Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18](/[N:20]=[CH:21]\[N:22](C)C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>CCO.CO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][N:22]=[CH:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)/C=N\C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: CCO
Solvent: CO
Solvent: c1ccncc1
Product: O=C1N2C[C@@H](CC[C@H]2c2ncno2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
(2S,5R,Z)-6-(benzyloxy)-N-((dimethylamino)methylene)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (1.33 g, 4.03 mmol) in EtOH (22 mL) was treated with pyridine (0.64 ml, 8.06 mmol), followed by the addition of a solution of HOSA (547 mg, 4.84 mmol) in MeOH (4.5 mL). The resulting mixture was stirred at rt for 30 minutes and then concentrated under vacuum. The residue was dissolved in DCM/THF (1:2, 30 mL) and washed with water (10 mL). The organic layer was dried overNa2SO4, and concentrated. The residue was re-dissolved in EtOH (22 mL) and 2N HCl (8.0 mL). The mixture was heated at reflux for 20 minutes, concentrated and extracted with DCM (2×). The crude material was purified by prep-HPLC to give (2S,5R)-6-(benzyloxy)-2-(1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (50 mg, 4.1%) as a light yellow oil. ESI-MS (EI+, 301, m/z): [M+H]+. 1H-NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.45-7.35 (m, 5H), 5.09 (d, J=11.5 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 4.85 (d, J=8.0 Hz, 1H), 3.36 (m, 1H), 3.01 (d, J=12.0 Hz, 1H), 2.81 (d, J=12.0 Hz, 1H), 2.37-2.35 (m, 1H), 2.25-2.21 (m, 1H), 2.01-2.00 (m, 1H), 1.85-1.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:18]=O)[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].NO.[N:22]1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:18]#[N:22])[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH:9]=1)=[O:4]
Reactant: c1ccncc1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Agent: NO
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 2-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester (0.11 g, 0.38 mmol) (as prepared in the previous step) in methanol (2 mL) was added a 50% aqueous hydroxylamine solution (30 μL) and the reaction stirred for 3 h at RT and then concentrated. The residue was dissolved in DCM (2 mL), pyridine (0.13 mL), and trifluoroacetic anhydride (0.17 mL, 1.1 mmol) was added and the reaction stirred for 10 h at RT. The reaction was diluted with EtOAc (10 mL) and washed with satd. NaHCO3 (2×10 mL) and the organic layer dried over Na2SO4 and then concentrated. The title compound was eluted from a 10-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.085 g (76%) of a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 5.50 (s, 2H), 3.92 (s, 3H), 3.58 (m, 2H), 0.94 (m, 214), 0.00 (s, 9H).
Reaction SMILES: [OH2:1].O.O.C([O-])(=O)C.[Na+].[CH3:9][C:10]([C:13]1[CH:20]=[C:17]([CH:18]=O)[C:16]([OH:21])=[C:15]([I:22])[CH:14]=1)([CH3:12])[CH3:11].Cl.[NH2:24]O.C(O)C>O>[CH3:9][C:10]([C:13]1[CH:20]=[C:17]([CH:18]=[N:24][OH:1])[C:16]([OH:21])=[C:15]([I:22])[CH:14]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(I)c(O)c(C=O)c1
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(I)c(O)c(C=NO)c1
Temperature: 0 °C
Yield: 87.4 %

Procedure:
A solution of sodium acetate trihydrate (5.44 g) in water (10 ml) is added to a warm solution of 5-(1,1-dimethylethyl)-3-iodosalicylaldehyde (6 g) and hydroxylamine hydrochloride (3.5 g) in 80% by volume aqueous ethanol (50 ml). After refluxing for 3 hours the reaction mixture is diluted with hot water (10 ml) and then cooled to 0° C. to provide 5.5 g of 5-(1,1-dimethylethyl)-3-iodosalicylaldoxime, m.p. 154°-156° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1)(=O)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][CH2:6][C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(COS(C)(=O)=O)n1
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cccc(CNCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of methyl 6-((methylsulfonyloxy)methyl)picolinate (0.4 g, 1.63 mmol) in CH3CN (15 mL) were added 4-fluorobenzylamine (0.75 mL, 6.52 mmol) and Cs2CO3 (0.8 g, 2.45 mmol). The reaction mixture was stirred at rt for 4 h, filtered and the filtrate solution was concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing the desired product were combined and concentrated to give the desired compound (140 mg, 31%) as an oil. 1H NMR (CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.04-6.99 (m, 2H), 4.02 (s, 2H), 3.99 (s, 3H), 3.82 (s, 2H). MS (ESI): 275.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(3-aminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (131 mg) and triethylamine (0.067 ml) in dichloromethane (3 ml) was added benzoyl chloride (0.056 ml). The mixture was stirred at room temperature for 30 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The residue was crystallized from isopropyl ether to give 4-(3-benzoylaminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido-[2,3-b]pyrazine (110 mg).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][C:15]#N)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CO.[OH-:19].[K+].[OH2:21]>>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][C:15]([OH:21])=[O:19])=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: O
Reactant: [OH-]
Reactant: CC1(c2ccc(CC#N)s2)OCCO1
Agent: N#N
Agent: [K+]
Solvent: CO
Product: CC1(c2ccc(CC(=O)O)s2)OCCO1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-acetonitrile (2.67 g, 12.77 mmol) in a 1:1 mixture of MeOH and H2O (11 mL) was treated at rt with KOH (1.43 g, 25.54 mmol). After stirring at reflux for 1.5 h, the cooled reaction mixture was washed with ether. The aq. phase was carefully acidified to pH 4-5 with 1M HCl and the product was extracted several times with CH2CL2. The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=0.79 min.
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1>C(COC)OC>[CH3:14][C:12]1[CH:13]=[C:8]([Sn:3]([CH3:5])([CH3:4])[CH3:2])[CH:9]=[C:10]([CH3:15])[N:11]=1
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: C[Sn](C)(C)Cl
Agent: [Na]
Solvent: COCCOC
Product: Cc1cc([Sn](C)(C)C)cc(C)n1
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
To a mixture of 100 g sodium (30% dispersion in toluene) and 400 ml dimethoxyethane (DME) cooled in an ice-salt bath and under nitrogen was added a solution of 121 g trimethyltin chloride in 50 ml DME over a 2 hour period while keeping the temperature below 5° C. The mixture was stirred at 0°-5° C. for 2.5 hours and then 70 g 4-chloro-2,6-dimethylpyridine in 50 ml DME was added over a 1.5 hour period while keeping the temperature at 0°-10° C. The reaction mixture was stirred at the latter temperature for 1 hour and then allowed to stand at room temperature overnight. The mixture was filtered and concentrated, and the residue treated with ether and again filtered and concentrated. The resulting orange liquid was distilled, collecting the material boiling at 130° C. (20 mm) to give 80 g 2,6-dimethyl-4-(trimethylstannyl)pyridine.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)([O-:7])=[O:6]>CCOCC.CN(C=O)C>[N+:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:3])=[O:14])([O-:7])=[O:6]
Reactant: O=C(O)CCCO[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)CCCO[N+](=O)[O-]

Procedure:
Thionyl chloride (0.6 ml, 7.7 mmol) was slowly added, under stirring and under argon, to a solution of 4-(Nitrooxy)butanoic acid (1.00 g, 6.7 mmol) in anhydrous Et2O (25 ml) kept 0° C. A few drops of DMF (4-5 drops) were also added under stirring to the reaction mixture and the reaction temperature was allowed to rise to r.t. (ca. 20° C.). The reaction mixture was stirred at room temperature and under argon for 5 hours. The reaction mixture was concentrated in vacuo to provide crude 4-(nitrooxy)butanoyl chloride.
Reaction SMILES: [Br:1]Br.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9]1>>[Br:1][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH3:18])([CH3:7])[CH2:9][C:10]2=[O:17])=[CH:15][CH:14]=1
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)c2cc(Br)ccc21
Yield: 27 %

Procedure:
Bromine (0.2 ml, 3.8 mmol, 1.2 eq.) was added to a mixture of AlCl3 (1.04 g, 7.8 mmol, 2.5 eq.) and 3,3-dimethyl-indan-1-one (500 mg, 3.1 mmol) at 100° C. and the reaction mixture was heated at same temperature for 40-45 min. TLC (10% ethyl acetate/hexanes) showed the major product formation with little starting material and dibromo product. The reaction mass was quenched with crushed ice and extracted with ethyl acetate (3×50 ml). The organic part was separated, dried over Na2SO4 and evaporated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to give the desired compound as a pale yellow solid. Yield: 27% (280 mg, 0.85 mmol).
Reaction SMILES: O.C(O)(=O)C=[O:4].[CH2:7]1[CH2:12][CH2:11][CH:10]([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][CH2:8]1>CN(C=O)C>[C:14]([NH:13][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:4]
Reactant: O=CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To a stirred solution of glyoxylic acid monohydrate (431 mg, 4.56 mmol) in anhydrous DMF (5 mL) were added NHS (563 mg, 4.89 mmol) and DCC (1.00 g, 4.85 mmol). A white solid (dicyclohexylurea) formed immediately. As the reaction was exothermic, the flask was cooled in an ice-bath for a while (approximately 5 minutes). The reaction mixture was then stirred under nitrogen at room temperature for approximately 1 hour. The solid was filtered off and washed with DMF. The filtrate (containing glyoxylic acid NHS ester) was then added to the reaction mixture obtained above. After stirring the mixture for approximately 5 minutes, a clear solution was obtained. TLC revealed completion of the reaction. The solvent was removed under reduced pressure. Flash chromatography (20:1 and 15:1 CH2Cl2—CH3OH followed by 20:1, 15:1 and 12:1 CH2Cl2—CH3OH containing 1% acetic acid) provided the desired Pro4-de novo-CHO (132 mg, 55%). The mass spectrum was in agreement with the assigned structure.
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: O=C1CC(=O)C2CCCCC2C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)CC2CCCCC2C1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 10.0 (0.0768 mol) of decalin-1, 3-dione in 50 ml of ethanol was magnetically stirred under nitrogen and cooled to -10° C. To the solution was added 7.77 g (0.0768 mol) of triethylamine followed by 15.14 g (0.0768 mol) of p-toluenesulfonylazide added all at once. The mixture was stirred for one hour at 0° C., and the solvent removed at reduced pressure at a temperature of less than 40° C. To the residue was added 200 ml of ether, and the ether removed to yield a yellow solid. This was recrystallized from ethanol to give 5.23 g of yellow crystals, mp 81°-83° C.
Reaction SMILES: N1([C:6]23[CH2:21][CH2:20][CH2:19][CH2:18][CH:7]2[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[N:9][O:10]3)CCCC1.Cl.[OH-].[K+]>CO>[O:10]1[C:6]2[CH2:21][CH2:20][CH2:19][CH2:18][C:7]=2[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[N:9]1
Reactant: Brc1ccccc1C1=NOC2(N3CCCC3)CCCCC12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Brc1ccccc1-c1noc2c1CCCC2
Yield: 97.4 %

Procedure:
To a stirred solution of 5.8 g of 2-(3a,4,5,6,7,7a-hexahydro-7a-pyrrolidino1,2-benzisoxazol-3-yl)-bromobenzene in 60 ml of methanol was added 100 ml of concentrated hydrochloric acid and the solution was refluxed for 20 min. The solution was cooled to room temperature and neutralised with 10M potassium hydroxide solution. The solution was extracted with 400 ml then 200 ml of methylene chloride and the combined organic layers were dried over sodium sulfate and evaporated to yield 4.5 g of 2-(4,5,6,7-tetrahydro1,2-benzisoxazol-3-yl)-bromobenzene as a gum, GC-M.S. (E.I.) (MIZ): 277 [M]+.
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:26]2=[N:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[C:25]2[N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:29]4[CH:30]=[C:25]5[N:24]=[C:23]([CH3:22])[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:48])[CH3:47])[C:26]5=[N:27][CH:28]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1COCC[Si](C)(C)C
Reactant: Ic1ccc2ncnc(N3CCCc4ccccc43)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc2n1COCC[Si](C)(C)C
Yield: 56.3 %

Procedure:
0.25 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline, 0.30 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridine, 0.16 g of sodium hydrogencarbonate and 0.09 g of Pd(PPh3)2Cl2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 5 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-40% in 20 min), giving 0.19 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline as white powder (yield 50%, content 94%); MS-FAB (M+H+)=523.2; Rf (polar method): 2.54 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.N1CC[CH:22]([C:25]2[CH:26]=C(NC(=O)CCC)C=C[CH:30]=2)CC1.CN(C)C(NC1C=CC=C(C2CCNCC2)C=1)=O.N1CCC(C2C=C(N[C:68](=[O:77])[O:69]CC3C=CC=CC=3)C=CC=2)CC1.CC(C)C(NC1C=CC(C2CCNCC2)=CC=1)=O.N1CCC(C2C=CC(NC(=O)CCC)=CC=2)CC1>>[C:25]([O:77][C:68]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:17][CH2:18]3)=[O:15])[CH:8]=2)[CH2:3][CH2:2]1)=[O:69])([CH3:22])([CH3:30])[CH3:26]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CCCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)OCc1ccccc1
Agent: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)C3CC3)c2)CC1

Procedure:
ESMS m/e: 345.5 (M+H)+; N-[3-(4-PIPERIDINYL) PHENYL]CYCLOPROPANECARBOXAMIDE: ESMS m/e: 245.0 (M+H)+; N-[3-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 247.3 (M+H)+; N,N-DIMETHYL-N′-[3-(4-PIPERIDINYL) PHENYL]UREA: ESMS m/e: 248.2 (M+H)+; ISOPROPYL 3-(4-PIPERIDINYL)PHENYL CARBAMATE: ESMS m/e: 263.4 (M+H)+; BENZYL 3-(4-PIPERIDINYL)PHENY LCARBAMATE: ESMS m/e: 311.3 (M+H)+; 2-METHYL-N-[4-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: ESMS m/e: 247.1 (M+H)+; N-[4-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 247.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[CH3:16][C:17](=O)[CH2:18][C:19](=[O:21])[CH3:20].[NH2:23]/[C:24](/[CH3:32])=[CH:25]\[C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27].C(O)(=O)C>CC(O)C>[C:19]([C:18]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:14])=[CH:5][C:4]3=[O:15])[C:25]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[C:24]([CH3:32])[NH:23][C:17]=1[CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2c(Cl)ccc(C=O)c2o1
Reactant: CCCOC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1ccc(Cl)c2c(=O)cc(C)oc12

Procedure:
40 mg (0.18 mmol) of 5-chloro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 31 mg (0.18 mmol) of 2,4-pentanedione, 25 mg (0.18 mmol) of n-propyl 3-aminocrotonate and 11 mg (0.18 mmol) of acetic acid in 2 ml of 2-propanol and heated under reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 33 mg (42% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22][CH2:23]O.N1C=CC=CC=1.O>C(Cl)Cl>[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22][CH2:23][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCCc1occc1Br
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1occc1Br
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (4.47 g) was added to a solution of 2-(3-bromofuran-2-yl)-ethanol (Intermediate 35, 2.94 g) and pyridine (2.43 g) in DCM (40 mL) and the mixture was stirred for 90 minutes. Water was added and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane with a gradient of 0-25% to give [2-(3-bromo-furan-2-yl)-ethoxy]-tert-butyldimethylsilane (3.98 g) as a colourless oil. The material was used without further characterisation.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)nn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A stirred mixture of 6-ethoxy-pyridazine-3-carboxylic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 1 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (1.15 g, 88% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.89 min (98.61%); mp: 238-240° C.; 1H NMR (DMSO-d6) δ 1.42 (t, J=7.1 Hz, 3H, CH3), 1.96-2.14 (m, 1H, CHH), 2.42-2.69 (m, 2H, CHH, CHH), 2.78-3.01 (m, 1H, CHH), 4.58 (q, J=7.0 Hz, 2H, CH2), 4.68 (d, J=6.2 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.35 (d, J=9.1 Hz, 1H, Ar), 7.76-7.95 (m, 3H, Ar), 8.09 (d, J=9.1 Hz, 1H, Ar), 9.85 (t, J=6.2 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 21.99, 30.93, 42.39, 48.99, 63.47, 117.91, 122.10, 123.53, 128.83, 129.82, 131.59, 133.57, 147.30, 149.11, 162.93, 165.86, 166.99, 167.13, 169.83, 172.75; LCMS: MH=438; Anal Calcd for C21H19N5O6: C, 57.66; H, 4.38; N, 16.01. Found: C, 57.32; H, 4.16; N, 15.80.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH3:58])=[O:56]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:55]([O:57][CH3:58])=[O:56])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 81.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) and CH2Cl2 (15 mL) followed by DIEA (0.16 mL, 0.9 mmol). The reaction mixture was stirred for 5 min at RT then treated with methyl chloroformate (Aldrich) (84.6 mg, 0.9 mmol) at 0° C. The reaction mixture was stirred at RT for 12 h then quenched with satd NaHCO3 (15 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The organic fractions were combined, washed with satd NaCl (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (412 mg). MS (ESI, pos. ion) m/z: 675 (M+1); MS (ESI, neg. ion) m/z: 673 (M−1). Calc'd for C11H13ClN4O6: 674.29.