O)NN(C)C)c1
Reactant: Cc1csc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)N(Cc2nc(C)cs2)N(C)C)c1
Temperature: 3.5 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To the sodium hydride (16 mg, 0.68 mmol) in THF (3 ml) at 0° C., methyl 3-(2,2-dimethylhydrazinecarbonyl)benzoate (100 mg, 0.45 nmol) was added. After 10 min, 4-methyl-2-bromo methyl thiazole (103 mg, 0.54 mmol) was added and reaction mixture was stirred at 3-4° C. overnight. Reaction mixture was quenched with MeOH and diluted with ethylacetate. Organic layer was washed with water, brine and dried. Crude residue was purified by column chromatography to yield 70% of methyl 3-(2,2-dimethyl-1-((4-methylthiazol-2-yl)methyl)hydrazinecarbonyl)benzoate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Br:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([Cl:29])[CH:19]=1>N1C=CC=CC=1.Cl.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([S:25]([NH:14][CH:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:2]([F:1])([F:15])[F:16])(=[O:26])=[O:27])=[C:20]([Cl:29])[CH:19]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(Cl)cc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 170 mg (0.75 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 243 mg (0.75 mmol) of 4-bromo-2,6-dichlorobenzensulfonyl chloride in 4 mL of pyridine was warmed at 65° C. The reaction was monitored by TLC indicating a new less polar product compared to amine. After 16 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with 1 N aqueous hydrochloric acid until acidic and extracted with ethyl acetate. The combined organic layers were washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by preparative TLC using EtOAc-hexanes (15:85). Material from the preparative TLC was isolated by suspending the silica gel in ethyl acetate followed by filtration. The filtrate was concentrated in vacuo to afford 112 mg (30%) of the title compounds as an off-white crystalline solid.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]([CH3:25])=[CH:19][C:17]=1[OH:18].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:25][C:20]1[C:21](=[O:24])[C:22]([CH3:23])=[C:16]([CH3:15])[C:17](=[O:18])[C:19]=1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: OC(c1ccccc1)c1cccnc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(C(c2ccccc2)c2cccnc2)=C(C)C1=O
Yield: 72.9 %

Procedure:
To a solution of 1.0 g (5.4 mmol) of phenyl-(3-pyridyl)methanol and 823 mg (5.4 mmol) of 2,3,5-trimethylhydroquinone in 15 ml of dichloromethane, 0.5 ml (9.4 mmol) of concentrated sulfuric acid was added, and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, from which the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was washed with water, dried, and oxidized with air, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (isopropyl ether-ethyl acetate (1:1)), to give 1.25 g (72.7%) of 3,5,6-trimethyl-2-[phenyl-(3-pyridyl)methyl]-1,4-benzoquinone. The physical data are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](Cl)(=O)[CH:12]([CH3:14])[CH3:13]>O1CCOCC1.CN(C)C=O>[CH3:10][C:4]1[CH:5]=[C:6]([OH:9])[N:7]2[N:8]=[C:11]([CH:12]([CH3:14])[CH3:13])[N:1]=[C:2]2[N:3]=1
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(O)n2nc(C(C)C)nc2n1

Procedure:
A solution of Intermediate 1 (0.35 g, 2.497 mmol) and iso-butyryl chloride (FLUKA, 0.262 mL, 2.497 mmol) in a mixture of 1,4-dioxane (4 mL) and N,N-dimethylformamide (1 mL) was heated under reflux overnight. The reaction was then concentrated under vacuum and the residue was purified by flash chromatography (Si, eluting with DCM:MeOH mixtures, gradient from 100:0% to 90:10%) to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23]([N:35]2[CH2:39][C@H:38]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:37][C:36]2=[O:45])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30]1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:42]([NH:41][CH2:40][C@@H:38]1[O:37][C:36](=[O:45])[N:35]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3([OH:34])[CH2:33][CH2:32][N:31]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:30]3)=[C:21]([F:20])[CH:22]=2)[CH2:39]1)(=[O:44])[CH3:43]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1, step 7 with 39 mg 7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.24 mmol), 99 mg N-{(5S)-3-[3-fluoro-4-(3-hydroxy-pyrrolidin-3-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide. (MW: 367.38, 0.24 mmol) 101 mg triethylamine (MW: 101.19, 1.0 mmol) and 80 mg trimethylchlorsilan (MW: 108.64, 0.75 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 70 mg, 46%. MS: 614.7 (M+H)+, 612.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CC(C)=O>[O:11]=[C:9]1[N:8]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]2[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=2[O:10]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1c(=O)oc2ccc(C(F)(F)F)cc21

Procedure:
To a mixture of 5-trifluoromethyl-1,3-benzoxazol-2(3H)-one (999 mg) and acetone (25 mL) were added K2CO3 (1.02 g) and ethyl bromoacetate (708 μL) at room temperature, followed by heating to reflux for 4 hours. The reaction mixture was filtered while hot, and washed with acetone. The filtrate and the washed solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=100/0-75/25) to obtain ethyl [2-oxo-5-(trifluoromethyl)-1,3-benzoxazol-3(2H)-yl]acetate (1.33 g).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C[S-:19].[Na+].Cl>CN(C=O)C>[C:2]1([SH:19])[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Sc1ccc2ccc3cccc4ccc1c2c34
Temperature: 150 °C
Yield: 65.3 %

Procedure:
1-Bromopyrene (550 mg, 1.96 mmol) and sodium methanethiolate (480 mg, 6.85 mmol) were dissolved in freshly distilled DMF under dry nitrogen. The reaction was stirred at 150° C. and monitored by GC-MS until complete. After completion 50 mL of HCl 0.1M were added to the reaction mixture and extracted with 3 portions of ether. The organic phase was washed with 2 portions of water. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 5:1 petroleum ether (60-80):EtOAc as eluent to afford a yellow solid (300 mg, 65%). 1H-NMR (500 MHz, toluene-d8, DMSO-d6): δ 7.35 (s, 1H), 8.10-8.37 (m, 8H), 8.67 (d, J=9.2 Hz, 1H). 13C-NMR (125 MHz, toluene-d8, DMSO-d6): δ 123.7, 123.8, 124.6, 124.9, 125.7, 125.8, 126.3, 127.0, 127.7, 128.6, 130.1, 130.3, 130.6, 130.8, 131.2, 131.7. EI-MS: m/z M+ Calculated 234.0, found 234.0.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13]>CN(C)C=O>[C:1]([N:17]1[CH2:18][CH2:19][N:14]([CH:12]=[O:13])[CH2:15][CH2:16]1)(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=CN1CCNCC1
Reactant: O=C(O)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: O=CN1CCN(C(=O)C=Cc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 50 %

Procedure:
trans-Cinnamic acid (1.48 g) and N-formylpiperazine (2.28 g) were dissolved in N,N-dimethylformamide (20 mL), and the atmosphere was purged with nitrogen. While the solution was stirred in an ice-water bath, triethylamine (2.53 g) and diphenylphosphoryl azide (5.78 g) were added thereto, and stirring was continued for 1 hour and 45 minutes. The reaction mixture was poured in a mixture of ice and saturated sodium hydrogencarbonate solution, followed by extraction twice with ethyl acetate. The organic layers were combined and sequentially washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate solution, and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure, and the residue (colorless, oily) was purified through silica gel chromatography (silica gel 45 g, eluent; chloroform:methanol=200:1-100:1). The thus-purified product was dissolved in ethyl acetate, and the solution was sequentially washed with saturated sodium hydrogencarbonate solution and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby yield 1.22 g of the product of interest as a colorless oil (yield 50.0%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:37][O:38][CH3:39])[C:11]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].CO>[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:37][O:38][CH3:39])[C:11]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1cccc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1cccc(NC=O)n1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (1.43 g.), 10% palladium on carbon (0.8 g.), methanol (30 ml.) and tetrahydrofuran (60 ml.) was subjected to catalytic reduction at ambient temperature under ordinary pressure for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6, washed with ethyl acetate, and then adjusted to pH 1 to 2. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (30 ml.) was added to the residue, stirred for one hour, and then the precipitates were collected by filtration to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (680 mg.), brownish yellow powder, mp. 200° to 204° C. (dec.).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:22]1[CH2:31][CH2:30][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:21][C:18]1[CH:17]=[N:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:22]3[CH2:31][CH2:30][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23]3)=[CH:9][CH:10]=2)=[N:20][CH:19]=1
Reactant: COC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc(Br)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(CCc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
The reaction mixture of 4-(5-bromopyrimidin-2-ylamino)phenethyl methanesulfonate 19 (1.55 mmol) and methyl isonipecotate (3.10 mmol) in DMF (5 mL) is stirred at 90° C. for 12 h. After the reaction is complete, Na2CO3 (2.0 M, 20 mL) is added and the resulting mixture is extracted with EtOAc (50 mL). The organic layer is separated and concentrated to give crude methyl 1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate 20. MS (m/z) (M+1)+: 419.1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[N:30]=[CH:29]1>>[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:37][CH:36]=2)[N:30]=[CH:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CCc2c[nH]cn2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CCc2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(2-(imidazol-4-yl)-ethyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=5:1) C28H24N4O3
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22])[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)=[O:25]
Reactant: Cc1cccc(CNC(=O)C(C)C(=O)O)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: Cc1cccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)c1

Procedure:
The title compound, MS: m/e=442.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-methyl-benzyl)-malonamic acid.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5].O.[NH2:25][NH2:26]>C(O)C>[NH:25]([C:3](=[O:23])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)=[N:11][CH:12]=1)=[O:5])[NH2:26]
Reactant: COC(=O)C(=O)Nc1ccc(N2CCC(C(=O)OC)CC2)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a vigorously stirred suspension of methyl 1-(5-{[methoxy(oxo)acetyl]amino}pyridin-2-yl)piperidine-4-carboxylate (3.12 g, 9.71 mmol) in absolute ethanol was added hydrazine monohydrate (0.52 mL, 10.76 mmol) and the suspension was allowed to stir at ambient temperature for 2 hours. The suspension was filtered, washed with ether (4×100 mL) and dried under vacuum at ambient temperature to provide the title compound (2.62 g, 7.81 mmol, 80%). 1H NMR δ 1.18 (s, 3H), 1.40-1.47 (m, 2H), 1.98-2.03 (m, 2H), 3.07-3.14 (m, 3H), 3.66 (s, 3H), 3.80-3.86 (m, 2H), 4.58 (s, 1H), 6.83 (d, 1H), 7.90 (d, 1H), 8.49 (s, 1H), 10.17 (s, 1H), 10.46 (s, 1H); MS m/e MH+ 336.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14]>C1(C)C=CC=CC=1.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>[CH2:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)[CH:13]=[CH2:12]
Reactant: Brc1cncc2ccccc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cncc2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-bromoisoquinoline (2.0 g) in 70 mL of toluene was added allyl tributyl stannane (3.28 mL) and Pd(PPh3)4 (1.10 g). The resulting solution was heated at reflux for 12 hours and then cooled to room temperature. The solution was concentrated in vacuo, dissolved in ether and washed successively with an aqueous solution of trithiocyanuric acid trisodium salt, water and brine. The organic layer was then dried over magnesium sulfate, filtered, concentrated in vacuo, and purified using flash chromatography (silica, 0-30% EtOAc/hexanes) to provide 0.965 g of 4-(2-propenyl)-isoquinoline. Mass spectrum [NH3/CI], (M+H)+=170.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8](=[O:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I.Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:24])[CH:7]([CH3:27])[C:8](=[O:23])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)CCc1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A solution of 5-biphenyl4-yl-3-oxo-pentanoic acid tert-butyl ester (Intermediate 2, 0.30 g, 0.93 mmol) in dimethyl formamide (1.5 mL) was added to a suspension of sodium hydride (60%; 38 mg, 0.94 mmol) in dimethyl formamide (1 mL) at 0° C. under nitrogen. After stirring for 20 minutes methyl iodide (58 μL, 0.93 mmol) was added and the reaction warmed to room temperature at which stirring was continued for 2 hours. 0.5 M Hydrochloric acid (5 mL) was added and the quenched reaction mixture extracted with diethyl ether (3×5 mL). The organic phases were combined, washed with brine (5 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (1:6 diethyl ether: 40–60 petroleum ether) to give the title compound (163 mg, 52%) as a colourless oil. LC/MS: 3.81 min; z/e 356, calcd (M+NH4) 356. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.51 (2 H), 7.42 (2 H), 7.32 (1 H), 7.22 (2 H), 3.42 (1 H), 2.97 (3 H), 2.83 (1 H), 1.42 (9 H), 1.28 (3 H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:55][C@@H:56]([CH3:61])[CH2:57][C:58](O)=[O:59]>CN(C)C=O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:58](=[O:59])[CH2:57][C@@H:56]([OH:55])[CH3:61])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: C[C@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 16 h
Yield: 56 %

Procedure:
5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (S)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (97 mg, 56%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=1.[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)=[O:13])[CH:5]=1
Reactant: COC(=O)c1cccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1

Procedure:
A solution of methyl-3-[N-(4-nitrophenoxycarbonyl)amino]benzoate (0.19 g, 0.60 mmol) and 4-tert-butylaniline (0.10 mL, 0.60 mmol) in pyridine (5 mL) was heated to reflux for 16 h. The solution was cooled and evaporated, and the residual material was taken up in ethyl acetate (100 mL). This was washed with 1 N aq. sodium hydroxide and brine, dried over magnesium sulfate, filtered and evaporated. The residual solid was triturated with ether, collected by filtration and dried under vacuum to afford the product, methyl-3-[3-(4-tert-butylphenyl)-ureido]-benzoate, as a solid (0.19 g, 0.58 mmol, 97%).